NZ723233B2 - Compositions of selenoorganic compounds and methods of use thereof - Google Patents
Compositions of selenoorganic compounds and methods of use thereof Download PDFInfo
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- NZ723233B2 NZ723233B2 NZ723233A NZ72323314A NZ723233B2 NZ 723233 B2 NZ723233 B2 NZ 723233B2 NZ 723233 A NZ723233 A NZ 723233A NZ 72323314 A NZ72323314 A NZ 72323314A NZ 723233 B2 NZ723233 B2 NZ 723233B2
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- New Zealand
- Prior art keywords
- compound
- alkyl
- aralkyl
- formula
- cells
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- AEMOLEFTQBMNLQ-BKBMJHBISA-N α-D-galacturonic acid Chemical compound O[C@H]1O[C@H](C(O)=O)[C@H](O)[C@H](O)[C@H]1O AEMOLEFTQBMNLQ-BKBMJHBISA-N 0.000 description 1
Abstract
The present application relates to compositions comprising selenium compounds, such as 5'-Methylselenoadenosine, Se-Adenosyl-L -homocysteine, Gamma- glutamyl-methylseleno-cysteine, a compound of formula (I), formula (II), a compound of formula (III) and combinations thereof, and methods of using the same in enhancing mitochondrial function, or treating mitochondrial dysfunction. same in enhancing mitochondrial function, or treating mitochondrial dysfunction.
Description
COMPOSITIONS OF SELENOORGANIC COMPOUNDS AND
METHODS OF USE THEREOF
Field of the present application
The present application relates to compositions of selenoorganic
compositions and compounds and methods for their use in various biological
pathways to enhance mitochondrial function, treat disease, and inhibit or enhance
specific processes in particular types of animal and human cells.
Background
um (Se) is an essential trace t that plays a al role in many
biological processes, such as reproduction, thyroid hormone metabolism, DNA
synthesis, and protection from oxidative damage and infection. Selenium is
incorporated at the catalytic site of various selenium dependent enzymes such as
hione peroxidase (GPx), thioredoxin reductases, and one methionine-
sulfoxidereductase. These selenoenzymes contribute to regulation of metabolic
activity, immune function, antioxidant defense, intracellular redox regulation, and
mitochondrial on.
The organelle known as the mitochondrion (“MT”) is the main energy
source in cells of higher organisms. Mitochondria provide direct and indirect
biochemical regulation of a wide array of cellular respiratory, oxidative and
metabolic processes. These include electron transport chain (ETC) activity, which
drives oxidative phosphorylation to e metabolic energy in the form of
adenosine triphosphate (ATP), and which also underlies a central ondrial role
in ellular calcium homeostasis. Mitochondrial respiration occurs on the inner
mitochondrial membrane and is achieved by the flow of electrons through the
electron transport system, which ns four complexes (complex I, 11, Ill, and IV)
with a r complex (complex V) serving as a site for ATP synthesis (ATP
synthase). ment or reduction of ty of any complex disrupts electron
flow and may cause mitochondrial respiratory dysfunction (See, e.g., Schildgen et
al., Exp Hematol 2011;39:666-67510,11; Arthur et al., M0] Neurodegener
2009;4337).
ondrial dysfunction leading to cell death, reactive oxygen species
production, increased ive DNA damage, increased autophagy, and loss of
mitochondrial membrane potential has been associated with conditions such as
diabetes, obesity, aging related neurodegeneration including Alzheimer's disease,
stroke, insulin resistance, and atherosclerosis. An nic form of um,
sodium selenite, has been shown to affect mitochondrial function in certain
circumstances. Mehta et al. showed a marker of mitochondrial biogenesis, PGCla, is
increased in ischemic brain tissue and that sodium selenite further increases PGCla
after ischemia and recirculation. (Mehta et al., BMC Neuroscience 2012 13 :79).
Tirosh et al. showed that a high dose but not an intermediate dose of sodium selenite
prevented hapten induced impairment of mitochondrial function due to hapten
induced ation in colon tissue. (Tirosh et al., Nutrition 2007 23:878). These
results t that inorganic selenium can impact mitochondrial function in cells
undergoing damage. However, some studies have found that sodium selenite is less
bioavailable than other forms of selenium calling into question its effectiveness.
(Rider et al., J Anim Physiol Anim Nutr (Berl) 2010 94(1):99—110).
In addition, results in the literature indicate that different chemical forms of
selenium have different ivities. For example, a selenozolidine was more
effective at reducing the number of lung tumors than selenomethionine (Poerschke
et al, J Biochem Molecular Toxicology 2012 26:344). Barger et al. showed that mice
fed different sources of selenium, for example, selenium methionine, sodium
selenite and selenized yeast, had differential s on gene sion and on
specific functional pathways of mitochondrial structure and function. (Barger et al,
Genes and Nutrition 2012 7: 155).
e of the apparent difference in bioactivity and availability of distinct
chemical forms of um, there is a need to identify chemical forms of selenium
and to characterize their effects on biological processes. Characterization of these
effects on biological processes can lead to medicinal regulation of significant
ical processes to prevent or combat diseases, such as those diseases linked to
mitochondrial dysfunction. Diseases linked to ondrial dysfunction may be
prevented or treated by administering particular chemical forms of selenium that
reduce mitochondrial dysfunction or upregulate mitochondrial on in one or
more types of animal or human cells. One explanation for the variation in
bioactivity could be that different forms of selenium have ent effects on
biological ys at the molecular level.
SUMNLARY OF THE ION
The present application is directed to seleno—organic compounds,
compositions, and methods of using the compounds and compositions. The
compounds include 5’—Methylselenoadenosine (“compound C”), Se—Adenosyl—L—
homocysteine (“compound D”), Gamma-glutamyl-methylseleno-cysteine
(“compound E”), a compound of formula I, compound of formula II, a compound of
formula III, and combinations thereof. As described herein, compositions and
combinations thereof are useful to enhance mitochondrial function, to treat
mitochondrial dysfunction, to treat Alzheimer’s disease, and to modulate glucose
metabolism in a tissue-specific and tissue-appropriate manner.
In one aspect of the present application, different chemical forms of organic
selenium are identified as ically active. Selenium containing compounds as
described herein can be obtained from selenized yeast or can be chemically
synthesized as described herein. Selenized yeast contains many selenium and sulfur
compounds but not all of the selenium nds in selenized yeast impact
biological ses. In addition, a e of selenium and sulfur compounds in
selenized yeast have been shown to be inhibitory to each other or to negatively
impact biological processes.
Another aspect of the present application provides s or derivatives of
the biologically active um compounds described herein. Analogs and/or
derivatives of the selenium-containing compounds can be prepared synthetically. In
some embodiments, the analogs have increased stability, decreased oxidation,
increased half—life, and/or target the compounds to a specific tissue.
In r aspect of the present application, different chemical forms of
selenium have been shown to have different tissue specificity (e.g. some compounds
are active on al cells but not liver cells). In on, the same selenium
containing composition may activate a transcriptional activator in one cell type
while it inactivates the same transcriptional activator in a different cell type. These
differential activities and tissue specificities of different selenium-containing
compounds and combinations thereof are surprising and unexpected.
One aspect of the present ation es compositions comprising a
compound selected from the group consisting of 5’—Methylselenoadenosine, Se—
Adenosyl-L-homocysteine, Gamma-glutamyl-methylseleno-cysteine, a compound of
a (I), a compound of formula II, a compound of formula (III), and
combinations thereof. In further embodiments, one or more of these compounds can
be isolated and/or purified.
In other embodiments, compositions may e one or more of 5’—
thioadenosine, osyl-L-homocysteine, Gamma-glutamyl-methyl-
cysteine, or glutamyl selenocysteine, because one or more of these compounds may
be unnecessary to the composition or inhibitory to other compounds in the
composition.
Another aspect of the present application es methods of using the
compositions described herein to enhance mitochondrial function, treat
ondrial dysfunction, treat Alzheimer’s disease, and/ or modulate glucose
metabolism.
In embodiments, a method for treating Alzheimer’s disease comprises:
administering an effective amount of a composition to a subject, the composition
comprising 5’-Methylselenoadenosine, a compound of formula (I), or mixtures
thereof. In other embodiments, one or more of these compounds can be isolated
and/or purified.
In still other embodiments, a method for ng Alzheimer’s disease
ses: administering an effective amount of a composition to a subject, the
composition comprising at least three different nds selected from the group
ting of 5’—Methylselenoadenosine, Se—Adenosyl—L—homocysteine,Gamma—
glutamyl-methylseleno-cysteine, a compound of formula (I), and a compound of
formula (III). In embodiments of this invention, one or more of these compounds
can be isolated and/or purified.
In other embodiments, a method for inhibiting B amyloid accumulation in
one or more neuronal cells comprises: administering an ive amount of a
composition to the one or more neuronal cells, the ition comprising a
compound selected from the group consisting of 5’-Methylselenoadenosine, a
compound of formula (I), and es thereof, wherein the effective amount
inhibits B amyloid accumulation in one or more neuronal cells as compared to
neuronal cells not treated with the composition. In further embodiments, one or
more of these compounds can be isolated and/or purified.
In another embodiment, a method for inhibiting B amyloid accumulation in
one or more neuronal cells comprises: administering an effective amount of a
composition to one or more al cells, the composition comprising at least three
different compounds selected from the group consisting of 5’—
Methylselenoadenosine, Se—Adenosyl—L—homocysteine,Gamma—glutamylmethylseleno
—cysteine, a compound of formula (I), and a compound of formula
(III), wherein the effective amount inhibits B d accumulation in al
cells as ed to neuronal cells not treated with the composition. In further
embodiments, one or more of these compounds can be isolated and/or purif1ed.
In embodiments, a method for inhibiting tau phosphorylation in one or more
neuronal cells comprises: administering an effective amount of a composition to the
one or more neuronal cells, the composition comprising a nd selected from
the group consisting of 5’—Methylselenoadenosine, a compound of formula (I), and
mixtures thereof, wherein the effective amount inhibits tau orylation in one
or more al cells as compared to neuronal cells not treated with the
composition. In further embodiments, one or more of these compounds can be
ed and/or purif1ed.
In other embodiments, a method for inhibiting tau phosphorylation in one or
more al cells comprises: administering an effective amount of a composition
to the one or more neuronal cells, the composition comprising at least three different
compounds selected from the group consisting of 5’—Methylselenoadenosine, Se—
Adenosyl-L-homocysteine,Gamma-glutamyl-methylseleno-cysteine, a compound of
formula (I), and a nd of a (III), wherein the effective amount inhibits
tau orylation in neuronal cells as compared to neuronal cells not treated with
the composition. In further embodiments, one or more compounds can be isolated
and/or purified.
In embodiments, a composition comprises 5’—Methylselenoadenosine, or a
nd of formula (I) or a selenoglycoside thereof. In yet other embodiments, the
composition may exclude glutamyl selenocysteine, methionine, or selenomethionine
because of their potential inhibitory effects in the composition on active compounds
in the composition.
In some embodiments, the ive amount administered to a subject is 200
micrograms or less per day. In embodiments, the composition of the present
invention is administered once daily to a subject.
In another aspect, a method for enhancing mitochondrial function in one or more
cells selected from the group consisting of skeletal muscle cell, neuronal cell, and
combinations f, comprises: administering an effective amount of a
composition to the one or more cells, the composition comprising a compound
selected from the group consisting of 5’—Methylselenoadenosine, Se—Adenosyl—L—
homocysteine,Gamma-glutamyl-methylseleno-cysteine, a compound of formula (I),
a compound of formula (III), and combinations thereof, wherein the effective
amount enhances mitochondrial function as compared to cells not treated with the
composition. In further embodiments, one or more compounds can be isolated
and/or purified.
In other embodiments, a method for enhancing mitochondrial function in
one or more liver cells comprises: administering an effective amount of a
composition to the one or more liver cells, the composition comprising at least
three different compounds selected from the group consisting of 5’—
Methylselenoadenosine, Se—Adenosyl—L—homocysteine,Gamma—glutamyl-
methylseleno—cysteine, a compound of formula (I), and a compound of a
(III), wherein the effective amount es mitochondrial function as compared to
cells not treated with the composition. In further embodiments, one or more
nds can be isolated and/or purif1ed.
In another aspect, a method of modulating glucose metabolism in one or more
cells selected from the group consisting of liver cells, skeletal muscle cells, and
mixtures thereof, said method ses: administering an ive amount of a
composition to the one or more cells, the composition comprising at least three
different compounds selected from the group consisting of 5’—
Methylselenoadenosine, Se—Adenosyl—L—homocysteine,Gamma—glutamylmethylseleno
—cysteine, a compound of formula (I), and a compound of formula
(III), wherein the effective amount modulates glucose metabolism as compared to
cells not treated with the composition. In further embodiments, one or more
nds can be ed and/or purif1ed.
In embodiments, a method of decreasing expression of glucose 6 phosphatase
complex in one or more liver cells, comprises: administering an effective amount of
a composition to the one or more cells, the composition sing at least three
different compounds ed from the group ting of 5’—
Methylselenoadenosine, Se—Adenosyl—L—homocysteine,Gamma—glutamyl-
methylseleno—cysteine, a compound of formula (I), and a compound of formula
(III), wherein the effective amount inhibits expression glucose 6 phosphatase as
compared to cells not treated with the composition. In further embodiments, one or
more compounds can be isolated and/or purified.
BRIEF DESCRIPTION OF THE DRAWINGS
The accompanying drawings, which are incorporated in and constitute a part
of the description, illustrate several aspects of the invention and together with the
description, serve to explain the principles of the invention. A brief description of
the drawings is as follows:
Fig. 1 shows enhanced mitochondrial (“MT”) potential (fluorescence) upon
treatment of HEK293T kidney cells with 5’—Methylselenoadenosine (“compound
C”) but not Se—Adenosyl—L—homocysteine (“compound D”). Images were captured
at the same exposure time and magnification under the fluorescence microscope.
Fig. 2 shows enhanced ondrial (“MT”) potential in al muscle
C2C12 cells upon treatment with compounds C (5’-Methylselenoadenosine) and D
(Se—Adenosyl—L—homocysteine). The sulfur analogs H (5’—Methylthioadenosine)
and enosyl—L—homocysteine) decreased mitochondrial potential at all
concentrations.
Fig.3 shows a transient increase of mitochondrial (“MT”) potential in IMR-
32 human neuronal cells treated with compounds C thylselenoadenosine), D
(Se—Adenosyl-L-homocysteine), and E (Gamma-glutamyl-methylseleno-cysteine) or
combinations thereof at 6 hours and 24 hours. Their sulfur analogs H (5’-
Methylthioadenosine), enosyl-L-homocysteine), J (Gamma-glutamyl-methyl-
cysteine) and ations thereof also exhibited a transient increase in
mitochondrial function. Data were normalized by the fluorescence ities of
stained cell nuclei. * s P values
vs control.
Fig.4 shows that repeated treatments of ethylselenoadenosine), D
(Se—Adenosyl—L-homocysteine), and E ( Gamma-glutamyl-methylseleno-cysteine)
or their sulfur analogs H(5’—Methylthioadenosine) ), I(S—Adenosyl—L—homocysteine),
J (Gamma-glutamyl-methyl-cysteine) enhanced mitochondrial (MT) potential in
IMR—32 neuronal cells. Cells were treated once with compounds for 48 hours (hr.)
(top panel) or twice with nds for a total of 48 hours. m panel). Data
were normalized by the fluorescence intensities of stained cell nuclei.
Fig. 5 shows the lack of toxic effects of compounds C(5’—
Methylselenoadenosine), D enosyl-L—homocysteine), and E ( Gamma—
glutamyl-methylseleno-cysteine) or combinations thereof on the viability (indicated
by OD490 nm) of human IMR-32 neuronal cells over a 72 hour time period. In
contrast, sulfur analogs H(5’-Methylthioadenosine)), I nosyl-L-
homocysteine), J (Gamma-glutamyl-methyl-cysteine) and combinations thereof
exhibited a slight se in viability over the 72 hour time period. The results are
shown as mean :: sem; n=8.
Fig.6 shows the restoration of mitochondrial function by compounds D and E
in rat cortex cells stressed ble micromolar calcium. The figure shows the
respiration chart of normal ondria (top line) with the final OCR being the
measured distance between the end of the graph line and the X—axis. The bottom line
shows the tion of respiration of mitochondria by 10 micromolar calcium. The
two lines in the middle represent the respiration of mitochondria in the presence of
compounds C or D and 10 micromolar calcium.
Fig. 7 shows a significant increase of mitochondrial (MT) ial in AML-
l2 mouse liver cells treated with the combination of selenium compounds C(5’—
Methylselenoadenosine), D (Se—Adenosyl-L—homocysteine), and E ( Gamma—
glutamyl—methylseleno—cysteine)(150 ppb of each compound) as compared to a
combination of H(5’—Methylthioadenosine) ), 1(S—Adenosyl-L—homocysteine), and J
(Gamma—glutamyl-methyl-cysteine) at 6 and 24 hours. Data were normalized by the
cence intensities of stained cell nuclei. The P values shown in the bar graphs
were determined by comparing CDE group to control or HIJ group.
Fig. 8 shows inant sion of mitochondrial Uncouple Protein 2
(Ucp2) in AML-l2 mouse liver cells, and downregulation of its expression by the
combination of compounds C(5’—Methylselenoadenosine), D (Se—Adenosyl—L—
homocysteine), and E ( Gamma-glutamyl-methylseleno-cysteine) (150 ppb of each
compound)(A) ve expression of mitochondrial Uncouple Protein 1 (Ucpl) and
Ucp2 in normal AML-l2 cells (after treatment with water vehicle for 6 hours). n=4
as d in the bar. (B) No effect of the combination of C(5’—
Methylselenoadenosine), D (Se—Adenosyl-L—homocysteine), and E ( Gamma—
glutamyl—methylseleno—cysteine) on Ucpl expression. (C) Ucp2 expression
downregulated by the combination of C(5’—Methylselenoadenosine), D (Se—
Adenosyl-L-homocysteine), and E ( Gamma-glutamyl-methylseleno-cysteine). Data
are presented as mean :: sem of denoted number of sample in each bar. Different
letters (a vs. b)in the bar graph means a significant difference among those groups (P
< 0.05).
WO 37983
Fig.9 shows no toxic effects of nds C(5’—Methylselenoadenosine), D
(Se—Adenosyl—L—homocysteine), E ( Gamma-glutamyl-methylseleno-cysteine) and
combinations thereof or their sulfur analogs H(5’-Methylthioadenosine) ), 1(S-
Adenosyl-L-homocysteine), J (Gamma-glutamyl-methyl-cysteine) and
combinations thereof on the ity (indicated by OD490 nm) of AML-l2 mouse
liver cells.
Fig. 10 shows gulation of Ucp2, Ucp3 and Presenilin (PSEN)
expression in human IMR-32 neuronal cells after the treatment with the combination
of C(5’—Methylselenoadenosine), D (Se—Adenosyl-L—homocysteine), and E
(Gamma—glutamyl—methylseleno—cysteine) (150 ppb of each compound) nds.
(A) Ucp2 mRNA expression at 6 and 24 hours. (B) Ucp3 mRNA expression at 6 and
24 hours. (C) Relative PSEN and PSEN2 mRNA level in human IMR-32 neuronal
cells treated with e (water) at 6 and 24 hours. (D) PSEN mRNA expression
after normalization by the amount of actin beta (ACTB) mRNA level in human
IMR—32 neuronal cells treated with a combination of C (5’—Methylselenoadenosine),
D (Se-Adenosyl-L-homocysteine), E (Gamma-glutamyl-methylseleno-cysteine)
(150 ppb of each compound) or a combination of H (5’-Methylthioadenosine), I (S—
Adenosyl-L-homocysteine), and J (Gamma—glutamyl-methyl-cysteine) (150 ppb of
each compound) at 6 and 24 hours. (E) PSEN2 expression after normalization by
(ACTB) mRNA level in human IMR-32 neuronal cells treated with a combination of
C(5’—Methylselenoadenosine), D (Se—Adenosyl-L-homocysteine), and E ( Gamma—
yl-methylseleno-cysteine) or a combination of H(5’-Methylthioadenosine) ),
1(S—Adenosyl-L-homocysteine), and J (Gamma—glutamyl-methyl-cysteine) at 6 and
24 hours. Data are presented as mean :: sem of 3-4 samples per group. Different
alphabetic s (a vs. b) and different numbers (1 vs. 2) in the bar graph means a
significant difference among those groups (P < 0.05)
Fig. 11 shows gamma secretase complexes PSEN and Nicastrin were the
targets of Compound C(5’—Methylselenoadenosine) as determined by Western blot
and real time polymerase chain on (“RT-PCR”) analyses. (A) Photographs of
Western blot analysis of various proteins (key for plaque formation in Alzheimer’s
disease (AD) in human IMR—32 neuronal cells treated with 150 ppb compound C
(5’—Methylselenoadenosine), D (Se—Adenosyl-L-homocysteine), or E ( Gamma—
glutamyl-methylseleno-cysteine) for 6 and 24 hours. (B-C) Quantitative analysis of
(B) PSEN and (C) Nicastrin protein levels in the above Western blots (after
treatment with the listed compound for 24 hours, right panel). Data are presented as
mean :: sem of 3 samples. (D-G) Quantitative RT-PCR analysis of (D-E) PSEN and
(F-G) Nicastrin expression in human IMR-32 neuronal cells treated with water
vehicle (control) and the listed compounds for (D, F) 6 and (E, G) 24 hr. Data are
presented as mean :: sem of 4 samples. Different letters (a vs. b, a vs. c, or b vs. c)in
the bar graphs means a cant difference between those two groups (P < 0.05).
The s “a,b” denote no significant ence from a or b.
Fig. 12 shows that Compound C (5’—Methylselenoadenosine) is a novel
tor of Tau phosphorylation, and a glycogen synthase kinase 3 beta (“GSK3b”)
downregulator as determined by Western blot and RT—PCR analyses. (A)
Photographs of Western blot analysis of various proteins (key for tangle formation
in AD) in human IMR—32 neuronal cells treated with 150 ppb compound C (5’—
selenoadenosine), D (Se—Adenosyl-L—homocysteine), or E ( Gamma—
glutamyl-methylseleno-cysteine) for 6 and 24 hours. (B-E) Quantitative is of
(B) phosphorylated Tau at serine residue at position 396 (“pTau S396”) and (C)
phosphorylated Tau at serine residue at serine residue at position 400, at ine
residue at position 403, and serine residue at position 404 (“pTau
S400/T403/S404”), (D) total Tau, and (E) combined pTauS3 96 and pTau
S400/T403/S404 per total Tau protein levels in the above Western blots (after 24 hr
treatment, right panels). Data are presented as mean :: sem of 3 samples. (F)
Quantitative analysis of GSK3b protein levels in the above Western blots of IMR—32
cells treated with water e (control) or compounds for 24 hours). Data are
ted as mean :: sem of 3 samples. (G-H) Quantitative RT—PCR analysis of
GSK3b mRNA expression in human IMR-32 neuronal cells treated with water
vehicle ol) and the listed compounds for (G) 6 and (H) 24 hours. Data are
presented as mean :: sem of 4 samples. Different letters (a vs. b, a vs. c, or b vs. c)in
the bar graphs means a significant difference between those two groups (P < 0.05).
The letters “a,b” or “b,c” denote no significant difference from a or b or c.
Fig. 13 shows reduced FOXO phosphorylation and increased PGCla protein
expression in human IMR—32 neuronal cells by the combination of compounds C(5’—
Methylselenoadenosine), D enosyl-L—homocysteine), and E ( Gamma—
glutamyl—methylseleno—cysteine) b of each compound).
Fig. 14 shows a western blot analysis of various other signaling molecules
including phosphorylated forkhead box protein 04 phosphorylated at threonine 28
(“pFOXO4 T28”), forkhead box protein 04 (“FOXO4”), phosphorylated murine
thymoma viral oncogene homolog 1 at threonine 308 (“pAktT308”),
phosphorylated murine thymoma viral oncogene homolog 1 at serine 471
(“pAktS47l”) and peroxisome proliferator activated or gamma
, Akt,
coactivator 1 alpha (“PGCla”) in IMR-32 neuronal cells treated with compounds
C(5’—Methylselenoadenosine), D enosyl-L-homocysteine), or E ( Gamma—
glutamyl-methylseleno-cysteine), each compound at . (A) Photographs of
Western blots. (B-C) Quantitative analysis of orylated ad box protein
04 at threonine at position 28 (pFoxo4 T28) in the above Western blots of AML-12
cells treated with the listed compounds for (B) 6 and (C) 24 hours. Data are
presented as mean :: sem of 3 s. ent letters (a vs. b)in the bar graphs
means a significant difference between those two groups (P < 0.05). The letters
“a,b” denote no significant difference from a or b.
Fig. 15 shows a Western blot analysis of various other signaling molecules
including FOXOs, PDKl, AKT, Gsk3 a/b, 4EBP1, Elf2be, and PGCla in mouse
liver AML-12 cells treated with a combination of ethylselenoadenosine), D
(Se—Adenosyl—L-homocysteine), and E ( Gamma-glutamyl-methylseleno-cysteine)
(each compound at 150 ppb) for 6 hours. (A) Photographs of n blots. (B-C)
Quantitative analysis of (B) phosphorylated Foxo3 at T32, and (C) phosphorylated
Foxo4 at T28 in AML-12 cells shown in the above Western blots. Data are presented
as mean :: sem of 3 samples. Different letters (a vs. b)in the bar graphs means a
significant difference between those two groups (P < 0.05).
Fig. 16 shows a Western blot analysis of various listed molecules in mouse
liver AML-12 cells after treated with vehicle (water, control), or nd C (5’—
Methylselenoadenosine), D (Se—Adenosyl-L—homocysteine), or E ( Gamma—
glutamyl-methylseleno-cysteine), each at 150 ppb, for 6 and 24 hours.
Fig. 17 shows glucose 6 phosphatase catalytic subunit (“G6pc”) sion
in mouse liver AML-12 cells is significantly downregulated by the combination of
compounds C(5’—Methylselenoadenosine), D (Se—Adenosyl-L-homocysteine), and E
( Gamma—glutamyl—methylseleno—cysteine), but not by the individual compounds.
Cells were treated with vehicle (control), individual selenium compound (150 parts
per billion (ppb) or the combination of CDE (150 ppb of each compound) as well as
their respective sulfur analog(s) for 48 hour, and then subjected to tative RT-
PCR. Data are presented as mean :: sem of four samples in the bar graph.
Fig. 18 shows a schematic representation of the ation of compounds
CDE in the regulation of G6pc expression in liver cells.
Fig. 19 shows the presence of Foxo binding motifs in the er regions of
human GSKSB, PSEN, and NICASTRIN genes, as well as a schematic representation
of the effect of compound C on the regulation of mediators important in plaque and
tangle formation in neuronal cells. Panel (A) shows the location of five FOXOl/3/4
binding motifs on the human GSKSB promoter. Panel (B) shows the location of two
FOXOl/3/4 binding motifs on the human PSEN er. Panel (C) shows the
location of a 3/4 binding motif on the human Nicastrin (NCSTN) promoter.
Panel (D) shows the tic representation of the effect of compound C on the
regulation of mediators important in plaque and tangle formation in neuronal cells.
DETAILED DESCRIPTION
Definitions
As used herein, the terms istration" and "administering" refer to the
act of giving a drug, prodrug, or other agent, or therapeutic ent (e. g.,
compositions of the present application) to a subject (e.g., a t or in vivo, in
vitro, or ex vivo cells, tissues, and organs). Exemplary routes of administration to
the human body can be through the eyes (ophthalmic), mouth (oral), skin (topical or
transdermal), nose ), lungs (inhalant), oral mucosa (buccal), ear, rectal,
vaginal, by injection (e.g., intravenously, subcutaneously, intratumorally,
eritoneally, etc.) and the like.
The term "alkyl" refers to a branched or unbranched saturated hydrocarbon
group of l to 24 carbon atoms. Preferred "alkyl" groups herein contain 1 to 16
carbon atoms; i.e. C1_16 alkyl. Examples of an alkyl group include, but are not limited
to, methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl, secondary—butyl, tertiary—butyl,
pentyl, iso-pentyl, neo-pentyl, hexyl, xyl, 3-methylpentyl, 2,3-dimethylbutyl,
neo—hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl,
pentadecyl, and hexadecyl. Most preferred are "lower alkyl" which refer to an alkyl
group of one to six, more preferably one to four, carbon atoms. The alkyl group may
be ally substituted with an acyl, amino, amido, azido, carboxyl, alkyl, aryl,
halo, guanidinyl, oxo, sulfanyl, sulfenyl, sulfonyl, heterocyclyl or hydroxyl group.
The term “alkali metal” refers to refers to metallic salts include, but are not
limited to, appropriate alkali metal (group la) salts, alkaline earth metal (group Ila)
salts, and other physiological acceptable metals. Such salts can be made from
aluminum, calcium, lithium, magnesium, potassium, sodium and zinc.
The term "alkenyl" refers to a straight or branched carbon chain containing at
least one carbon—carbon double bond. In exemplary embodiments, "alkenyl" refers
to a arbon containing 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms, i.e. C1_10
alkenyl. Examples of an alkenyl group include, but are not limited to, ethene,
propene, , pentene, hexene, heptene, octene, nonene and decene. The alkenyl
group may be optionally substituted with an amino, alkyl, halo, or hydroxyl group.
The term "amido" refers to either a C-amido group such as 'R" or an
N amido group such as ——NR'COR" wherein R' and R" as used in this definition are
independently hydrogen, alkyl, alkenyl, alkynyl, alkoxy, carbocyclic, heterocylic,
aryl, or aralkyl. A "sulfoamido" group includes the ——NR'——SOz--R". Most preferably,
R' and R" are hydrogen, alkyl, aryl, or aralkyl.
The term "alkynyl" refers to a straight or branched carbon chain containing
at least one carbon-carbon triple bond. In exemplary embodiments, "alkynyl" refers
to a hydrocarbon containing 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms, i.e., C240
alkynyl. Examples of an alkynyl group include, but are not limited to, ethyne,
propyne, , pentyne, hexyne, heptyne, octyne, nonyne and decyne. The alkynyl
group may be optionally substituted with an amino, alkyl, halo, or hydroxyl group.
The term "aryl" refers to a carbocyclic aromatic system containing one, two
or three rings wherein such rings may be attached together in a pendant manner or
may be fused. The term "fused" means that a second ring is present (i.e., attached or
) by haVing two adjacent atoms in common (i.e., ) with the first ring.
The term "fused" is equivalent to the term nsed." The term "aryl" embraces
aromatic groups such as phenyl, naphthyl, ydronaphthyl, tetralin, indane,
indene, and biphenyl. The aryl group may optionally be substituted with an amino,
alkyl, halo, hydroxyl, carbocyclic, heterocyclic, or another aryl group.
The term "cycloalkyl" refers to a clic saturated or partially saturated
carbon ring, wherein the number of ring atoms is ted by a range of numbers. In
exemplary embodiments, "cycloalkyl" refers to a carbon ring as defined above
containing 3—12 ring atoms (i.e. €3.12 cycloalkyl). As used , lkyl
encompasses monocyclo, bridged, spiro, fused, bicyclo and tricyclo ring structures.
Examples of a cycloalkyl group include, but are not limited to, cyclopropyl,
utyl, cyclopentyl, cyclopentenyl, cyclohexyl, exenyl, cycloheptyl,
cycloheptenyl, norbornyl, decalin, adamantyl, and ctyl. The cycloalkyl group
may be optionally substituted with an amino, alkyl, halo, or hydroxyl group.
The term "aralkyl" refers to aryl-substituted alkyl moieties. Preferable
l groups are "lower aralkyl" groups having aryl groups ed to alkyl
groups having one to six carbon atoms. Examples of such groups include benzyl,
diphenylmethyl, triphenylmethyl, phenylethyl, and diphenylethyl. The terms benzyl
and methyl are interchangeable.
The term "aryloxy" refers to aryl groups, as defined above, attached to an
oxygen atom. The aryloxy groups may ally be substituted with a halo,
hydroxyl, or alkyl group. Examples of such groups include phenoxy, 4—chloro—3—
ethylphenoxy, 4-chloromethylphenoxy, 3-chloroethylphenoxy, 3,4-
dichlorophenoxy, 4-methylphenoxy, 3-trifluoromethoxyphenoxy, 3-
trifluoromethylphenoxy, ophenoxy, 3,4-dimethylphenoxy, 5-bromo-2—
fluorophenoxy, 4—bromo—3—fluorophenoxy, o—3 —methylphenoxy, 5,6,7,8—
tetrahydronaphthyloxy, 3—isopropylphenoxy, 3—cyclopropylphenoxy, 3—
ethylphenoxy, 4-tert-butylphenoxy, 3-pentafluoroethylphenoxy, and 3-(l,l,2,2-
tetrafluoroethoxy)phenoxy.
The term "alkoxy"refers to ntaining groups substituted with an alkyl,
or cycloalkyl group. Examples include, without limitation, methoxy, ethoxy, tert-
butoxy, and cyclohexyloxy. Most preferred are "lower alkoxy" groups having one to
six carbon atoms. Examples of such groups include methoxy, ethoxy, propoxy,
butoxy, isopropoxy, and utoxy groups.
The term "aralkoxy" refers to oxy-containing aralkyl groups attached through
an oxygen atom to other groups. "Lower aralkoxy" groups are those phenyl groups
attached to lower alkoxy group as described above. Examples of such groups include
benzyloxy, l-phenylethoxy, 3-trifluoromethoxybenzyloxy, 3-
trifluoromethylbenzyloxy, 3,5—difluorobenyloxy, 3—bromobenzyloxy, 4—
propylbenzyloxy, 2—fluorotrifluoromethylbenzyloxy, and 2—phenylethoxy.
The term "acyl" refers to —C(=O)R wherein R used in this definition is hydrogen,
alkyl, l, l, carbocyclic, heterocylic, aryl, or aralkyl. Most ably, R
is hydrogen, alkyl, aryl, or aralkyl.
The term "carboxyl" refers to --R'C(=O)OR", wherein R' and R" as used in
this definition are independently hydrogen, alkyl, l, alkynyl, carbocyclic,
heterocylic, heterocyloalkyl, aryl, ether, or aralkyl, or R' can additionally be a
covalent bond. "Carboxyl" includes both carboxylic acids, and carboxylic acid
. The term "carboxylic acid" refers to a yl group in which R" is
hydrogen, or a salt. Such acids include formic, acetic, propionic, c, valeric
acid, 2-methyl nic acid, oxirane-carboxylic acid, and cyclopropane carboxylic
acid. The term "carboxylic acid ester" or "ester" refers to a yl group in which
R" is alkyl, alkenyl, alkynyl, carbocyclic, heterocylic, aryl, or aralkyl. Examples of
ylic acids include, but are not limited to formic acid, acetic acid, propionic
acid, ic acid, pentanoic acid, hexanoic acid, heptanoic acid, ic acid,
nonanoic acid, decanoic acid, cyclopropanecarboxylic acid, cyclobutanecarboxylic
acid, cyclopentanecarboxylic acid, cyclohexanecarboxylic acid,
cycloheptanecarboxylic acid, cyclooctanecarboxylic acid, or cyclononanecarboxylic
acid.
The term “carbonyl” refers to refers to a C=O moiety, also known as an
“oxo” group.
The term "heterocycle" or "heterocyclyl" or “heterocyclic ring” refers to an
optionally substituted, saturated or unsaturated, aromatic or non-aromatic cyclic
hydrocarbon with 3 to 12, or 5 to 6, carbon atoms, wherein at least one of the ring
atoms is an O, N, S, P or Se. For e, in some embodiments, a ring N atom
from the heterocyclyl is the bonding atom to -C(O) to form an amide, carbamate, or
urea. In exemplary embodiments, "heterocyclyl" refers to a cyclic hydrocarbon as
described above containing 4, 5, or 6 ring atoms (i.e., C4_6 heterocyclyl). Examples
of a heterocyclic group include, but are not limited to, aziridine, oxirane, thiirane,
azetidine, oxetane, thietane, pyrrolidine, ole, tetrahydrofuran, pyran,
thiopyran, thiomorpholine, thiomorpholine S-oxide, oxazoline, tetrahydrothiophene,
piperidine, tetrahydropyran, thiane, olidine, oxodioxolenyl, oxazolidine,
thiazolidine, dioxolane, dithiolane, piperazine, oxazine, dithiane, dioxane, pyridinyl,
furanyl, benzofuranyl, isobenzofuranyl, pyrrolyl, thienyl, 1,2,3-triazolyl, 1,2,4-
triazolyl, indolyl, olyl, thiazolyl, thiadiazolyl, pyrimidinyl, oxazolyl, nyl,
and tetrazolyl. Exemplary heterocycles include benzimidazole, dihydrothiophene,
, dioxane, dioxolane, dithiane, dithiazine, dithiazole, dithiolane, furan, indole,
3-H indazole, 3-H-indole, indolizine, isoindole, isothiazole, isoxazole, morpholine,
oxazole, oxadiazole, oxathiazole, oxathiazolidine, oxazine, oxadiazine, piperazine,
piperidine, purine, pyran, pyrazine, pyrazole, pyridine, pyrimidine, pyrimidine,
pyridazine, e, pyrrolidine, tetrahydrofuran, tetrazine, thiadiazine, thiadiazole,
thiatriazole, thiazine, thiazole, thiophene, triazine, and triazole. The heterocycle may
be optionally substituted with an amino, alkyl, alkenyl, alkynyl, halo, hydroxyl,
carbocyclic, thio, other heterocyclic, or aryl group.
The term "heteroaryl" refers to a cyclic hydrocarbon, where at least one of
the ring atoms is an O, N, S, P or Se, the ring is characterized by delocalized [pi]
electrons (aromaticity) shared among the ring members, and wherein the number of
ring atoms is indicated by a range of numbers. Heteroaryl moieties as defined herein
have C, N, S, P or Se bonding hands. For e, in some embodiments, a ring N
atom from the heteroaryl is the bonding atom to -C(O) to form an amide, carbamate,
or urea. In exemplary embodiments, "heteroaryl" refers to a cyclic hydrocarbon as
described above ning 5 or 6 ring atoms (i.e. C5_6 heteroaryl). es of a
heteroaryl group include, but are not limited to, e, furan, thiene, oxazole,
thiazole, isoxazole, isothiazole, imidazole, pyrazole, oxadiazole, thiadiazole,
le, tetrazole, pyridine, pyrimidine, pyrazine, pyridazine, and triazine.
The term "hydroxy" or "hydroxyl" refers to the substituent —OH.
The term "oxo" refers to the substituent =O.
The term "nitro" refers to N02.
The term “azido” refers to N3.
The term “sulfur analog(s)” refers to an ue of a compound of interest
in which one or more selenium atoms have been replaced by one or more sulfur
atoms, respectively.
The term "sulfanyl" refers to --SR' where R' as used in this definition is
hydrogen, alkyl, alkenyl, alkynyl, yclic, heterocylic, aryl, or aralkyl.
The term "sulfenyl" refers to --SOR' where R' as used is this definition is hydrogen,
alkyl, alkenyl, alkynyl, yclic, heterocylic, aryl, or aralkyl.
The term nyl" refers to --SOR' where R' refers to hydrogen, alkyl,
alkenyl, alkynyl, carbocyclic, heterocylic, aryl, or l.
The term "ketone" refers to a moiety containing at least one carbonyl group
where the carbonyl carbon is bound to two other carbon atoms. In exemplary
embodiments, "ketone" refers to a yl—containing moiety as described above
containing 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms (i.e. C3_10ketone). Examples ofa
ketone group include, but are not limited to, acetone, ne, pentanone,
hexanone, heptanone, octanone, nonanone, decanone, cyclobutanone,
cyclopentanone, cyclohexanone, cycloheptanone, cyclooctanone, cyclononanone
and cyclodecanone.
The term "amino" refers to a primary, secondary or tertiary amino group of
the formula --NR'R" wherein R' and R" as used in this definition are ndently
hydrogen, acyl, alkyl, alkyenyl, alkynyl, aralkyl, aryl, yl, cycloalkyl,
heterocyclic, or other amino (in the case of hydrazide) or R' and R" together with the
nitrogen atom to which they are attached, form a ring haVing 4-8 atoms. Thus, the
term "amino", includes unsubstituted, monosubstituted (e. g., monoalkylamino or
ylamino), and disubstituted (e.g., dialkylamino or aralkylamino) amino
. Amino groups e -—NH2, methylamino, ethylamino, dimethylamino,
diethylamino, methyl-ethylamino, pyrrolidin-l-yl or piperidino, morpholino, etc.
Other exemplary " groups forming a ring include pyrrolyl, imidazolyl,
pyrazolyl, isothiazolyl, isoxazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl,
indolizinyl, imidazolyl, olyl, indolyl, indazolyl, purinyl, quinolizinyl. The ring
containing the amino group may be optionally substituted with another amino, alkyl,
l, alkynyl, halo, or hydroxyl group.
The term “amine” refers to a primary, secondary or ry amino group of
the formula --NR'R" wherein R' and R" as used in this definition are independently
hydrogen, acyl, alkyl, alkyenyl, alkynyl, aralkyl, aryl, carboxyl, cycloalkyl,
heterocyclic, or other amino (in the case of hydrazide) or R' and R" together with the
nitrogen atom to which they are attached, form a ring haVing 4-8 atoms. Thus, the
term "amino", as used , includes unsubstituted, monosubstituted (e.g.,
monoalkylamino or monoarylamino), and disubstituted (e. g., dialkylamino or
aralkylamino) amino groups. Amino groups include --NH2, methylamino,
ethylamino, dimethylamino, diethylamino, methyl-ethylamino, pyrrolidin-l-yl or
piperidino, morpholino, etc. Other ary "amino" groups forming a ring include
pyrrolyl, imidazolyl, pyrazolyl, isothiazolyl, isoxazolyl, pyridyl, nyl,
pyrimidinyl, pyridazinyl, indolizinyl, imidazolyl, isoindolyl, indolyl, indazolyl,
purinyl, quinolizinyl. The ring containing the amino group may be optionally
substituted with another amino, alkyl, alkenyl, alkynyl, halo, or hydroxyl group.
The term “alcohol” refers to"hydroxy" or "hydroxyl" refers to the substituent
—OH.
The term "amino alcohol" refers to a functional group containing both an
alcohol and an amine group. As used herein, "amino alcohols" also refers to amino
acids as defined above having a carbon bound to an alcohol in place of the
carboxylic acid group. In exemplary embodiments, the term "amino alcohol" refers
to an amino alcohol as defined above wherein the amine is bound to the carbon
adjacent to the alcohol-bearing . In exemplary embodiments, "amino alcohol"
refers to an amine and l- containing moiety as bed above containing 1,
2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 carbon atoms (i.e., C142 amino alcohol). Examples
of amino alcohols include, but are not limited to, ethanolamine, heptaminol,
isoetarine, norepinephrine, propanolamine, sphingosine, methanolamine, 2-amino
mercaptobutanol, 2-amino(methylthio)butanol, cysteinol, phenylglycinol,
ol, o-3 -phenyl- l-propanol, 2-amino-l-propanol, cyclohexylglycinol, 4-
hydroxy-prolinol, leucinol, tert-leucinol, phenylalaninol, a- phenylglycinol, 2-
pyrrolidinemethanol, tyrosinol, valinol, serinol, 2-dimethylaminoethanol, histidinol,
isoleucinol, leucinol, methioninol, l-methylpyrrolidinemethanol, threoninol,
tryptophanol, alaninol, argininol, glycinol, inol, 4-amino
hydroxypentanamide, 4- aminohydroxypentanoic acid, 3-amino
hydroxybutanoic acid, lysinol, 3-amino hydroxybutanamide, and 4-hydroxyprolinol.
The term "amino acid" refers to a group containing a carboxylic acid and an
amine bound to the carbon atom immediately adjacent to the carboxylate group, and
includes both natural and synthetic amino acids. Examples of amino acids include,
but are not limited to, arginine, histidine, lysine, aspartic acid, glutamic acid, serine,
threonine, asparagine, glutamine, cysteine, selenocysteine, glycine, proline, alanine,
valine, isoleucine, leucine, methionine, phenylalanine, tyrosine, tryptophan . The
carboxyl is substituted with H, a salt, ester, alkyl, or l. The amino group is
substituted with H, acyl, alkyl, l, alkynyl, carboxyl, lkyl, aralkyl, or
cyclyl.
The term "ether" refers to the group --R'--O--R” wherein R' and R" as used in
this definition are independently hydrogen, alkyl, alkenyl, alkynyl, carbocyclic,
heterocylic, aryl, or aralkyl, and R' can additionally be a nt bond attached to a
carbon.
The term "halogen" refers to a fluorine, chlorine, bromine or iodine atom.
The term "halide" refers to a functional group containing an atom bond to a
fluorine, chlorine, bromine or iodine atom. Exemplary ments disclosed
herein may include "alkyl halide," "alkenyl halide, H H l halide, H H cycloalkyl
halide," "heterocyclyl halide," or "heteroaryl " groups. In exemplary
embodiments, "alkyl halide" refers to a moiety containing a -halogen bond
containing 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms (i.e., C1_10 alkyl halide).
Examples of an alkyl halide group include, but are not limited to, fluoromethyl,
fluoroethyl, chloromethyl, chloroethyl, bromomethyl, bromoethyl, iodomethyl and
iodoethyl groups. Unless otherwise indicated, any carbon— containing group referred
to herein can contain one or more carbon-halogen bonds. By way of non-limiting
example, a Cialkyl group can be, but is not limited to, methyl, fluoromethyl,
difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, oromethyl,
bromomethyl, dibromomethyl, tribromomethyl, thyl, diiodomethyl,
triiodomethyl, chlorofluoromethyl, dichlorofluoromethyl, and difluorochloromethyl.
In the compounds bed herein, heteroatoms are capable of bearing
multiple different valencies. By way of non-limiting example, S, Se and N can be
neutral or hold a ve , and O can be neutral or hold a positive or negative
charge.
In some embodiments, compounds according to formula (I), (II), or (III)
encompass diastereomers and enantiomers of the illustrated compounds.
omers are defined as one of a pair of molecular entities which are mirror
images of each other and non—superimposable. Diastereomers or diastereoisomers
are d as stereoisomers other than enantiomers. Diastereomers or
diastereoisomers are stereoisomers not related as mirror images. Diastereoisomers
are characterized by differences in physical properties.
The terms “compound C” or “Compound C”, shown herein, refers to 5'—
Methylselenoadenosine; also known as (2R,4S,5S)(6-amino-9H-purinyl)
((methylselanyl)methyl)tetrahydrofuran-3,4-diol, CAS Registry Number 0—0,
and es any pharmaceutically acceptable salts thereof.
H C i / 3 \Se
0 N/J
"Compound C"
HO OH
2014/029542
The terms “compound D” or “Compound D”, shown herein, refers to 5'—
Selenoadenosyl homocysteine; —amino—4—((((ZS,3S,5R)—5—(6—amino—9H-purin-
9-yl)-3,4-dihydroxytetrahydrofuranyl)methyl)selanyl)butanoic acid, CAS
ry Number 40532, and includes any pharmaceutically acceptable salts
thereof.
H \\NH2 / \N
HO ‘
Se 0 N/J
HCompound D"
HO OH
The terms und E” or “Compound E”, shown herein, refers to gamma-
glutamyl-methylseleno-cysteine or y-L-glutamyl-Se-methyl-L-cysteine; also known
as N5-(l-carboxy(methylselanyl)ethyl)-L-glutamine, or any pharmaceutically
acceptable salt thereof.
OH "Compound E"
H2” H ,CH3
HO O
The terms “compound H” or “Compound H”, shown herein, refers to 5’—
Methylthioadenosine; 5'—S-Methyl—5'—thioadenosine, CAS Registry No. 2457—80—9,
or a pharmaceutically acceptable salt thereof
(/N / \N
HBC\S N
O N/J
"Compound H"
HO OH
The terms “compound 1” or “Compound 1” refers to S—Adenosyl—L—
homocysteine, also known as (S)—5'—(S)—(3—Amino—3—carboxypropyl)—5'—
thioadenosine, CAS Registry No. 979-92—0, or a pharmaceutically acceptable salt
thereof.
H \NH2 / \
.\ N
S O N/
"Compound 1"
HO OH
The terms “compound J” or “Compound J”, shown , refers to y—L—
glutamyl-methyl-L-cysteine, also known as Gamma-glutamyl-methyl-cysteine, or a
ceutically acceptable salt thereof.
H2N H [CH3
HO 0
"Compound J"
The term “compounds CDE” refers to a mixture of compound C, compound
D and nd E, or pharmaceutically acceptable salts thereof.
The term “compounds HIJ” refers to a mixture of compound H, compound I
and compound J, or pharmaceutically acceptable salts thereof
The terms "analog" and "derivative" are interchangeable and refer to a
l or tural modification of at least one position of a given molecule. For
example, a derivative of a given compound or le is modified either by
addition of a functional group or atom, removal of a functional group or atom or
change of a functional group or atom to a different onal group or atom
(including, but not limited to, isotopes).
The term “comprising” refers to a composition, compound, formulation or
method that is inclusive and does not exclude additional elements or method steps.
The term “consisting of” refers to a compound, composition, formulation, or
method that excludes the presence of any additional component or method steps.
The term “consisting essentially of” refers to a composition, compound,
formulation or method that is inclusive of additional elements or method steps that
do not materially affect the characteristic(s) of the composition, compound,
formulation or method.
The term "compound(s)" refers to any one or more chemical entity,
pharmaceutical, drug, and the like that can be used to treat or prevent a disease,
illness, sickness, or disorder of bodily function. Compounds comprise both known
and potential therapeutic compounds. A compound can be determined to be
therapeutic by screening using the ing methods of the present application. A
"known therapeutic compound" refers to a therapeutic compound that has been
shown (e.g., through animal trials or prior experience with administration to
humans) to be effective in such treatment. In other words, a known therapeutic
compound is not limited to a compound efficacious in the treatment of disease (e. g.,
neurodegenerative disease).
The term "composition(s)" refers to the combination of one or more
nds with or without another agent, such as but not limited to a carrier agent.
(e.g., one or more selenium ning nds with a carrier, inert or active,
making the composition especially suitable for diagnostic or therapeutic use in vitro,
in vivo or ex vivo.
The term “component” refers to a constituent part of a compound, or a
composition. For example, ents of a composition can include a compound, a
carrier, and any other agent present in the ition.
The term "effective amount" refers to the amount of a composition or
compound sufficient to effect beneficial or desired results. An effective amount can
be administered in one or more applications or dosages and is not intended to be
limited to a particular formulation or stration route.
The term "hydrate" refers to a compound disclosed herein which is
associated with water in the molecular form, i.e., in which the H- OH bond is not
split, and may be represented, for e, by the formula R x H20, where R is a
compound disclosed herein. A given compound may form more than one hydrate
including, for example, drates (R x H20), ates (R2 x H20), trihydrates
(R3 x H20), and the like.
The term “inhibitory” or onistic” refers to the property of a compound
that decreases, limits, or blocks the action or function of another compound.
The term “isolated” refers to the separation of a material from at least one
other material in a mixture or from materials that are naturally associated with the
al. For example, a compound synthesized synthetically is separated from a
starting material or an intermediate.
The term “mitochondrial ial” refers to voltage difference across the
inner mitochondrial membrane maintained by the net movement of positive charges
across the membrane.
The term “modulates” refers to a change in the state (e.g. activity or amount)
of a compound from a known or ined state.
"Optional" or "optionally" refers to a circumstance in which the subsequently
described event or circumstance may or may not occur, and that the description
includes instances where said event or circumstance occurs and ces in which it
does not. "Optionally" is inclusive of ments in which the described
conditions is present and ments in which the described ion is not
t. For example, "optionally substituted phenyl" means that the phenyl may or
may not be substituted, and that the description includes both unsubstituted phenyl
and phenyl wherein there is substitution. "Optionally" is inclusive of embodiments
in which the described conditions is present and ments in which the
described condition is not t.
The term ic selenium" or “seleno-organic compound” refers to any
organic compound wherein um replaces sulfur. Thus, organic selenium can
refer to any such compound biosynthesized by yeast, or it can refer to free organic
seleno—compounds that are chemically synthesized. An example of the latter is free
selenomethionine. In some cases, seleno—organic compounds also include
selenometabolites.
The terms "patient" or "subject" are used interchangeably and refer to any
member of Kingdom Animalia. Preferably a subject is a mammal, such as a human,
domesticated mammal or a livestock mammal.
The phrase "pharmaceutically acceptable" refers to those compounds,
materials, compositions, and/or dosage forms which are, within the scope of sound
medical judgment, le for use in contact with the tissues of human beings and
animals without excessive toxicity, irritation, allergic response, or other problem or
complication, commensurate with a reasonable benefit/risk ration.
The phrase "pharmaceutically-acceptable carrier" refers to a
pharmaceutically-acceptable material, ition or vehicle, such as a liquid or
solid filler, diluent, excipient, solvent or encapsulating material, involved in carrying
or transporting the subject selenium containing compound or analogue or derivative
from one organ, or portion of the body, to another organ, or portion of the body.
Each carrier must be "acceptable" in the sense of being compatible with the other
ingredients of the ation and not injurious to the patient. Some examples of
materials which may serve as pharmaceutically-acceptable carriers include: (1)
sugars, such as lactose, glucose and sucrose; (2) starches, such as corn starch and
potato starch; (3) ose, and its derivatives, such as sodium carboxymethyl
cellulose, ethyl cellulose and cellulose e; (4) powdered tragacanth; (5) malt;
(6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9)
oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil
and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as
glycerin, sorbitol, mannitol and polyethylene glycol; (12) , such as ethyl oleate
and ethyl laurate; (13) agar; (14) buffering agents, such as magnesium hydroxide
and aluminum hydroxide; (15) c acid; (16) n-free water; (17) isotonic
saline; (18) Ringer's on; (19) ethyl alcohol; (20) phosphate buffer solutions;
and (21) other non-toxic compatible substances employed in pharmaceutical
ations.
The term “prodrug” refers to a pharmacologically active or more typically an
inactive compound that is converted into a pharmacologically active agent by a
lic ormation. Prodrugs of a compound of any of the formulae above are
prepared by modifying onal groups present in the compound of any of the
ae above in such a way that the modifications may be cleaved in vivo to
release the parent compound. In vivo, a prodrug readily undergoes chemical
s under physiological conditions (e.g., are hydrolyzed or acted on by
naturally occurring enzyme(s)) resulting in liberation of the cologically
active agent. Prodrugs include compounds of any of the formulae above wherein a
hydroxy, amino, or carboxy group is bonded to any group that may be cleaved in
vivo to regenerate the free hydroxyl, amino or carboxy group, respectively.
Examples of prodrugs include, but are not limited to esters (e. g., acetate, formate,
and benzoate derivatives) of compounds of any of the formulae above or any other
derivative which upon being brought to the physiological pH or through enzyme
action is converted to the active parent drug. Conventional procedures for the
selection and preparation of suitable prodrug derivatives are described in the art (see,
for e, Bundgaard. Design of Prodrugs. Elsevier, 1985).
The term "purified" or "to purify" or antially purified” refers to the
removal of a component such as inactive, inhibitory components, unreacted
compounds, or alternative compounds produced during synthesis, (e. g.,
contaminants) from a ition to the extent that 10% or less (e. g., 10%, 9%, 8%,
7%, 6%, 5%,4%, 3%, 2%, l% or less) of the composition is not active compounds
or pharmaceutically acceptable carrier.
The term “salts” can include acid addition salts or addition salts of free
bases. Preferably, the salts are pharmaceutically acceptable. Examples of acids
which may be employed to form pharmaceutically acceptable acid addition salts
include, but are not limited to, salts derived from ic inorganic acids such as
nitric, phosphoric, sulfuric, or hydrobromic, hydroiodic, hydrofluoric, phosphorous,
as well as salts derived from nontoxic organic acids such as aliphatic mono- and
dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxyl ic acids,
alkanedioic acids, aromatic acids, tic and aromatic sulfonic acids, and ,
maleic, succinic, or citric acids. Non-limiting examples of such salts include
napadisylate, besylate, sulfate, pyrosulfate, bisulfate, sulf1te, 1te, nitrate,
phosphate, monohydrogenphosphate, dihydrogenphosphate, osphate,
pyrophosphate, chloride, bromide, iodide, acetate, trifluoroacetate, propionate,
caprylate, isobutyrate, oxalate, malonate, succinate, te, sebacate, fumarate,
maleate, mandelate, te, chlorobenzoate, methylbenzoate, dinitrobenzoate,
phthalate, benzenesulfonate, toluenesulfonate, phenylacetate, citrate, lactate,
maleate, tartrate, methanesulfonate, and the like. Also contemplated are salts of
amino acids such as te and the like and gluconate, galacturonate (see, for
example, Berge, et a]. “Pharmaceutical Salts,” J. Pharma. Sci. l977;66:l).
The term "pharmaceutically able salts" includes, but is not limited to,
salts well known to those skilled in the art, for example, mono-salts (e.g. alkali metal
and ammonium salts) and poly salts (e.g. di- or tri-salts,) of the nds of the
invention. Pharmaceutically acceptable salts of compounds of the disclosure are
where, for example, an exchangeable group, such as hydrogen in --OH, --NH--, or ——
P(=O)(OH)--, is replaced with a pharmaceutically acceptable cation (e. g. a sodium,
potassium, or ammonium ion) and can be conveniently be prepared from a
corresponding compound disclosed herein by, for example, reaction with a suitable
base. In cases where compounds are sufficiently basic or acidic to form stable
nontoxic acid or base salts, administration of the compounds as salts may be
appropriate. Examples of pharmaceutically acceptable salts are organic acid addition
salts formed with acids that form a logical acceptable anion, for example,
te, methanesulfonate, acetate, citrate, malonate, tartarate, succinate, te,
ascorbate, alpha-ketoglutarate, and alpha-glycerophosphate. le inorganic salts
may also be formed, including hydrochloride, sulfate, nitrate, bicarbonate, and
carbonate salts. Pharmaceutically acceptable salts may be obtained using standard
procedures well known in the art, for example, by reacting a iently basic
nd such as an amine with a suitable acid affording a physiologically
acceptable anion. Alkali metal (for example, sodium, potassium or lithium) or
alkaline earth metal (for example, calcium) salts of carboxylic acids can also be
made.
The terms "selenium-enriched yeast" and "selenized yeast" refer to any yeast
(e. g., Saccharomyces cerevisiae) that is cultivated in a medium containing inorganic
selenium salts. The present application is not limited by the selenium salt used.
Indeed, a variety of selenium salts are contemplated to be useful in the present
application including, but not limited to, sodium selenite, sodium selenate, cobalt
selenite or cobalt selenate. A selenium-containing compound in such yeast
preparations is selenomethionine which will be present in a form that is incorporated
into ptides/proteins. The amount of total cellular selenium t in the form
of methionine in such preparations will vary, but can be between 10 and
100%, 20—60%, 50—75% and between 60 and 75%. The remainder of the c
selenium in selenized yeast preparations is predominantly made up of intermediates
in the pathway for selenomethionine biosynthesis. These include, but are not limited
to, selenocysteine, selenocystathionine, selenohomocysteine and seleno—
adenosylselenomethionine. The amount of residual inorganic selenium salt in the
finished product is generally quite low (e. g., < 2%).
The term ituted" in connection with a moiety refers to a further
substituent which is attached to the moiety at any acceptable location on the moiety.
Unless otherwise indicated, es can bond through a , nitrogen, oxygen,
sulfur, or any other acceptable atom. Examples of substituents include, but are not
d to amines, alcohols, thiols, ethers, alkenes, alkynes, es, aziridines,
oxiranes, azetidines, dihydrofurans, pyrrolidines, pyrans, piperidines, aldehydes,
ketones, esters, carboxylic acids, carboxylates, imines, imides, azides, azo groups,
eneamines, alkyl halides, alkenyl halides, alkynyl halides, aryl halides, phosphines,
phosphine oxides, phophinites, onites, ites, phohsphonates,
phosphates, sulfates, sulfoxides, sulfonyl , sulfoxyl groups, sulfonates,
nitrates, nitrites, nitriles, nitro groups, nitroso groups, cyanates, thiocyanates,
ocyanates, carbonates, acyl s, des, hydroperoxides, hemiacetals,
hemiketals, acetals, ketals, orthoesters, orthocarbonate , sulf1des, disulf1des,
sulfonic acids, sulfonic acids, thiones, thials, phosphodiesters, boronic acids, boronic
esters, boronic acids and boronic .
The terms “treating3’ ECtreat” or “treatment” refer to therapeutic treatment
where the object is to slow down (e. g., lessen or postpone the onset of) an undesired
physiological condition, disorder or disease, or to obtain beneficial or desired
results such as partial or total ation or inhibition in decline of a parameter,
value, function or result that had or would become abnormal. Beneficial or desired
results include, but are not limited to, alleviation of symptoms; diminishment of the
extent or vigor or rate of development of the condition, er or disease;
ization (i.e., not worsening) of the state of the condition, disorder or disease;
delay in onset or slowing of the ssion of the condition, disorder or disease;
amelioration of the condition, disorder or e state; and remission (whether
partial or total), whether or not it translates to immediate lessening of actual clinical
symptoms, or enhancement or improvement of the ion, disorder or disease.
The term "reagent(s) capable of specifically detecting gene expression"
refers to reagents capable of or sufficient to detect the expression of various genes
described in detail herein. Examples of suitable reagents include, but are not limited
to, nucleic acid probes capable of specifically hybridizing to mRNA or cDNA, and
antibodies (e.g., monoclonal or polyclonal antibodies).
The term "toxic" refers to any ental or harmful effects on a subject, a
cell, or a tissue as compared to the same cell or tissue prior to the stration of
the toxicant.
Compounds and compositions
One aspect of the t application is directed to 5’—Methylselenoadenosine
(“compound C”), Se—Adenosyl—L—homocysteine (“compound D”), Gamma—
glutamyl—methylseleno—cysteine (“compound E”) and analogs thereof. Some
embodiments include a composition comprising an compound of Formula 1,
Formula 11, and/or Formula 111 and combinations f.
In some embodiments, a composition is ed comprising a compound
according to formula (I):
or a pharmaceutically acceptable salt, hydrate, or prodrug thereof,
n R1 is H, acyl, alkyl, alkenyl, alkynyl, aralkyl, carboxyl, cycloalkyl, C(O)R’,
C(O)OR’, where R’ is alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, or
heterocyclyl; or R1 together with R2 form a heterocyclic ring haVing 4 to 8 ring
members with at least one heteroatom selected from oxygen or nitrogen;
R2 is H, acyl, alkyl, alkenyl, alkynyl, aralkyl, carboxyl, cycloalkyl, C(O)R’,
C(O)OR’, where R’ is selected from alkyl, lkyl, aryl, aralkyl, or heterocyclyl;
or R1 er with R2 form a heterocyclic ring haVing 4 to 8 ring members with at
least one atom selected from oxygen or nitrogen;
R3 is H, acyl, alkyl, alkenyl, alkynyl, aralkyl, cycloalkyl, yl, or C—amido; or
R3 together with R4 and the atoms to which they are attached form a heterocyclic
ring haVing 4 to 8 ring members with at least one heteroatom selected from oxygen
or nitrogen;
R4 is H, acyl, alkyl, alkenyl, alkynyl, aralkyl, cycloalkyl, carboxyl, or C—amido; or
R3 together with R4 and the atoms to which they are attached form a heterocyclic
ring haVing 4 to 8 ring members with at least one heteroatom selected from oxygen
or en;
R5 is oxo, hydroxyl, alkyl, alkenyl, alkynyl, OR’, or is absent; where R’ is selected
from alkyl, l, alkynyl, lkyl, aryl, or l;
R6 is oxo, hydroxyl, alkyl, alkenyl, alkynyl, OR’, or is absent; where R’ is selected
from alkyl, alkenyl, alkynyl, cycloalkyl, aryl, or aralkyl;
R7 is H, alkyl, alkenyl, alkynyl, ketone, amino alcohol, amino acid, OR’, Se—R’, S—
R’, where R’ is selected from H, alkyl, cycloalkyl, aryl, aralkyl, or heterocyclyl; and
R8 is hydrogen, azido, alkyl, alkenyl, alkynyl.
In further embodiments, one or more of these compounds of Formula (I) can
be isolated and/or purified.
In some embodiments, a composition is provided comprising a compound
according to formula (I), or a pharmaceutically acceptable salt, hydrate, or prodrug
thereof, wherein R1, R3, R4 and R8 are each H; R2 is H, acyl, alkyl, alkenyl, alkynyl,
aralkyl, carboxyl, cycloalkyl, C(O)R’, or C(O)OR’, where R’ is selected from alkyl,
cycloalkyl, aryl, aralkyl, or heterocyclyl; R5 and R6 are each absent; and R7 is alkyl,
or amino acid.
In some embodiments, a composition is provided comprising a compound
according to formula (I), or a pharmaceutically acceptable salt, e, or prodrug
thereof, wherein R1, R3, R4 and R8 are each H; R2 is H, acyl, alkyl, alkenyl, alkynyl,
aralkyl, carboxyl, cycloalkyl, , C(O)OR’, where R’ is selected from alkyl,
cycloalkyl, aryl, l, or heterocyclyl; R5 and R6 are each absent; and R7 is alkyl,
or amino acid; with the o that 5'-selenoadenosyl nine, oxy 5'—
methylselenoadenosine, elenoadenosine, seleno(hydroxyl)—selenophene—(3'—
deoxy—adenosine), allylselenoadenosyl homocysteine, seleno—adenosyl
homocysteine, seleno—hydroxy adenosyl homocysteine, seleno adenosine, seleno—
adenosyl—Se(methyl)—selenoxide, adenosyl—hydroxy selenoxide, ethyl
selenoadenosine, seleno—(hydroxy)—selenophene—(3'—desoxy—adenosine), adenosyl—
hydroxy ide, and seleno—adenosyl—Se(methyl)—selenoxide may each be
excluded from the composition.
In a specific , a composition is provided comprising a compound, or a
pharmaceutically acceptable salt, e, or prodrug thereof, according to formula
(I) that is 5'—methylselenoadenosine (“compound C”).
In some embodiments, compositions comprise a compound ing to
formula (I), or a pharmaceutically acceptable salt, hydrate, or prodrug thereof, with
the proviso that 5'—selenoadenosyl methionine, oxy 5'—methylselenoadenosine,
ethylselenoadenosine, seleno(hydroxyl)—selenophene—(3'—deoxy—adenosine),
allylselenoadenosyl steine, seleno—adenosyl homocysteine, seleno—hydroxy
adenosyl homocysteine, seleno adenosine, seleno—adenosyl—Se(methyl)—selenoxide,
adenosyl—hydroxy selenoxide, ethyl selenoadenosine, seleno—(hydroxy)—
phene—(3'—desoxy—adenosine), adenosyl—hydroxy selnoxide, and selenoadenosyl
—Se(methyl)—selenoxide may each be excluded from the composition.
In some embodiments, a composition is provided comprising a compound
according to formula (11):
\ /R2
r N
R N
H .\N/10 REY
R11Wse / \N
O N/J
0 R5 \R6
0 o
l | (11)
or a pharmaceutically acceptable salt, hydrate, or g thereof,
wherein R1 is H, acyl, alkyl, alkenyl, alkynyl, aralkyl, carboxyl, cycloalkyl, C(O)R’,
C(O)OR’, where R’ is alkyl, alkenyl, l, cycloalkyl, aryl, aralkyl, or
heterocyclyl; or R1 together with R2 form a heterocyclic ring haVing 4 to 8 ring
members with at least one heteroatom selected from oxygen or nitrogen;
R2 is H, acyl, alkyl, alkenyl, alkynyl, aralkyl, carboxyl, cycloalkyl, C(O)R’,
C(O)OR’, where R’ is ed from alkyl, cycloalkyl, aryl, l, or heterocyclyl;
or R1 together with R2 form a cyclic ring haVing 4 to 8 ring members with at
least one heteroatom selected from oxygen or nitrogen;
R3 is H, acyl, alkyl, alkenyl, alkynyl, aralkyl, cycloalkyl, carboxyl, or C-amido; or
R3 together with R4 and the atoms to which they are attached form a heterocyclic
ring haVing 4 to 8 ring members with at least one heteroatom selected from oxygen
or nitrogen;
R4 is H, acyl, alkyl, alkenyl, alkynyl, aralkyl, cycloalkyl, yl, or C—amido; or
R3 together with R4 and the atoms to which they are ed form a heterocyclic
ring haVing 4 to 8 ring members with at least one heteroatom selected from oxygen
or nitrogen;
R5 is oxo, hydroxyl, alkyl, l, alkynyl, OR’, or is absent; where R’ is selected
from alkyl, alkenyl, alkynyl, cycloalkyl, aryl, or aralkyl;
R6 is oxo, hydroxyl, alkyl, alkenyl, alkynyl, OR’, or is absent; where R’ is selected
from alkyl, alkenyl, alkynyl, cycloalkyl, aryl, or aralkyl;
R3 is hydrogen, azido, alkyl, alkenyl, alkynyl;
R9 is H, acyl, alkyl, alkenyl, alkynyl, aralkyl, yl, cycloalkyl, C(O)R’,
C(O)OR’, where R’ is alkyl, cycloalkyl, aryl, l, or heterocyclyl; or R9 together
with R10 form a heterocyclic ring having 4 to 8 ring members with at least one
heteroatom selected from oxygen or nitrogen;
R10 is H, acyl, alkyl, alkenyl, alkynyl, aralkyl, yl, cycloalkyl, C(O)R’,
C(O)OR’, where R’ is selected from alkyl, cycloalkyl, aryl, aralkyl, or heterocyclyl;
or R9 together with R10 form a heterocyclic ring having 4 to 8 ring members with at
least one heteroatom selected from oxygen or nitrogen; and
R11 is OH, OR, alkoxy, xy, or amino, where R is selected from alkyl,
cycloalkyl, aryl, aralkyl, heterocyclyl, or a pharmaceutically acceptable salt, or inner
salt.
In further embodiments, one or more of these compounds of a (II) can
be isolated and/or purifled.
In some embodiments, a ition is provided comprising a compound
according to formula (II), or a pharmaceutically acceptable salt, hydrate, or prodrug
thereof, wherein R1, R3, R4, R8 and R9 are each H; R2 is H, acyl, alkyl, yl,
C(O)R’, or C(O)OR’, where R’ is selected from alkyl, cycloalkyl, aryl, l, or
heterocyclyl; R5 and R6 are ; R10 is H, acyl, alkyl, alkenyl, alkynyl, l,
carboxyl, cycloalkyl, C(O)R’, C(O)OR’, where R’ is selected from alkyl, cycloalkyl,
aryl, aralkyl, or heterocyclyl; and R11 is OH, OR, alkoxy, aralkoxy, or amino, where
R is selected from alkyl, cycloalkyl, aryl, aralkyl, heterocyclyl, or a
pharmaceutically acceptable salt, or inner salt.
In some embodiments, a composition is provided comprising a compound
according to formula (II), or a pharmaceutically acceptable salt, hydrate, or prodrug
thereof, wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, R10 are as defined above and
wherein R11 is OH or OR, where R is selected from methyl, ethyl, propyl, isopropyl,
butyl, sec—butyl, or tert—butyl.
In a specific aspect, a composition is provided comprising a compound
ing to a (II), or a pharmaceutically acceptable salt, hydrate, or prodrug
thereof, that is 5'-selenoadenosyl homocysteine (compound “D”), or a
pharmaceutically acceptable salt, hydrate, or prodrug thereof.
In some embodiments, compositions comprise a compound according to
formula (II), or a pharmaceutically acceptable salt, e, or prodrug f; with
the proviso that 5'-selenoadenosyl methionine, allylselenoadenosyl homocysteine,
seleno—adenosyl homocysteine, and —hydroxy adenosyl homocysteine may
each be excluded from the composition.
In some embodiments, a composition is provided comprising a nd
according to formula (111):
R1\N H
/ N S’R79
R2 0 I / \R5
0 0 R6
or a pharmaceutically acceptable salt, hydrate, or prodrug thereof, wherein
R1 is H, acyl, alkyl, alkenyl, alkynyl, aralkyl, carboxyl, cycloalkyl, C(O)R’,
C(O)OR’, where R’ is alkyl, l, l, cycloalkyl, aryl, aralkyl, or
heterocyclyl; or R1 together with R2 form a heterocyclic ring haVing 4 to 8 ring
members with at least one atom selected from oxygen or nitrogen;
R2 is H, acyl, alkyl, l, alkynyl, aralkyl, carboxyl, cycloalkyl, C(O)R’,
C(O)OR’, where R’ is selected from alkyl, cycloalkyl, aryl, aralkyl, or heterocyclyl;
or R1 together with R2 form a heterocyclic ring haVing 4 to 8 ring members with at
least one atom selected from oxygen or nitrogen;
R3 is OH, OR, alkoxy, aralkoxy, or amino, where R is selected from alkyl,
cycloalkyl, aryl, l, heterocyclyl, or a pharmaceutically acceptable salt, or inner
salt;
R4 is H, alkyl, alkenyl, alkynyl, lkyl, aryl, aralkyl, heterocyclyl, or a
pharmaceutically acceptable salt, or inner salt;
R5 is oxo, hydroxyl, alkyl, alkenyl, alkynyl, OR’, or is absent; where R’ is selected
from alkyl, alkenyl, alkynyl, cycloalkyl, aryl, or aralkyl;
R6 is oxo, hydroxyl, alkyl, alkenyl, alkynyl, OR’, or is absent; where R’ is selected
from alkyl, alkenyl, l, cycloalkyl, aryl, or aralkyl; and
R7 is H, alkyl, alkenyl, alkynyl, ketone, OR’, Se—R’, S-R’, where R’ is selected from
H, alkyl, cycloalkyl, aryl, aralkyl, or heterocyclyl.
In some embodiments, a composition is provided comprising or a compound
according to formula (III), or a pharmaceutically acceptable salt, e, or prodrug
thereof, wherein
R1 and R2 are each H;
R3 is OH, OR, alkoxy, aralkoxy, or amino, where R is selected from alkyl,
cycloalkyl, aryl, aralkyl, heterocyclyl, or a pharmaceutically acceptable salt, or inner
salt;
R4 is H, or a pharmaceutically acceptable salt, or inner salt;
R5 and R6 are absent; and
R7 is alkyl, alkenyl or alkynyl.
In further embodiments, one or more of these compounds of Formula (III)
can be isolated and/or purified.
In some embodiments, a composition is provided comprising a nd
according to formula (III), or a pharmaceutically acceptable salt, hydrate, or prodrug
thereof, wherein R1 and R2 are each H; R3 is OH or OR, where R is ed from
methyl, ethyl, propyl, isopropyl, butyl, tyl, or tert-butyl; R4 is H; R5 and R6
are absent; and R7 is alkyl that is methyl, ethyl, propyl, isopropyl, butyl, iso-butyl,
sec—butyl, or utyl.
In some embodiments, a ition is provided comprising a compound
according to formula III, or a pharmaceutically acceptable salt, hydrate, or prodrug
thereof, wherein R1 and R2 are each H; R3 is OH or OR, where R is selected from
methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, or tert-butyl; R4 is H; R5 and R6
are absent; and R7 is methyl.
In a specific aspect, a composition is ed comprising a compound
according to formula (III), or a pharmaceutically acceptable salt, hydrate, or prodrug
thereof, that is gamma-glutamyl-methylseleno-cysteine (“compound E”), or a
pharmaceutically acceptable salt, hydrate, or prodrug thereof.
In some embodiments, a ition comprises a compound according to
formula (III), or a pharmaceutically acceptable salt, hydrate, or prodrug f, with
the proviso that y-glutamoyl selenocysteine- y -glutamoyl cysteine, y—
glutamoylcysteine-2,3—DHP—selenocysteine, lutamoylselenocysteine,
selenoglutathione-y-glutamoylcysteine,y-glutamoyl selenocysteine-y-glutamoyl
cysteine, y—glutamoylcysteine—2,3-DHP—selenocysteine, di—y—
glutamoylselenocysteine, and selenoglutathione-y-glutamoylcysteine may each be
excluded from the ition.
In some ments, a composition is ed comprising one or more
compounds according to one or more of formulas (I), (II) and/or (III), wherein each
of the following compounds is excluded from the composition in order to minimize
selenium toxicity, remove inactive or inhibitory compounds, and/or maximize the
therapeutic index of the composition, wherein the excluded compounds are y —
oyl selenocysteine-y-glutamoyl cysteine, y -glutamoylcysteine-2,3-DHP-
cysteine, di—y moylselenocysteine, selenoglutathione—yglutamoylcysteine
, y moyl selenocysteine-y-glutamoyl cysteine, y—
glutamoylcysteine-2,3—DHP—selenocysteine, di—y —glutamoylselenocysteine,
selenoglutathione—y—glutamoylcysteine, dehydroxy 5'—methylselenoadenosine,
ethylselenoadenosine, seleno(hydroxyl)—selenophene—(3'—deoxy—adenosine),
elenoadenosyl homocysteine, seleno—adenosyl homocysteine, —hydroxy
adenosyl homocysteine, seleno adenosine, seleno—adenosyl—Se(methyl)—selenoxide,
adenosyl—hydroxy xide, ethyl selenoadenosine, seleno—(hydroxy)—
selenophene—(3'—desoxy—adenosine), adenosyl—hydroxy selenoxide, and seleno—
adenosyl—Se(methyl)—selenoxide.
In embodiments, any of the compounds described herein can be modified
with a prodrug to prolong half-life, to protect the compound against oxidation, to
target the compound to a , and/or to allow the compound to pass the blood
brain barrier.
In ments, a prodrug comprises a selenoglycoside. Glycosides include
mono, di and oligo saccharides. Saccharides can include ribose, glucose, galactose,
or mannose. For example a galactose conjugated to a selenium moiety could target
the nd to the liver.
In other embodiments, a prodrug comprises a selenazolidine. These
compounds provide for slow release of the compound.
In yet other embodiments, a prodrug comprises conjugation of a seleno—
organic compound as described herein to a vitamin such as C or E. These g
conjugates have improved protective effects.
In yet other embodiments, a prodrug is a cytochrome P450 activated
prodrug. For example, cyclic phosphates or phosphonates. In particular, nucleosides
have been modified with these molecules and provide for targeting of molecules to
the liver. Exemplary prodrugs include HepDirect prodrugs. Other embodiments of
cytochrome P450 activated prodrug improve ilability and are described in
Huttunen et al, Current Medicinal Chemistry 2008 152346.
In embodiments, any of the compounds of formula (I), Formula (II), Formula
(III) can be modified to reduce oxidation of selenium. In embodiments, compounds
can form a dimer through linkage between selenium atoms.
In embodiments, any of the compounds of a (I), Formula (II),
a (III) can be modified by linkage to a tissue ing agent or other agent
for increasing half-life of the compound. In embodiments, tissue targeting agents
include antibodies specific for binding to a tissue specific antigen, a transferrin
receptor, or a g as described herein.
In other embodiments, the compounds can be linked to or combined with a
polymeric carrier or rticle carrier to deliver compositions to the brain and to
provide for other tissue targeting. Such polymeric carriers include, but are not
limited to, polyethylene glycol, polylactides, polyglycolides, polyorthoesters,
nyl pyrrolidone, and polyvinyl alcohols. Microspheres and liposomes include
polydilactic coglycolic acid (PLGA) microspheres. Other nanoparticles include
phospholipids, chitosan, lactic acid, and dextran.
Lipid gs are also suitable for use with the compounds of the invention.
By non-limiting example, certain lipid prodrugs are described in Hostetler et al.,
(1997 Biochem. Pharm. 53:1815-1822), and Hostetler et al., 1996 Antiviral
ch 31:59—67), both of which are incorporated in their ty herein by
reference. Additional examples of suitable prodrug technology is bed in WO
90/00555; WO 96/39831; WO 03/095665A2; U.S. Pat. Nos. 5,411,947; 5,463,092;
6,312,662; 6,716,825; and U.S. hed Patent Application Nos. 2003/0229225
and 2003/0225277 each of which is incorporated in their entirety herein by
reference. Such prodrugs may also possess the ability to target the drug compound to
a particular tissue within the patient, e. g., liver, as described by Erion et al., (2004 J.
Am. Chem. Soc. 126:5154—5163; Erion et al., Am. Soc. Pharm. & Exper. Ther.
DOI:10.1124/jept.104.75903 (2004); WO 01/18013 A1; U.S. Pat. No. 6,752,981),
each of which is incorporated in their entirety herein by reference. By way of non-
limiting example, other prodrugs le for use with the compounds of the
invention are described in WO 03/090690; U.S. Pat. No. 6,903,081; U.S. Patent
Application No. 2005/0171060A1; U.S. Patent Application No. 2002/0004594A1;
and by Harris et al., (2002 Antiviral Chem & Chemo. 12: 293—3 00; Knaggs et al.,
2000 Bioorganic & Med. Chem. Letters 10: 078) each of which is
incorporated in their entirety herein by reference.
In some embodiments, a composition is provided comprising one or more
compounds each according to a (I). In some aspects, the composition
comprising one or more nds each ing to formula (I) comprises 5'—
methylselenoadenosine, or a pharmaceutically acceptable salt, hydrate, or prodrug
thereof; and 5'—selenoadenosyl homocysteine, or a pharmaceutically acceptable salt,
hydrate, or prodrug f.
In some embodiments, a composition is provided comprising one or more
compounds each according to formula (I) and formula (III). In some aspects, the
composition comprising one or more compounds each according to formula (I) and
formula (III) comprises 5'-methylselenoadenosine, or a pharmaceutically acceptable
salt, e, or prodrug thereof; enoadenosyl homocysteine, or a
pharmaceutically acceptable salt, hydrate, or prodrug thereof; and gamma-glutamylmethylseleno-cysteine
, or a pharmaceutically acceptable salt, e, or prodrug
thereof.
In some embodiments, the composition comprising one or more compounds
each according to formula (I) and formula (III) comprises 5'-methylselenoadenosine,
or a pharmaceutically acceptable salt, e, or prodrug thereof; and gamma-
glutamyl-methylseleno-cysteine, or a pharmaceutically acceptable salt, hydrate, or
g thereof.
In some embodiments, a composition is provided comprising one or more
compounds each according to formula (II) and formula (III). In some aspects, the
composition comprising one or more compounds each according to formula (II) and
formula (III) comprises 5'-selenoadenosyl homocysteine, or a pharmaceutically
able salt, hydrate, or prodrug thereof; and gamma-glutamyl-methylseleno-
cysteine, or a pharmaceutically acceptable salt, hydrate, or prodrug thereof.
According to another aspect, the t invention provides a pharmaceutical
composition, which comprises a therapeutically-effective amount of one or more
compounds of the present invention or a pharmaceutically-acceptable salt, ester or
g thereof, together with a pharmaceutically-acceptable diluent or carrier.
Pharmaceutically able carriers include : (l) sugars, such as e, glucose
and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose, and its
derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose
acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) ents, such
as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil,
safflower oil, sesame oil, olive oil, corn oil and soybean oil; (10) glycols, such as
propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol and polyethylene
; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering
agents, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid;
(16) pyrogen-free water; (17) ic saline; (18) Ringer's solution; (19) ethyl
alcohol; (20) phosphate buffer solutions; and (21) other xic compatible
substances employed in pharmaceutical formulations.
The compositions may be formulated for any route of administration, in
particular for oral, rectal, transdermal, subcutaneous, intravenous, intramuscular or
intranasal stration. The compositions may be ated in any conventional
form, for example, as tablets, capsules, caplets, solutions, suspensions, sions,
syrups, sprays, gels, suppositories, s and emulsions.
As is well known in the medical arts, s for any one subject may
depend upon many factors, including the patient's size, body surface area, age, the
particular compound to be administered, sex, time and route of administration,
general health, and interaction with other drugs being concurrently administered.
Depending on the target sought to be d by treatment, pharmaceutical
compositions may be formulated and administered systemically or locally.
Techniques for formulation and administration may be found in the latest edition of
"Remington's Pharmaceutical Sciences" (Mack Publishing Co, Easton Pa.). Suitable
routes may, for example, include oral or transmucosal stration; as well as
parenteral ry, including uscular, subcutaneous, intramedullary,
intrathecal, intraventricular, intravenous, intraperitoneal, or intranasal
administration.
Pharmaceutical compositions suitable for use in the present application
include compositions wherein the active ingredients (e. g., 5’—
Methylselenoadenosine, Se—Adenosyl-L—homocysteine, Gamma—glutamyl—
methylseleno—cysteine, a compound of a I, a compound of formula II, a
compound of Formula 111, and combinations thereof are contained in an effective
amount to achieve the intended purpose. For example, in a preferred embodiment,
an effective amount of a pharmaceutical composition ses an amount of a
compound selected from the group consisting of 5’—Methylselenoadenosine, Se—
Adenosyl-L-homocysteine, Gamma-glutamyl-methylseleno-cysteine, a compound of
formula I, a compound of a II, a compound of Formula 111, and combinations
thereof . Determination of effective amounts is well within the capability of those
skilled in the art, especially in light of the disclosure provided herein.
Selenized yeast comprising 2% or less inorganic selenium generally contains
many selenium containing components. Major selenium components of a typical
water extract of selenized yeast are selenoproteins and selenomethionine. Other
small molecular weight components with a lar weight of less than 1000
kilodaltons (“Kda “) have been identified, isolated, and ed. Some of the
components and compounds present in selenized yeast or a water extract thereof
have a less desirable bioactivity or even tory bioactivity on mitochondrial
function when isolated from such selenized yeast. Compounds such as glutamyl
selenocysteine, and sulfur containing compounds such as 5’—Methylthioadenosine,
osyl-L-homocysteine, and Gamma-glutamyl-methyl-cysteine are inactive or
in some cases inhibitory as described and shown .
Some selenium—containing compounds have also been prepared synthetically,
purified and screened in a ivity assay. tration ranges for screening
include about 15 to about 500 parts per billion. Bioactivity can be detected even at
ppb for the compositions described herein. In embodiments, the bioactivity assay
is the mitochondrial potential assay. Not all components and compounds found in
selenized yeast or a water extract thereof have biological activity when obtained
from such yeast and some inhibit d biological activity.
In embodiments, synthetically produced selenium-containing compounds are
formulated in compositions in ratios that differ from that present in the water extract.
For example, a typical water extract would have a ratio of Gamma-glutamyl-
methylseleno—cysteine to hylselenoadenosine or Se—Adenosyl—L—
homocysteine of 7 to 1. In embodiments, compositions containing tically
produced compounds may comprise an equal amount of each selenium-containing
nd, for example, a ratio of at least 1:1:1 of Gamma-glutamyl-methylseleno-
cysteine to 5’—Methylselenoadenosine to Se—Adenosyl—L—homocysteine . In other
embodiments, a composition may comprise at least two components in ratios of 5:1
to 1:1.
Compositions comprising one or more compounds including 5’—
Methylselenoadenosine, Se—Adenosyl-L—homocysteine, Gamma—glutamyl—
methylseleno—cysteine, a compound of formula (I), a compound of formula (II), a
compound of a (III), and ations thereof can be administered to a
subject (e. g., a patient) enously in a pharmaceutically acceptable carrier such
as physiological saline. Standard methods for intracellular delivery of nds
can be used (e. g., delivery via liposome). Such methods are well known to those of
ry skill in the art.
Compositions comprising selenium are useful for enous administration
as well as parenteral administration, such as intravenous, aneous,
intramuscular, and intraperitoneal. For injection, a composition comprising
selenium (e. g., a pharmaceutical composition) of the present application may be
formulated in aqueous solutions, preferably in physiologically compatible buffers
such as Hanks' solution, Ringer's solution, or physiologically buffered saline. For
tissue or ar administration, penetrants appropriate to the particular r to be
permeated are used in the formulation. Such penetrants are generally known in the
art.
Compositions comprising 5’—Methylselenoadenosine, Se—Adenosyl—L—
homocysteine, Gamma-glutamyl-methylseleno-cysteine, a compound of formula
(I), a compound of formula (II), a nd of formula (III), and combinations
thereof may be added to a nutritional drink or food (e.g., ENSURE, POWERBAR,
or the like), a multi—vitamin, nutritional products, food products, etc. for daily
consumption.
In other embodiments, compositions of the present application can be
formulated using pharmaceutically acceptable carriers well known in the art in
dosages suitable for oral administration. Such carriers enable the pharmaceutical
compositions to be formulated as tablets, pills, capsules, liquids, gels, syrups,
slurries, suspensions and the like, for oral or nasal ingestion by a patient to be
d.
In some embodiments of the present application, compositions and/or
formulations comprising selenium can be stered to a t alone, or in
combination with other forms of selenium, drugs, small molecules, or in
pharmaceutical compositions where it is mixed with excipient(s) or other
pharmaceutically acceptable carriers. In embodiments, the compositions may
include one or more amino acids or selenoamino acids, such as methionine, cysteine,
or selenocysteine in order to minimize toxicity. In one embodiment of the present
ation, the pharmaceutically able carrier is ceutically inert. In
another embodiment of the present application, compositions comprising selenium
may be administered alone to individuals subject to, at risk of, or suffering from a
disease or condition associated with mitochondrial dysfunction.
Methods of Using Compounds and Compositions
As described herein, the compounds and combinations thereof are useful to
enhance mitochondrial function, to treat mitochondrial dysfunction, to treat
Alzheimer’s disease, and to modulate glucose metabolism in a tissue—specific and
—appropriate manner.
A. Mitochondrial Function and Dysfunction
Mitochondria are the main energy-producing organelles in cells of higher
organisms. Mitochondria e direct and indirect biochemical tion of a
wide array of cellular respiratory, ive and lic processes. These include
electron transport chain (ETC) activity, which drives oxidative phosphorylation to
produce metabolic energy in the form of adenosine triphosphate (ATP), and which
also underlies a central mitochondrial role in intracellular calcium homeostasis.
In addition to their role in energy production in growing cells, mitochondria
(or, at least, mitochondrial components) participate in programmed cell death
(PCD), also known as apoptosis (See, e.g., Newmeyer et al., Cell 1994, 79:353—364;
Liu et al., Cell 1996, 86: 147—157). sis is required for normal development of
the nervous system, and for proper functioning of the immune system. Moreover,
some disease states are thought to be associated with either icient or ive
levels of apoptosis (e.g., cancer and mune diseases, and stroke damage and
neurodegeneration in Alzheimer's disease in the latter case, respectively). The role
of mitochondria in apoptosis has been documented (See, e. g., Green and Reed,
Science, 1998, 281:1309—1312; Green, Cell, 1998, 94:695—698; and Kromer, Nature
ne, 1997, 3:614—620).
Mitochondria—associated es (e. g., caused by ctional
mitochondria) may also be related to loss of mitochondrial membrane
electrochemical potential by mechanisms other than free radical oxidation, and
permeability transition may result from direct or indirect effects of mitochondrial
genes, gene products or related ream mediator molecules and/or
extramitochondrial genes, gene products or related downstream mediators, or from
other known or unknown causes. Loss of mitochondrial potential therefore may be a
critical event in the progression of diseases associated with altered mitochondrial
function, including degenerative diseases as well as diseases/conditions associated
with aging (e.g., cancer, cardiovascular disease and cardiac failure, type 2 diabetes,
Alzheimer's and Parkinson's es, fatty liver disease, cataracts, osteoporosis,
muscle wasting, sleep disorders and inflammatory diseases such as psoriasis,
arthritis and colitis).The methods as described herein are useful to enhance
mitochondrial function whether or not the cells in a subject are in a stressed or
diseased condition.
The compounds and compositions as sed herein t tissue specificity
regarding their effects on mitochondrial function.
ments include a method or use of enhancing mitochondrial function in
one or more kidney cells comprising: administering an effective amount of the
composition to the cells, the composition comprising a compound selected from the
group consisting of 5’—Methylselenoadenosine, a compound of a I, and
mixtures thereof, n the effective amount enhances mitochondrial on as
compared to cells not treated with the composition. In r embodiments, one or
more compounds can be isolated and/or purified.
In embodiments, the composition may e one or more of Se—Adenosyl—L—
homocysteine, Gamma-glutamyl-methylseleno-cysteine, glutamyl selenocysteine, a
compound of formula III, 5’-Methylthioadenosine, or S—Adenosyl—L—homocysteine .
In embodiments, the present application provides a use of a composition
comprising a compound selected from the group consisting of 5’—
Methylselenoadenosine, a compound of Formula I and mixtures thereof, n the
effective amount enhances ondrial function in a kidney cell.
In embodiments, a composition comprises a compound selected from the group
consisting of 5’—Methylselenoadenosine and/ or a compound of formula I. In
embodiments, compositions for enhancing mitochondrial function in kidney cells
may not include one or more of Se—Adenosyl—L—homocysteine,
Methylthioadenosine, or S-Adenosyl—L—homocysteine.
Embodiments of the present ation include a method or use of enhancing
mitochondrial function in one or more cells selected from the group consisting of
skeletal muscle cell, al cell, and combinations thereof, said method
comprising: administering an effective amount of the ition to the cells, the
composition comprising a nd selected from the group consisting of 5’—
Methylselenoadenosine, Se—Adenosyl—L—homocysteine,Gamma—glutamylmethylseleno
—cysteine, a compound of formula I, a compound of formula II, a
compound of Formula III, and combinations thereof, wherein the effective amount
enhances mitochondrial function as compared to cells not treated with the
composition. In further embodiments, one or more compounds can be isolated
and/or purified.
In embodiments, the present application provides a use of a composition
comprising a compound selected from the group consisting of 5’—
Methylselenoadenosine, , Se-Adenosyl—L—homocysteine,Gamma—glutamyl-
methylseleno—cysteine, a compound of formula I, a compound of formula II, a
compound of Formula III, and combinations f, wherein the effective amount
enhances ondrial function in in one or more cells selected from the group
consisting of skeletal muscle cell, neuronal cell, and combinations thereof
In embodiments, a composition ses a compound selected from the
group consisting of hylselenoadenosine, Se—Adenosyl—L—homocysteine, a
compound of formula I, a compound of Formula II, and combinations thereof. In
embodiments, compositions for enhancing mitochondrial function in muscle cells
may not include one or more of Methylthioadenosine, or S—Adenosyl—L—
homocysteine. While not meant to limit the scope of the t application,
thioadenosine or osyl-L-homocysteine exhibit toxic effects on
mitochondrial function in skeletal muscle cells.
The presence of certain sulfur-containing les in commonly used
selenium ments, such as um—enriched yeast, may, in some cases, inhibit
mitochondrial activity and lead, over time, to a pro-diabetic state. It is well
documented in the literature that adult-onset diabetes is linked to a l decline in
mitochondrial activity over a period of several years. This is particularly important
in the case of skeletal muscle which, it is estimated, uses 75—80% of daily ingested
glucose. Even modest declines (e.g. a 20% inhibition) in the ability of muscle
mitochondria to efficiently burn glucose can, over time, lead to serious health
problems. The two-fold stimulation of mitochondrial activity noted in skeletal
muscle cells in response to compound Se—Adenosyl—L—homocysteine, for example,
may represent a way to avoid or delay ondrial decline in the muscle tissue of
pre—diabetic or diabetic subjects.
In embodiments, a composition for enhancing mitochondrial function in
neuronal cells comprises a compound selected from the group consisting of 5’—
Methylselenoadenosine, Se—Adenosyl-L-homocysteine, Gamma—glutamyl—
methylseleno—cysteine, a compound of formula I, a compound of formula II, a
nd of Formula III, and combinations thereof. In further ments, one or
more compounds can be isolated and/or purified. In embodiments, compositions for
enhancing ondrial function in neuronal cells may not include one or more of
selenomethionine, or glutamylselenocysteine.
In embodiments, a composition for enhancing mitochondrial function in
neuronal cells comprises a compound selected from the group consisting of Se—
Adenosyl—L—homocysteine, and/or a compound of formula II and at least one other
selenium compound selected from the group consisting of 5’—
Methylselenoadenosine, Gamma—glutamyl—methylseleno-cysteine, a compound of
formula I, a compound of Formula III and combinations thereof.
In embodiments, a ition for enhancing mitochondrial on in
neuronal cells comprises a composition comprising a compound selected from the
group ting of 5’-Methylthioadenosine, S-Adenosyl-L-homocysteine, Gamma-
glutamyl-methyl-cysteine, and ations thereof. In embodiments, a
composition targeted to neuronal cells may contain one or more sulfur analogs that
enhance the mitochondrial activity in neuronal cells.
Other embodiments include a method or use of enhancing mitochondrial
function in one or more liver cells comprising: administering an effective amount of
the composition to the cells, the composition comprising at least three different
nds selected from the group consisting of 5’—Methylselenoadenosine, Se—
Adenosyl-L-homocysteine,Gamma-glutamyl-methylseleno-cysteine, a compound of
formula I, and a compound of formula III, wherein the ive amount enhances
mitochondrial function as compared to cells not treated with the composition. In
further embodiments, one or more nds can be ed and/or purified.
In ments, the present application provides a use of a composition
comprising at least three different compounds selected from the group consisting of
’—Methylselenoadenosine, Se—Adenosyl-L—homocysteine, Gamma—glutamyl—
methylseleno—cysteine, a compound of a I, and a compound of a III, for
enhancing mitochondrial function in liver cells.
In embodiments, a composition for enhancing mitochondrial function in one or
more liver cells comprises at least three compounds selected from the group
consisting of 5’—Methylselenoadenosine, Se—Adenosyl-L-homocysteine, Gamma—
glutamyl-methylseleno-cysteine, a compound of formula I, a compound of formula
II, a compound of Formula III, and ations thereof to enhance mitochondrial
function in liver cells. In ments, a ition may exclude one or more
compounds selected from the group consisting of 5’—Methylthioadenosine, S—
yl-L-homocysteine, yl-methyl-cysteine, and combinations thereof.
In embodiments, the enhancement of mitochondrial function ranges from an
approximately 50% increase to a 500% increase as compared to a cell of identical
type not treated with the compound. The magnitude of the response depends on the
cell type, the specific compound and the time in contact with the cell. In
embodiments, the effect on mitochondrial function is about —66% to +200% as
compared to a cell of the same type treated with one or more sulfur analogs of the
selenium compounds. In the case of some cell types, the sulfur analogs have no
measureable effect on mitochondrial ty, in others they are inhibitory and in
others still, they are stimulatory.
In ments, one or more of the compounds have a tissue specific effect
on the expression of uncoupling proteins. Uncoupling proteins (UCP) in
mitochondria (MT) are important for thermogenesis and maintenance of
mitochondrial potential or integrity. Loss ofUCP2 has been documented to cause
shorter lifespan and elevated production of reactive oxygen species (ROS) in MT
(See, e.g., Andrews et al. Am J Physiol Endocrinol Metab, 2009. 296(4): p. ;,
Andrews et al., Curr Aging Sci, 2010. 3(2): p. 102—12). However, e UCPs
uncouple electron transport in mitochondria they have the net result of lowering
ATP production from glucose in a cell. It is well known that the production of
mitochondrial ATP is critical for glucose—stimulated insulin secretion (GSIS) by
pancreatic ells. In fact, it has been shown that inhibition of one UCP in
particular, UCP2, reverses diet—induced es by positively affecting both insulin
secretion and action (De Souza et al., FASEB J, 2007, 21(4): 1153-1163.
In ments, a method or use of downregulating Ucp2 and/or Ucp3 gene
expression in a neuronal cell comprises: administering an ive amount of a
composition to the cells, the composition comprising a compound selected from the
group consisting of 5’—Methylselenoadenosine, Se—Adenosyl—L—
homocysteine,Gamma-glutamyl-methylseleno-cysteine, a compound of formulaI
compound of formula II, a compound of formula III, and combinations thereof,
wherein the effective amount downregulates expression of Ucp2 and/or Ucp3 in
neuronal cells as compared to cells not treated with the composition. In further
embodiments, one or more compounds can be isolated and/or purif1ed.
In embodiments, the present application provides a use of a composition
comprising a compound selected from the group consisting of 5’—
selenoadenosine, Se—Adenosyl-L-homocysteine, Gamma—glutamyl—
methylseleno—cysteine, a compound of formula I compound of formula II, a
compound of formula III, and combinations thereof, for downregulating Ucp2
and/or Ucp3 gene expression in a neuronal cell.
In other embodiments, a method or use of downregulating Ucp2 gene
expression in a liver cell comprises: administering an effective amount of the
composition to the cells, the composition sing at least three nds
selected from the group consisting of 5’—Methylselenoadenosine, Se—Adenosyl—L—
homocysteine,Gamma-glutamyl-methylseleno-cysteine, a compound of formulaI
compound of formula II, a nd of formula III, and ations thereof,
wherein the effective amount downregulates expression of Ucp2 in liver cells as
compared to cells not treated with the composition. In r embodiments, one or
more compounds can be isolated and/or ed.
In embodiments, the present application provides a use of a ition
comprising at least three different nds selected from the group consisting of
’—Methylselenoadenosine, Se—Adenosyl-L—homocysteine, Gamma—glutamyl—
methylseleno—cysteine, a compound of formula I, and a nd of formula III, for
downregulating Ucp2 and/or Ucp3 gene expression in a liver cell.
Methods of determining gene expression in a cell are known to those of skill in
the art and include ization with probes such as on an array or by PCR
methods. Arrays and/or primers for determining gene expression are commercially
ble. Primers can readily be designed using exemplary sequences for Ucpl,
Ucp2 and/ or Ucp3. Exemplary sequences for Ucp l are found at
NM_021833/gIl94733736, Ucp2 are found at NM_003355/gIl3259540, and for
Ucp3 are found at NM_003356/gI 215273349.
In embodiments, the effective amount of compounds and compositions as
described herein is an amount effective to enhance mitochondrial function without
being toxic to the cells. Enhancing mitochondrial function can be determined using a
number of assays on a sample taken from a subject treated in accord with the
compositions described herein. The ive amounts selected do not show toxicity
for any of the exemplified cells including kidney, mouse skeletal, human neuronal,
or mouse liver cells.
As is well known in the l arts, dosages for any one subject may depend
upon many factors, including the patient's size, body surface area, age, the particular
compound to be administered, sex, time and route of administration, l health,
and interaction with other drugs being concurrently stered.
In embodiments, the effective amount of a composition to administer to a subject
for enhancing mitochondrial function in one or more kidney, neuronal, liver, or
skeletal muscle cells is about at least 5 ug or greater or 800 ug or less per day of a
single ble biologically active selenium-containing compound or multiple
desirable biologically active selenium-containing compounds. When multiple
desirable biologically active selenium-containing compounds are present, the
effective amount of the composition is the total for all ble biologically active
selenium-containing compounds in the composition.
In embodiments, an effective amount to administer to a subject is about 5ug to
about 800 ug and every number in between, 5 ug to about 700 ug and every number
in n, 5 ug to about 600 ug and every number in between 5 ug to about 500
ug and every number in between, 5 ug to about 400 ug and every number in
between, 5 ug to about 300 ug and every number in between, 5 ug to about 200 ug
and every number in between, 5 ug to about 100 ug and every number in between,
or 5 ug to 50 ug and every number in between.
In embodiments of compositions comprising desirable biologically active
um—containing compounds as described herein, an effective amount to
administer to a subject is preferably 200 ug or less per day or 50 ug or less per day.
In embodiments, the dose may be adjusted depending on eff1cacy or whether any
overt signs of selenium sis, such as garlicky breath, hair loss, or flaky nails are
observed in the subject.
In embodiments, in compositions that comprise at least two or more nds
selected from the group consisting of 5’—Methylselenoadenosine, nosyl—L—
homocysteine,Gamma-glutamyl-methylseleno-cysteine, a compound of formula (I),
a compound of formula (II), a compound of formula (III), and combinations thereof
the compounds are present in the composition in equal tions. In other
embodiments the ratio of one ble biologically active selenium-containing
compound to another can be about 4:1 to 1:1.
In ments, the dose is administered at least once daily for a period of time
to achieve a steady state of elemental selenium in the blood. In embodiments, the
dose is administered daily for at least 60 or 90 days. In embodiments, the dose is
administered while the subject is experiencing symptoms of the disease or disorder.
In embodiments, the subject is at an age where the risk of mitochondrial related
diseases is increased, e. g. at least 40 years of age.
The methods of the present application find use in treating (e. g.,
prophylactically or therapeutically) a subject (e.g., a subject with a condition
associated with mitochondrial dysfunction). While not meant to limit the scope of
the disclosure, evidence has been presented that three synthetic organoselenium
compounds have the ability, either singly or in various ations, to significantly
increase mitochondrial activity in diverse cell types; namely, kidney cells, skeletal
muscle cells, neuronal cells and liver cells. Mechanistically, modulation of UCPs
may offer one explanation for this increase and we t evidence below that the
expression of other proteins, critical to mitochondrial function and biogenesis, may
also be favorably affected by these compounds. Regardless of mechanism of action,
r, the fact that these nds can stimulate mitochondrial activity in a
cross-tissue manner means that they may be particularly valuable in ameliorating the
onset and progress of gly diverse es; for example, Alzheimer’s disease
(AD) and Type2Diabetes (TZDM).
Compositions comprising one or more of compounds including 5’—
Methylselenoadenosine, Se—Adenosyl-L—homocysteine, Gamma—glutamyl—
methylseleno—cysteine, a nd of formula I, a compound of formula II, a
compound of Formula III, and combinations thereof can be stered to a subject
(e. g., a patient) in any number of ways as described herein.
In embodiments for delivery to skeletal muscles, the compositions as
described herein can be applied topically in the form of a gel, a patch or a cream.
In other embodiments, delivery to the brain can be targeted by using
liposomes or PLGA spheres having an antibody, transferrin or, or prodrug as a
targeting agent.
In other embodiments, delivery to the liver can be targeted by using
ed prodrugs as described herein, including HepDirect or selenoglycosides.
ingly, in some embodiments of the present application, compositions
and/or formulations comprising selenium can be administered to a subject alone, or
in combination with other forms of selenium, drugs, small molecules, or in
pharmaceutical compositions where it is mixed with excipient(s) or other
pharmaceutically acceptable carriers.
In another embodiment of the present application, compositions comprising
seleno—organic compounds described herein may be administered alone to
individuals subject to, at risk of, or suffering from a disease or condition associated
with mitochondrial dysfunction. Such es include diabetic kidney disease,
Alzheimer’s disease, and type II diabetes.
B. Alzheimer’s disease
Alzheimer’s Disease (“AD”) is the 6m leading cause of death in the United States of
America (“USA”) and is the most common form of dementia. Currently, this e is
estimated to affect 5.1 million people aged 65 and over in the USA. AD is
histopathologically characterized by two rk lesions AB plaques (See Kumar et al.,
2000) and NFTs which are ed of phosphorylated forms of the
microtubule-associated protein tau (See Dunckley et al., published online 2005 October
19, 2005, and paragraphs 155-163 of the published patent Application - 201110038889
A1). There exists abundant ce in the ture that both AB and NFTs are crucial
partners in the pathogenesis of Alzheimer's disease and that they act individually and in
concert to maximize cognitive impairment and neuronal loss in affected individuals.
Mutations in amyloid precursor protein (APP) induce AD with 100% penetration, and
familial AD associated mutations ofAPP, presenilin-l (PSEN) and presenilin-2
(PSEN-2) lead to an increased level of amyloid B tion and AB aggregation.
er, the APP-overexpressing mouse (APP-Tg) exhibits AB deposition and
memory impairment without forming NFTs or suffering al loss. Plaques are
formed when amyloid precursor protein (APP) is aberrantly processed by two enzymes
called B secretase and y-secretase, resulting in the formation of the 39 to 42 amino acid
peptide of B amyloid. The y-secretase enzyme is actually a multi-enzyme complex
which incorporates presenilin-l (PSEN) and ilin-2 (PSEN-2) as two key
components.
WO 37983
Accumulation of AB is associated with loss of memory in AD models and a
reduction in APP expression reverses this loss (See Kumar et al., Peptides 21 : 1769
2000). Therefore, reduction in APP expression (either at a gene or protein level) is
understood by practitioners as an approach to take to counter age-dependent or
neurodegenerative disorders like AD that involve memory loss.
Modulation or inhibition of PSEN, PSEN-2, Nicastrin (which controls protein
trafficking in the y-secretase complex) has been an ant goal ofAD therapeutic
research and some notable successes have been published. For example, highly specific
inhibitors that modulate PSEN activity in human neurons not only ed AB
tion but also affected the Notch signaling pathway (See Seiffert et al., J Biol.
Chem. 275:34086 2000).This was accompanied by changes in neurite morphology and
indicated that regulation of y secretase PSEN- 1 activity has clinically beneficial effects
on the neuritic pathology ofAD (See Figueroa et al., Neurobiology Dis. 9:49 2002).
Furthermore, downregulation of PSEN was shown to decrease the secretion of AB
protein (See Luo et al., Acta Pharmacol.Sin.25:l6l3 2004) and inhibition of PSEN in
SAMP8 mice was found to icantly improve memory (See Kumar et al., J.Exp.
Biol. 212:494 2009).
Thus, AB is toxic to neurons, butes to neuronal cell death and, AB levels can
be d in the brain by modulating the /activities of its precursor, APP, or the
enzyme complex(es) which process APP. A practitioner immediately understands and
appreciates that an agent capable of inhibiting APP expression and/or APP processing
into AB (e.g., B or y secretase) is a therapeutic target for AD therapy.
The selenium-containing nds and compositions as disclosed herein affect
the gene expression of genes involved in B d processing and tau
phosphorylation. In addition, such compounds and compositions t tissue
specificity regarding gene expression of genes relating to transcriptional activators.
In embodiments, a method or use for inhibiting B amyloid accumulation in one
or more neuronal cells comprises: administering an effective amount of a
composition to the one or more neuronal cells, the composition comprising a
compound selected from the group consisting of 5’-Methylselenoadenosine, a
compound of formula (I), and mixtures thereof n the effective amount
inhibits B amyloid accumulation in al cells as compared to neuronal cells
not treated with the composition.
WO 37983
In embodiments, a method or use for ting B amyloid accumulation in one
or more neuronal cells comprises: stering an effective amount of a
composition to the one or more neuronal cells, the composition comprising at least
three ent compounds selected from the group consisting of 5’—
selenoadenosine, Se—Adenosyl—L—homocysteine,Gamma—glutamylmethylseleno
—cysteine, a compound of a (I), and a compound of formula
(III), wherein the effective amount inhibits B amyloid accumulation in neuronal
cells as compared to neuronal cells not treated with the composition. In further
embodiments, one or more nds can be isolated and/or purifled.
In embodiments, the present application provides a use of a composition
comprising a compound selected from the group consisting of 5’—
Methylselenoadenosine, a compound of formula (I), or at least three different
nds selected from the group consisting of 5’—Methylselenoadenosine, Se—
Adenosyl-L-homocysteine,Gamma-glutamyl-methylseleno-cysteine, a compound of
formula (I), and a compound of formula (III)5’-Methylselenoadenosine, a
compound of Formula I and mixtures thereof, for inhibiting B amyloid accumulation
in neuronal cells.
In embodiments, a composition comprises a compound selected from the group
consisting of 5’—Methylselenoadenosine, a compound of formula (I) and mixtures
thereof to inhibit expression of Presenilin l (PSEN)and Nicastrin in neuronal cells.
In embodiments, the al cells are IMR 32 cells. IMR 32 cells are human
al cells that are a model for Alzheimer’s disease. (Neill et al., J. Neuroscience
Res. 1994 39:482) In embodiments, compositions for inhibiting gene expression in
neuronal cells may not include one or more of Se—Adenosyl—L—homocysteine, or
Methylthioadenosine.
In ments, the present application provides a use of a composition
comprising a compound selected from the group consisting of 5’—
Methylselenoadenosine, a compound of formula (I), or at least three different
compounds selected from the group consisting of 5’—Methylselenoadenosine, Se—
Adenosyl-L-homocysteine,Gamma-glutamyl-methylseleno-cysteine, a compound of
formula (I), and a compound of formula (III)5’-Methylselenoadenosine, a
compound of Formula I and mixtures thereof, for inhibiting expression of presenilin
l and rin in neuronal cells.
In embodiments, a composition ses a compound selected from the group
consisting of 5’—Methylselenoadenosine, Se—Adenosyl-L-homocysteine, Gamma—
glutamyl—methylseleno—cysteine, a nd of formula (I), a nd of
formula (II), a compound of formula (III), and combinations f to inhibit gene
sion of nicastrin and presenilin l in neuronal cells. In embodiments,
compositions for inhibiting gene expression in neuronal cells may not include one or
more of selenomethionine or glutamyl cysteine.
In embodiments, compositions include 5’—Methylselenoadenosine and/or a
nd of a (I) and at least one other selenium compound selected from
the group consisting of Se—Adenosyl-L-homocysteine, Gamma—glutamyl—
seleno—cysteine, a compound of formula (II), a compound of formula (III) and
combinations thereof In further embodiments, one or more compounds can be
isolated and/or purified.
In embodiments, a composition comprises at least three nds selected
from the group consisting of 5’—Methylselenoadenosine, Se—Adenosyl—L—
homocysteine, Gamma-glutamyl-methylseleno-cysteine, a compound of formula
(I), a compound of formula (II), a compound of formula (III), and combinations
thereof inhibit gene expression in neuronal cells.
In embodiments, a method or use for inhibiting tau phosphorylation in one or
more neuronal cells comprises: administering an effective amount of a ition
to the one or more neuronal cells, the composition comprising a compound selected
from the group consisting of 5’-Methylselenoadenosine, a compound of a (I),
and mixtures thereof, wherein the effective amount inhibits tau phosphorylation in
neuronal cells as compared to neuronal cells not treated with the composition.
In embodiments, a method or use for inhibiting tau phosphorylation in one or
more neuronal cells comprises: administering an effective amount of a composition
to the one or more neuronal cells, the composition comprising at least three
different compounds selected from the group ting of 5’—
Methylselenoadenosine, Se—Adenosyl—L—homocysteine,Gamma—glutamyl-
methylseleno—cysteine, a compound of formula (I), and a compound of formula
(III), wherein the effective amount inhibits tau phosphorylation in neuronal cells as
ed to neuronal cells not treated with the composition. In further
embodiments, one or more compounds can be isolated and/or purified.
In embodiments, the present application provides a use of a composition
comprising a compound selected from the group consisting of 5’—
Methylselenoadenosine, a compound of a (I), or at least three different
compounds selected from the group consisting of 5’—Methylselenoadenosine, Se—
Adenosyl-L-homocysteine,Gamma-glutamyl-methylseleno-cysteine, a compound of
formula (I), and a compound of formula (III)5’-Methylselenoadenosine, a
compound of Formula I and mixtures thereof, for inhibiting tau orylation in a
al cell .
In embodiments, a composition comprises a compound selected from the group
consisting of 5’—Methylselenoadenosine and/ or a compound of formula I to t
expression of Gsk3B in neuronal cells. In embodiments, compositions for inhibiting
Gsk3B gene expression in neuronal cells may not include one or more of Se—
Adenosyl-L-homocysteine, or Methylthioadenosine.
In embodiments, a composition comprises a compound selected from the group
consisting of 5’—Methylselenoadenosine, Se—Adenosyl-L-homocysteine, Gamma—
glutamyl-methylseleno-cysteine, a compound of formula I, a nd of formula
II, a compound of Formula III, and combinations thereof to inhibit to
phosphorylation of tau in neuronal cells. In embodiments, compositions for
ting phosphorylation of tau in neuronal cells may not include one or more of
methionine or other sulfur ning compounds.
In embodiments, compositions include 5’—Methylselenoadenosine and/or a
compound of formula (I) and at least one other um compound selected from
the group consisting of Se—Adenosyl—L—homocysteine Gamma—glutamyl—
methylseleno—cysteine, a compound of formula (II), a compound of formula (III) and
combinations f.
In embodiments, a composition comprises at least two compounds selected from
the group consisting of hylselenoadenosine, Gamma-glutamyl-methylseleno-
cysteine, a nd of formula I, a compound of Formula III, and ations
thereof to inhibit phosphorylation of tau in neuronal cells.
In embodiments, a composition comprises a compound selected from the group
consisting of Gamma—glutamyl-methylseleno—cysteine and/ or a compound of
formula (III) to inhibit total tau in neuronal cells. In ments, compositions for
inhibiting total tau in neuronal cells may not include one or more of Se—Adenosyl—L—
homocysteine, or Methylthioadenosine.
2014/029542
In embodiments, a method or use for inhibiting FOXO phosphorylation in one
or more al cells comprises: administering an effective amount of a
composition to the one or more neuronal cells, the composition comprising a
compound ed from the group consisting of 5’—Methylselenoadenosine, Se—
Adenosyl-L-homocysteine,Gamma-glutamyl-methylseleno-cysteine, a compound of
formula (I), a compound of formula (III), and combinations thereof, wherein the
effective amount inhibits FOXO orylation as compared to cells not treated
with the composition. In further embodiments, one or more compounds can be
isolated and/or purifled.
In embodiments, the present application provides a use of a composition
comprising a compound selected from the group consisting of 5’—
Methylselenoadenosine, Se—Adenosyl—L—homocysteine,Gamma—glutamylmethylseleno
—cysteine, a nd of formula (I), a nd of formula (III), and
combinations thereof for inhibiting FOXO orylation in neuronal cells.
In embodiments, a method or use for inhibiting FOXO phosphorylation in one or
more neuronal cells while ing FOXO phosphorylation in one or more liver
cells, comprises: administering an effective amount of a composition to the liver and
neuronal cells, the composition comprising at least three compounds ed from
the group consisting of consisting of :5’—Methylselenoadenosine, Se—Adenosyl—L—
homocysteine,Gamma-glutamyl-methylseleno-cysteine, a compound of formula (I),
a compound of formula (III), and combinations f, wherein the effective
amount decreases FOXO phosphorylation in neuronal cells and increases FOXO
phosphorylation in liver cells as compared to cells not d with the composition.
In embodiments, a composition comprises a compound selected from the group
consisting of 5’—Methylselenoadenosine, nosyl-L-homocysteine, Gamma—
glutamyl—methylseleno—cysteine, a nd of formula (I), a compound of
formula (II), a compound of formula (III), and combinations thereof to inhibit
phosphorylation of FOXO3 and/ or FOXO 4 in neuronal cells. In embodiments,
compositions for inhibiting phosphorylation of FOXO 3 and /or FOXO4 in neuronal
cells may not include methionine or selenomethionine. In embodiments,
compositions include 5’—Methylselenoadenosine and/or a compound of formula (I)
and at least one other selenium compound selected from the group consisting of Se—
Adenosyl-L-homocysteine, Gamma-glutamyl-methylseleno-cysteine, a compound of
formula (II), a compound of formula (III) and combinations thereof.
In ments, a composition comprises at least three compounds selected
from the group consisting of 5’—Methylselenoadenosine, Se—Adenosyl—L—
homocysteine, glutamyl-methylseleno-cysteine, a compound of formula
(I), a nd of formula( II), a compound of formula (III), and combinations
thereofto inhibit phosphorylation of FOXO 3 and FOXO 4 in neuronal cells.
In embodiments, a composition comprises a compound selected from the group
consisting of 5’—Methylselenoadenosine, Se—Adenosyl-L-homocysteine, Gamma—
glutamyl—methylseleno—cysteine, a compound of formula (I), a compound of
formula (II), a compound of formula (III), and combinations thereof to enhance
sion of PGCla in neuronal cells. In ments, compositions for ing
expression of PGC la in neuronal cells may not include methionine or seleno
methionine.
In embodiments, the present ation provides a use of a composition
comprising a compound selected from the group consisting of 5’—
Methylselenoadenosine, Se—Adenosyl-L—homocysteine, Gamma—glutamyl—
methylseleno—cysteine, a compound of formula (I), a compound of formula (II), a
compound of formula (III), and combinations thereof to enhance expression of
PGCla in al cells.
In embodiments, a method or use of increasing expression of PGCla in one or
more neuronal cells, comprises: administering an ive amount of a composition
to the one or more neuronal cells, the composition comprising at least three
different compounds selected from the group ting of :5’—
Methylselenoadenosine, Se—Adenosyl—L—homocysteine,Gamma—glutamylmethylseleno
—cysteine, a compound of formula (I), and a nd of formula
(III), n the effective amount increases expression PGCla as compared to
cells not treated with the composition.
In embodiments, a method or use for increasing expression of PGCla in one or
more neuronal cells and not affecting expression of PGCla in one or more liver
cells, comprises: administering an effective amount of a composition to the liver and
neuronal cells, the composition comprising at least three compounds selected from
the group consisting of consisting of hylselenoadenosine, Se—Adenosyl—L—
homocysteine,Gamma-glutamyl-methylseleno-cysteine, a compound of formula (I),
a compound of formula (III), and combinations thereof, wherein the effective
amount increases expression of PGCla in one or more neuronal cells and does not
affect expression of PGCla in one or more liver cells as compared to cells not
treated with the composition.
In embodiments, compositions comprise a compound selected from the group
consisting of hylselenoadenosine and/or a compound of formula I and at least
one other selenium compound selected from the group consisting of Se—Adenosyl—L—
homocysteine, Gamma-glutamyl-methylseleno-cysteine, a compound of a II,
a compound of Formula III and combinations thereof.
In embodiments, a composition comprises at least three compounds selected
from the group consisting of 5’—Methylselenoadenosine, nosyl—L—
homocysteine, Gamma-glutamyl-methylseleno-cysteine, a compound of formula
(I), a compound of formula (II), a compound of formula( III), and combinations
thereof to enhance expression of PGCl a in neuronal cells.
In embodiments, the enhancement of PGCla expression, decrease in FOXO
phosphorylation, decrease in PSEN, decrease in nicastrin, decrease in Gsk3b ranges
from an approximately 50% increase or decrease to a 500% increase or decrease,
respectively, as compared to a cell of identical type not treated with the compound.
The magnitude of the se depends on the cell type, the specific compound and
the time in contact with the cell.
The effects of the compounds and compositions of the present application on
the phosphorylation of FOXO 3 and FOXO 4 and on the expression of PGCla
exhibit a tissue specificity. While not meant to limit the present application, in
neuronal cells, the inhibition of orylation of FOXO3 and FOXO4 allows
FOXO to enter the nucleus and activate ription. PGCla is also a transcriptional
activator that regulates energy metabolism in the cell including gluconeogenesis.
FOXO and PGCla contribute to transcriptional activation of genes such as glucose —
6—phophatase (G6pc). An enhancement of gluconeogenesis would provide neuronal
cells with the y to generate glucose and maintain energy stores.
As discussed above, the generation of AB and orylated tau bute
significantly to the pathology of Alzheimer’s disease. The results presented herein
provide evidence that the compounds and compositions described herein affect gene
expression of presenilin l and rin. These two enzymes have been shown to be
involved in the generation of AB. In on, the inhibition of phosphorylation of
tau and/or total tau are evidence that the compounds and itions as bed
herein also affect the production of NFT. In addition, the effect of the compounds on
enhancing mitochondrial function, enhancing FOXO activation, and increasing gene
expression of PGCla provide neuronal cells with enhanced mitochondrial function
that may also work to treat Alzheimer’s by minimizing oxidative stress. Previous
studies have shown that App transgenic mice fed selenium enriched yeast but not a
normal diet or selenium deficient diet had decreased production of B amyloid
plaque. (Lovell et al., Free Rad. Biol. Med. 46:1527 2009)
Methods of ining gene expression in a cell are known to those of skill in
the art and include ization with probes such as on an array or by PCR
methods. Arrays and/or s for determining gene expression are commercially
available. Primers can readily be designed using exemplary ces for PSEN l,
PSEN2, Nicastrin and Gsk3b. Exemplary ces for PSEN l are found at
NM_000021/ 318, PSEN2 are found at NM_000447/NM_012486,
rin are found at NM_01533 land for Ucp3 are found at 093.
In embodiments, a method or use of ng mer’s disease comprises:
administering an effective amount of a composition comprising a compound
selected from the group consisting of 5’—Methylselenoadenosine, a compound of
formula (I) and combinations thereof to a subject. In embodiments, compositions
for treating Alzheimer’s disease may not include one or more Methylthioadenosine,
or osyl—L—homocysteine.
In ments, a method or use of treating mer’s disease comprises:
administering a nd selected from the group consisting of 5’—
Methylselenoadenosine, Se—Adenosyl-L-homocysteine, Gamma—glutamyl—
methylseleno—cysteine, a compound of formula (I), a compound of formula II, a
compound of Formula III, and ations thereof. In embodiments, compositions
for treating Alzheimer’s may not include methionine or selenomethionine.
In embodiments, the present application provides a use of a composition
comprising a compound selected from the group consisting of 5’—
Methylselenoadenosine, Se—Adenosyl-L-homocysteine, Gamma—glutamyl—
methylseleno—cysteine, a compound of formula (I), a compound of formula (II), a
compound of formula (III), and combinations thereof to treat Alzheimer’s disease.
In embodiments, compositions include 5’—Methylselenoadenosine and/or a
compound of formula (I) and at least one other selenium compound selected from
the group consisting of Se—Adenosyl-L-homocysteine, Gamma—glutamyl—
methylseleno—cysteine, a compound of formula (II), a compound of formula (III) and
combinations thereof. In r embodiments, one or more compounds can be
isolated and/or purified.
In embodiments, a method or use of treating Alzheimer’s disease further
comprises selecting a composition that treats the symptoms of Alzheimer’s e
without causing an adverse effect on glucose metabolism in the liver. In
embodiments, the composition comprises 5’—Methylselenoadenosine and/or a
compound of formula (I). In embodiments, the composition may exclude one or
more of Se—Adenosyl—L-homocysteine, Gamma—glutamyl-methylseleno-cysteine, a
compound of formula (II), or a compound of formula (III). In embodiments, the
composition comprises at least three compounds selected from the group consisting
of 5’—Methylselenoadenosine, nosyl-L—homocysteine, Gamma—glutamyl—
methylseleno—cysteine, a compound of formula (I), a nd of formula (II), a
compound of formula (III), and combinations f. In embodiments, the
composition es one or more of H (5’—Methylthioadenosine), I (S-Adenosyl—L—
homocysteine), or J (Gamma-glutamyl-methyl-cysteine).
In embodiments, a composition comprises at least three compounds selected
from the group consisting of 5’—Methylselenoadenosine, Se—Adenosyl—L—
homocysteine, Gamma-glutamyl-methylseleno-cysteine, a compound of formula
(I), a compound of formula (II), a compound of formula (III), and combinations
thereof for treating Alzheimer’s disease.
In embodiments, the effective amount of compounds and compositions as
described herein is an amount effective to treat Alzheimer’s disease without being
toxic to the cells. The effective amounts selected do not show toxicity for any of the
exemplified cells including kidney, mouse skeletal, human neuronal, or mouse liver
cells.
In embodiments, the effective amount of compounds and compositions as
described herein is an amount effective to ameliorate symptoms of Alzheimer’s
disease and/ or tes gene expression as described herein without being toxic to
the cells. Modulation of gene expression in al cells can be ined as
described herein using a number of assays on a sample taken from a t treated
in accord with the itions described herein.
As is well known in the medical arts, dosages for any one subject may depend
upon many factors, including the patient's size, body surface area, age, the particular
nd to be administered, sex, time and route of administration, general ,
and interaction with other drugs being concurrently administered.
In embodiments, an effective amount of a ition for treating Alzheimer’s,
inhibiting B amyloid processing and/or tau phosphorylation in neuronal cells is
about 5 ug or r or 800 ug or less per day of a single desirable biologically
active selenium-containing compound or multiple desirable biologically active
um-containing compounds. When multiple desirable biologically active
selenium-containing compounds are t, the effective amount of the
composition is the total for all compounds in the composition being administered to
a subject.
In embodiments an effective amount administered to a subject in a day is about
5ug to about 800 ug and every number in between, 5 ug to about 700 ug and every
number in between, 5 ug to about 600 ug and every number in between 5 ug to
about 500 ug and every number in between, 5 ug to about 400 ug and every number
in between, 5 ug to about 300 ug and every number in between, 5 ug to about 200
ug and every number in between, 5 ug to about 100 ug and every number in
between, and 5 ug to 50 ug and every number in between.
In embodiments, effective amounts of compositions administered to a subject
sing desirable biologically active selenium-containing compounds as
described herein, are preferably 200 ug or less per day or 50 ug or less per day. In
embodiments, the dose may be adjusted depending on eff1cacy or whether any overt
signs of selenium toxicosis, such as garlicky breath, hair loss, or flaky nails are
observed in the subject.
In embodiments, in compositions that comprise two or more compounds
selected from the group consisting of 5’—Methylselenoadenosine, Se—Adenosyl—L—
homocysteine,Gamma-glutamyl-methylseleno-cysteine, a nd of a (I),
a compound of formula (II), a compound of formula (III), and combinations thereof,
compounds are present in the composition in equal proportions. In other
embodiments the ratio of one compound to r can be about 4:1 to 1:1.
In embodiments, the dose is administered at least once daily for a period of time
to achieve a steady state of elemental selenium in the blood. In embodiments, the
dose is administered daily for at least 60 or 90 days. In embodiments, the dose is
administered while the subject is experiencing symptoms of the disease or disorder.
In embodiments, the subject is at an age where the risk of mitochondrial related
diseases is increased, e. g. at least 40 years of age.
The methods of the present ation find use in treating (e. g.,
prophylactically or therapeutically) a subject (e. g., a subject with a condition
associated with mer’s e, B amyloid processing, tau phosphorylation,
and gene expression of presenilin l, nicastrin, PGCla, and orylation of tau
and FOXO3 and FOXO 4). Compositions comprising one or more of compounds
ing 5’—Methylselenoadenosine, Se-Adenosyl-L-homocysteine, Gammaglutamyl
—methylseleno—cysteine, a compound of formula (I), a nd of
formula (II), a compound of formula (III), and combinations thereof can be
administered to a subject (e.g., a patient) intravenously in a pharmaceutically
acceptable carrier such as physiological saline. Standard methods for intracellular
delivery of compounds can be used (e.g., delivery via liposome). Such methods are
well known to those of ordinary skill in the art. Compositions comprising selenium
are useful for intravenous administration as well as parenteral stration, such
as intravenous, subcutaneous, intramuscular, and eritoneal.
In ments, a composition of the invention is formulated to cross the
blood brain barrier. The compositions of the invention can be combined with an
implant material suitable for delivery to the brain such as polymeric biodegradable
implants such as ethylene co vinyl acetate. Other types of targeting can involve
receptor mediated transport such as the insulin receptor and the transferrin receptor.
These receptors can be ated into liposomes or microspheres also including the
itions as described herein. In other ments, delivery to the brain can be
ed by using liposomes or PLGA spheres having an antibody, transferrin
receptor, or prodrug as a targeting agent.
Accordingly, in some embodiments of the present application, compositions
and/or formulations comprising selenium can be administered to a subject alone, or
in combination with other forms of selenium, drugs, small molecules, or in
pharmaceutical compositions where it is mixed with excipient(s) or other
pharmaceutically acceptable carriers. In one embodiment of the present application,
the pharmaceutically acceptable carrier is pharmaceutically inert. In another
embodiment of the present ation, compositions comprising selenium may be
administered alone to individuals subject to, at risk of, or suffering from a disease or
condition associated with B amyloid processing or tau phosphorylation.
Compositions comprising hylselenoadenosine, Se—Adenosyl—L—homocysteine,
Gamma-glutamyl-methylseleno-cysteine, a compound of formula (I), a compound
of formula (II), a nd of formula (III), and combinations thereof may be
added to a nutritional drink or food (e. g., ENSURE, POWERBAR, or the like), a
multi—vitamin, nutritional products, food products, etc. for daily consumption.
Glucose Metabolism
ulin-dependent (Type II) diabetes mellitus (DM) is a disease
characterized by insulin resistance in al muscle, liver and fat, combined with
defects in insulin ion due to pancreatic B-cell function. n resistance is a
central feature of Type II diabetes. It is known, for example, that the vast ty
of Type II diabetics are insulin-resistant. Likewise, n resistance in the
offspring of Type II diabetics is the best predictor for later development of the
disease (See, e. g., Warram et al., Ann Intern Med. 113:909 1990). Interventions that
reduce insulin resistance also prevent the development of diabetes. Optimal
mitochondrial function is required for normal glucose-stimulated insulin secretin
from pancreatic beta cells.
Skeletal muscle and liver are the two key insulin-responsive organs in the
maintenance of glucose homeostasis. The transition of these organs to an insulin-
resistant state accounts for most of the changes in glucose metabolism seen in
patients with Type II diabetes (See, e.g., Lowell and Shulman, e 21:307
2005). Of these two organs, skeletal muscle is the more important in terms of
consequences accruing from insulin resistance development. This is because
skeletal muscle has been found to e of or metabolize 80 to 90% of daily
ingested glucose (See, e.g., DeFronzo et al., 1985).
It has been documented by genome wide expression analysis that mitochondrial
oxidative phosphorylation (OXPHOS) genes exhibit reduced expression in pre—
ic and diabetic individuals when compared to healthy controls and that these
genes are, in many cases, targets of the transcriptional coactivator proliferator-
activated receptor gamma coactivator l-alpha (PGCl-(x, See, e. g., Mootha et al.,
2003). In these studies, the typical decrease in expression for OXPHOS genes was
modest (approximately 20%) but ely consistent, with 89% of the genes
d showing lower expression in individuals with either impaired e
tolerance or Type II diabetes relative to those with normal glucose tolerance.
It is generally understood and appreciated in the art that drugs or agents that
boost OXPHOS activity in muscle exist as le therapeutics for type 2 diabetes.
To bolster this hypothesis, it has long been known that aerobic se is the best
armacological intervention for treating diabetes as it increases mitochondrial
ty and number and promotes OXPHOS gene expression.
In liver, FOXO in its activated or unphosphorylated state resides in the
nucleus where it binds to the er region for glucose 6—phosphatase and,
together with other factors such as PGC—la, increases transcription of e—6—
phosphatase, thereby increasing the rate of e production. Glucose 6—
phosphatase catalyzes the last step in gluconeogenesis and glycogenolysis causing
the release of glucose from the liver. It is, therefore, important in the control of
glucose homeostasis, particularly in diabetic subjects.
Normally, the process of FOXO phosphorylation is controlled ly by
another kinase enzyme called AKT in Kinase B). AKT phosphorylates FOXO
and drives it from the s, thereby decreasing glucose production via a
decreased rate of transcription of glucose 6-phosphatase. AKT itself is under
upstream control by a mini molecular cascade reaction, which starts with insulin
binding to its receptor at the cell e. This initiates a series of events involving
two other kinase enzymes, Phosphatidylinositol 3-kinase (PI3K) and
Phosphoinositide-dependent protein kinase 1 (PDKl). The overall pathway is known
as the Insulin/PI3K/PDKl/Akt pathway and it has the job controlling glucose
homeostasis via insulin signaling. In the context of FOXO control, PDKl
phosphorylates and activates Akt which, in turn, phosphorylates and inactivates
FOXO.
In embodiments, a method or use is provided for increasing FOXO 3 and/ FOXO
4 phosphorylation in a one or more liver cells comprising administering a
composition comprising at least three compounds selected from the group
consisting of 5’—Methylselenoadenosine, Se—Adenosyl-L-homocysteine, Gamma—
glutamyl-methylseleno-cysteine, a compound of formula I, a compound of formula
II, a compound of Formula III, and combinations thereof.
In embodiments, a method of modulating e metabolism in one or more
cells selected from the group consisting of liver cells, skeletal muscle cells, and
2014/029542
combinations thereof comprises: administering an ive amount of a composition
to the one or more cells the composition comprising at least three different
compounds selected from the group consisting of 5’—Methylselenoadenosine, Se—
Adenosyl-L-homocysteine,Gamma-glutamyl-methylseleno-cysteine, a nd of
formula (I), and a compound of formula (III), wherein the effective amount alters
glucose metabolism in a liver or muscle cell as compared to cells not d with
the composition. In embodiments, the composition may exclude one or more of
H(5’-Methylthioadenosine) ), I(S-Adenosyl-L-homocysteine), and/or J (Gammaglutamyl
—methyl—cysteine).
In embodiments of the present application, a use is provided for a composition
comprising at least three different compounds selected from the group consisting of
’ —Methylselenoadenosine, nosyl—L—homocysteine,Gamma—glutamyl-
methylseleno—cysteine, a compound of formula (I), and a compound of formula (III)
for modulating glucose metabolism in a liver or muscle cell
In embodiments, a method of treating type II diabetes comprises: stering
an effective amount of a composition to a subject, the composition comprising at
least three different compounds selected from the group consisting of :5’—
Methylselenoadenosine, Se—Adenosyl—L—homocysteine,Gamma—glutamylmethylseleno
—cysteine, a compound of formula (I), and a nd of formula
(III), wherein the effective amount alters e metabolism in a liver or muscle
cell as compared to cells not treated with the composition. In embodiments, the
composition may exclude one or more of H(5’—Methylthioadenosine) ), I(S—
Adenosyl—L-homocysteine), and/or J (Gamma-glutamyl-methyl-cysteine).
In embodiments of the present application, a use is provided for a composition
comprising at least three different compounds selected from the group consisting of
’ —Methylselenoadenosine, Se—Adenosyl—L—homocysteine,Gamma—glutamyl-
methylseleno—cysteine, a compound of formula (I), and a compound of formula (III)
for treating diabetes in a subject.
In embodiments, a method or use is provided for inhibiting expression of G6pc
in one or more liver cells comprising: administering a composition sing at
least three compounds selected from the group consisting of 5’—
Methylselenoadenosine, Se—Adenosyl-L—homocysteine, glutamyl—
methylseleno—cysteine, a compound of formula I, a compound of formula II, a
nd of a III, and combinations thereof. In embodiments, the
composition may exclude one or more of H(5’—Methylthioadenosine) ), I(S—
Adenosyl—L-homocysteine), and/or J -glutamyl-methyl-cysteine).
In embodiments of the present application, a use is provided for a composition
comprising at least three ent compounds selected from the group consisting of
’ —Methylselenoadenosine, Se—Adenosyl—L—homocysteine,Gamma—glutamyl-
methylseleno—cysteine, a compound of formula (I), and a compound of formula (III)
for inhibiting glucose -6—phophatase.
In embodiments, the increase in FOXO phosphorylation, or a se in G6pc
ranges from an approximately 50% se or decrease to a 500% increase or
decrease, tively, as compared to a cell of identical type not treated with the
compound. The magnitude of the response depends on the cell type, the specific
compound and the time in contact with the cell.
um containing compounds affect gene expression in liver cells differently.
In contrast to the effect compounds and compositions have on liver cells as
described herein, the same or a similar composition can affect neuronal cells in an
opposite way. For example, a composition as described herein, decreases the
phosphorylation of FOXO3 and/or FOXO4 in neuronal cells. sion of PGCla
is increased resulting in an increase in gluconeogenesis in neuronal cells. In contrast,
the same compound or composition increases the phosphorylation of FOXO3 and/or
FOXO4 in liver cells and the expression of PGCla is not d.
As described in the context of neuronal IMR-32 cells, PGCla is a critical gene
for MT biogenesis and carbohydrate metabolism. In liver cells, it also acts in concert
with FOXO to drive the transcription of genes ed in gluconeogenesis, but
cannot do this in the nuclear absence of FOXO. We examined PGCla protein
expression, and did not observe a significant change of PGC protein level in liver
cells after the combination of CDE treatment by quantitative is. However, due
to the robust effect noted on FOXO phosphorylation in response to CDE, it is almost
n that it would be excluded from the nucleus and, hence, the level of PGCla
becomes of low importance because it requires FOXO to initiate the gluconeogenic
process. Together, these results suggest that the combination of CDE did not affect
DKl/AKT signaling and several other AKT direct or indirect ream
signaling molecules, except the above described but critical FOXOs. In other words,
the combination of CDE selectively inactivates FOXOs and this action appears to be
independent on the PI3K/PDKl/AKT signaling in the liver cells.
In embodiments, the effective amount of compounds and compositions as
described herein is an amount effective to inhibit expression of G6pc, modulate
glucose metabolism, or increase FOXO orylation in a liver cell without being
toxic to the cells. Gene expression in liver cells can be determined using a number of
assays on a sample taken from a subject treated in accord with the compositions
described herein. The effective amounts selected do not show toxicity for any of the
exemplified cells including kidney, mouse skeletal, human neuronal, or mouse liver
cells.
As is well known in the l arts, dosages for any one subject may depend
upon many factors, including the patient's size, body surface area, age, the particular
compound to be administered, sex, time and route of administration, general health,
and interaction with other drugs being concurrently administered.
In embodiments, the effective amount of a selenium-containing composition of
the invention to administer to a t to inhibit expression of G6pc, te
glucose lism, treat type II diabetes or se FOXO phosphorylation in
liver, or skeletal muscle cell is about 5 ug or greater or 800 ug or less per day of a
single desirable biologically active selenium-containing compound of the invention
or multiple desirable biologically active selenium-containing compounds of the
invention. When multiple ble biologically active selenium-containing
compounds are present, the effective amount of the composition to be administered
to a subject is the total amount for all desirable biologically active selenium-
containing compounds in the composition.
In ments an effective amount to ster to a subject of a desirable
biologically active selenium-containing compound of the invention is about 5ug to
about 800 ug and every number in between, 5 ug to about 700 ug and every number
in between, 5 ug to about 600 ug and every number in n 5 ug to about 500
ug and every number in between, 5 ug to about 400 ug and every number in
between, 5 ug to about 300 ug and every number in between, 5 ug to about 200 ug
and every number in n, 5 ug to about 100 ug and every number in between,
and 5 ug to 50 ug.
In embodiments of the invention, compositions comprising compounds as
described herein, are preferably administered at 200ug or less per day or 50 ug or
less per day. In embodiments of the invention, the dose may be adjusted depending
WO 37983
on efficacy or whether any overt signs of selenium sis, such as garlicky breath,
hair loss, or flaky nails are observed in the subject.
In ments, in compositions that comprise two or more compounds
selected from the group consisting of 5’—Methylselenoadenosine, Se—Adenosyl—L—
homocysteine,Gamma-glutamyl-methylseleno-cysteine, a compound of formula (I),
a compound of formula (II), a compound of formula (III), and combinations thereof
the compounds are present in the composition in equal proportions. In other
embodiments the ratio of one compound to another can be about 4:1 to 1:1.
In embodiments, the dose is administered at least once daily for a period of time
to achieve a steady state of elemental selenium in the blood. In embodiments, the
dose is administered daily for at least 60 or 90 days. In embodiments, the dose is
administered while the subject is encing symptoms of the disease or disorder.
In ments, the subject is at an age where the risk of mitochondrial related
diseases is increased, e. g. at least 40 years of age.
In other embodiments, delivery to the liver can be targeted by using
liposomes or PLGA spheres having an antibody, by preparing a selenoglycoside, or
a prodrug targeted to the liver.
Other Embodiments of the Present Application
In some ments, a ition is provided consisting essentially of or
consisting of a compound ing to formula (I):
or a pharmaceutically acceptable salt, hydrate, or prodrug thereof,
wherein R1 is H, acyl, alkyl, alkenyl, alkynyl, aralkyl, carboxyl, cycloalkyl, C(O)R’,
C(O)OR’, where R’ is alkyl, alkenyl, l, cycloalkyl, aryl, aralkyl, or
cyclyl; or R1 together with R2 form a heterocyclic ring having 4 to 8 ring
members with at least one heteroatom selected from oxygen or nitrogen;
R2 is H, acyl, alkyl, alkenyl, alkynyl, aralkyl, carboxyl, cycloalkyl, C(O)R’,
C(O)OR’, where R’ is selected from alkyl, lkyl, aryl, aralkyl, or heterocyclyl;
or R1 together with R2 form a heterocyclic ring having 4 to 8 ring members with at
least one atom selected from oxygen or nitrogen;
R3 is H, acyl, alkyl, alkenyl, l, aralkyl, cycloalkyl, carboxyl, or C—amido; or
R3 together with R4 and the atoms to which they are attached form a heterocyclic
ring having 4 to 8 ring members with at least one atom selected from oxygen
or nitrogen;
R4 is H, acyl, alkyl, alkenyl, alkynyl, aralkyl, lkyl, carboxyl, or C—amido; or
R3 together with R4 and the atoms to which they are attached form a cyclic
ring having 4 to 8 ring members with at least one heteroatom selected from oxygen
or nitrogen;
R5 is oxo, yl, alkyl, alkenyl, alkynyl, OR’, or is absent; where R’ is selected
from alkyl, alkenyl, l, cycloalkyl, aryl, or aralkyl;
R6 is oxo, hydroxyl, alkyl, alkenyl, alkynyl, OR’, or is absent; where R’ is selected
from alkyl, alkenyl, alkynyl, cycloalkyl, aryl, or aralkyl;
R7 is H, alkyl, alkenyl, alkynyl, ketone, amino alcohol, amino acid, OR’, Se—R’, S—
R’, where R’ is selected from H, alkyl, lkyl, aryl, aralkyl, or heterocyclyl; and
R3 is hydrogen, azido, alkyl, alkenyl, alkynyl.
In further embodiments, one or more of these compounds of Formula (I) can
be isolated and/or ed.
In some embodiments, a composition is provided consisting essentially of or
consisting of a compound according to formula (I), or a pharmaceutically acceptable
salt, hydrate, or prodrug thereof, wherein R1, R3, R4 and R8 are each H; R2 is H, acyl,
alkyl, alkenyl, alkynyl, aralkyl, carboxyl, cycloalkyl, C(O)R’, or C(O)OR’, where R’
is selected from alkyl, cycloalkyl, aryl, aralkyl, or heterocyclyl; R5 and R6 are each
absent; and R7 is alkyl, or amino acid.
In some embodiments, a composition is provided consisting essentially of or
consisting of a compound according to formula (I), or a ceutically acceptable
salt, hydrate, or prodrug thereof, wherein R1, R3, R4 and R8 are each H; R2 is H, acyl,
alkyl, alkenyl, alkynyl, aralkyl, yl, cycloalkyl, C(O)R’, C(O)OR’, where R’ is
selected from alkyl, cycloalkyl, aryl, aralkyl, or heterocyclyl; R5 and R6 are each
; and R7 is alkyl, or amino acid; with the proviso that 5'-selenoadenosyl
methionine, dehydroxy 5'—methylselenoadenosine, ethylselenoadenosine,
seleno(hydroxyl)—selenophene—(3'—deoxy—adenosine), allylselenoadenosyl
homocysteine, seleno—adenosyl homocysteine, seleno—hydroxy adenosyl
2014/029542
steine, seleno adenosine, seleno—adenosyl—Se(methyl)—selenoxide, adenosyl—
hydroxy selenoxide, ethyl selenoadenosine, seleno—(hydroxy)—selenophene—(3'—
—adenosine), adenosyl—hydroxy selnoxide, and seleno—adenosyl-Se(methyl)—
selenoxide may each be excluded from the composition.
In a specific aspect, a composition is provided consisting essentially of or
consisting of a compound, or a ceutically acceptable salt, hydrate, or g
thereof, according to a (I) that is 5'—methylselenoadenosine (“compound C”).
In some embodiments, compositions consist essentially of or consist of a
compound according to formula (I), or a pharmaceutically acceptable salt, hydrate,
or prodrug thereof, with the proviso that 5'-selenoadenosyl methionine, dehydroxy
'—methylselenoadenosine, ethylselenoadenosine, seleno(hydroxyl)—selenophene—(3'—
deoxy—adenosine), allylselenoadenosyl homocysteine, seleno—adenosyl
homocysteine, seleno—hydroxy adenosyl homocysteine, seleno adenosine, seleno—
adenosyl—Se(methyl)—selenoxide, adenosyl—hydroxy selenoxide, ethyl
selenoadenosine, seleno—(hydroxy)—selenophene—(3'—desoxy—adenosine), adenosyl—
hydroxy selnoxide, and seleno—adenosyl—Se(methyl)—selenoxide may each be
excluded from the composition.
In some embodiments, a composition is provided consisting essentially of or
consisting of a nd according to formula (II):
R\ R2
R9 N/
\ R N
/ 10
H N R8\(/ \
R / N
11 N J 0 N/
0 /Se
R5 \R6
0 O
| | (11)
R3 R4
or a ceutically acceptable salt, hydrate, or prodrug thereof,
wherein R1 is H, acyl, alkyl, l, alkynyl, aralkyl, carboxyl, cycloalkyl, C(O)R’,
C(O)OR’, where R’ is alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, or
heterocyclyl; or R1 together with R2 form a cyclic ring having 4 to 8 ring
members with at least one heteroatom selected from oxygen or nitrogen;
R2 is H, acyl, alkyl, alkenyl, alkynyl, l, carboxyl, cycloalkyl, C(O)R’,
C(O)OR’, Where R’ is selected from alkyl, cycloalkyl, aryl, aralkyl, or heterocyclyl;
or R1 together with R2 form a cyclic ring having 4 to 8 ring members with at
least one heteroatom selected from oxygen or nitrogen;
R3 is H, acyl, alkyl, alkenyl, alkynyl, aralkyl, cycloalkyl, carboxyl, or C—amido; or
R3 together with R4 and the atoms to which they are attached form a cyclic
ring having 4 to 8 ring members with at least one heteroatom selected from oxygen
or nitrogen;
R4 is H, acyl, alkyl, alkenyl, alkynyl, aralkyl, cycloalkyl, carboxyl, or C—amido; or
R3 together with R4 and the atoms to which they are attached form a heterocyclic
ring haVing 4 to 8 ring members with at least one atom selected from oxygen
or nitrogen;
R5 is oxo, hydroxyl, alkyl, alkenyl, alkynyl, OR’, or is absent; where R’ is ed
from alkyl, alkenyl, alkynyl, cycloalkyl, aryl, or aralkyl;
R6 is oxo, hydroxyl, alkyl, alkenyl, alkynyl, OR’, or is absent; where R’ is selected
from alkyl, alkenyl, alkynyl, cycloalkyl, aryl, or aralkyl;
R3 is hydrogen, azido, alkyl, alkenyl, alkynyl;
R9 is H, acyl, alkyl, alkenyl, alkynyl, aralkyl, carboxyl, cycloalkyl, C(O)R’,
C(O)OR’, where R’ is alkyl, cycloalkyl, aryl, aralkyl, or heterocyclyl; or R9 together
with R10 form a heterocyclic ring haVing 4 to 8 ring members with at least one
heteroatom selected from oxygen or nitrogen;
R10 is H, acyl, alkyl, alkenyl, alkynyl, aralkyl, carboxyl, lkyl, C(O)R’,
C(O)OR’, where R’ is selected from alkyl, cycloalkyl, aryl, aralkyl, or heterocyclyl;
or R9 together with R10 form a heterocyclic ring haVing 4 to 8 ring members with at
least one heteroatom selected from oxygen or nitrogen; and
R11 is OH, OR, alkoxy, aralkoxy, or amino, where R is selected from alkyl,
cycloalkyl, aryl, l, heterocyclyl, or a pharmaceutically acceptable salt, or inner
salt.
In further ments, one or more of these compounds of Formula (II) can
be isolated and/or purified.
In some embodiments, a composition is provided consisting essentially of or
consisting of a compound ing to formula (II), or a pharmaceutically
able salt, hydrate, or prodrug f, wherein R1, R3, R4, R3 and R9 are each
H; R2 is H, acyl, alkyl, carboxyl, C(O)R’, or C(O)OR’, where R’ is selected from
alkyl, cycloalkyl, aryl, l, or heterocyclyl; R5 and R6 are absent; R10 is H, acyl,
alkyl, alkenyl, alkynyl, aralkyl, carboxyl, lkyl, C(O)R’, C(O)OR’, where R’ is
2014/029542
selected from alkyl, cycloalkyl, aryl, aralkyl, or heterocyclyl; and R11 is OH, OR,
alkoxy, aralkoxy, or amino, where R is selected from alkyl, cycloalkyl, aryl, aralkyl,
heterocyclyl, or a pharmaceutically acceptable salt, or inner salt.
In some embodiments, a composition is provided consisting essentially of or
ting of a compound according to formula (II), or a pharmaceutically
acceptable salt, hydrate, or g thereof, wherein R1, R2, R3, R4, R5, R6, R7, R8,
R9, R10 are as defined above and wherein R11 is OH or OR, where R is selected from
methyl, ethyl, propyl, isopropyl, butyl, sec—butyl, or tert—butyl.
In a specific aspect, a composition is provided consisting essentially of or
consisting of a compound according to formula (II), or a pharmaceutically
acceptable salt, hydrate, or prodrug thereof, that is 5'—selenoadenosyl homocysteine
(compound “D”), or a pharmaceutically acceptable salt, hydrate, or prodrug thereof.
In some embodiments, compositions consist essentially of or consist of a
compound according to formula (II), or a pharmaceutically acceptable salt, hydrate,
or prodrug thereof; with the proviso that 5'-selenoadenosyl nine,
allylselenoadenosyl homocysteine, seleno—adenosyl steine, and seleno—
hydroxy adenosyl homocysteine may each be excluded from the ition.
In some embodiments, a composition is provided consisting essentially of or
consisting of a compound ing to formula (III):
R1\N H
/ N S’R7e
R2 0 I\/\R5
0 0R6
or a pharmaceutically acceptable salt, hydrate, or prodrug f, wherein
R1 is H, acyl, alkyl, l, alkynyl, aralkyl, carboxyl, cycloalkyl, C(O)R’,
C(O)OR’, where R’ is alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, or
heterocyclyl; or R1 together with R2 form a cyclic ring having 4 to 8 ring
members with at least one heteroatom selected from oxygen or nitrogen;
R2 is H, acyl, alkyl, alkenyl, alkynyl, aralkyl, carboxyl, cycloalkyl, C(O)R’,
’, where R’ is selected from alkyl, cycloalkyl, aryl, aralkyl, or heterocyclyl;
or R1 together with R2 form a heterocyclic ring having 4 to 8 ring members with at
least one heteroatom selected from oxygen or nitrogen;
WO 37983
R3 is OH, OR, alkoxy, aralkoxy, or amino, where R is selected from alkyl,
cycloalkyl, aryl, aralkyl, heterocyclyl, or a pharmaceutically able salt, or inner
salt;
R4 is H, alkyl, alkenyl, alkynyl, lkyl, aryl, aralkyl, heterocyclyl, or a
pharmaceutically acceptable salt, or inner salt;
R5 is oxo, hydroxyl, alkyl, l, alkynyl, OR’, or is absent; where R’ is selected
from alkyl, alkenyl, alkynyl, cycloalkyl, aryl, or aralkyl;
R6 is oxo, hydroxyl, alkyl, alkenyl, alkynyl, OR’, or is absent; where R’ is selected
from alkyl, alkenyl, alkynyl, lkyl, aryl, or aralkyl; and
R7 is H, alkyl, alkenyl, alkynyl, ketone, OR’, Se—R’, S-R’, where R’ is selected from
H, alkyl, cycloalkyl, aryl, aralkyl, or heterocyclyl.
In some embodiments, a composition is provided consisting essentially of or
consisting of a compound according to formula (III), or a pharmaceutically
acceptable salt, hydrate, or prodrug thereof, wherein
R1 and R2 are each H;
R3 is OH, OR, alkoxy, aralkoxy, or amino, where R is selected from alkyl,
cycloalkyl, aryl, aralkyl, heterocyclyl, or a pharmaceutically acceptable salt, or inner
salt;
R4 is H, or a pharmaceutically acceptable salt, or inner salt;
R5 and R6 are absent; and
R7 is alkyl, alkenyl or alkynyl.
In further embodiments, one or more of these compounds of a (III)
can be isolated and/or purified.
In some embodiments, a composition is provided consisting essentially of or
consisting of a nd ing to formula (III), or a pharmaceutically
acceptable salt, e, or prodrug thereof, wherein R1 and R2 are each H; R3 is OH
or OR, where R is selected from methyl, ethyl, , isopropyl, butyl, sec—butyl, or
tert-butyl; R4 is H; R5 and R6 are absent; and R7 is alkyl that is methyl, ethyl, propyl,
pyl, butyl, iso—butyl, sec—butyl, or tert—butyl.
In some embodiments, a composition is provided consisting essentially or
ting of a compound according to formula III, or a pharmaceutically acceptable
salt, hydrate, or prodrug thereof, wherein R1 and R2 are each H; R3 is OH or OR,
where R is selected from methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, or tert-
butyl; R4 is H; R5 and R6 are absent; and R7 is methyl.
In a specific aspect, a composition is provided consisting essentially of or
consisting of a compound ing to formula (III), or a pharmaceutically
acceptable salt, hydrate, or prodrug thereof, that is gamma-glutamyl-methylselenocysteine
(“compound E”), or a pharmaceutically acceptable salt, hydrate, or prodrug
thereof.
In some embodiments, a composition consisting essentially of or ting
of a compound according to formula (III), or a pharmaceutically acceptable salt,
hydrate, or g thereof, with the proviso that y-glutamoyl selenocysteine— y —
glutamoyl cysteine, y—glutamoylcysteine—2,3—DHP—selenocysteine, di—y—
oylselenocysteine, selenoglutathione-y-glutamoylcysteine,y-glutamoyl
selenocysteine—y—glutamoyl cysteine, y—glutamoylcysteine—2,3—DHP—selenocysteine,
di-y-glutamoylselenocysteine, and selenoglutathione-y-glutamoylcysteine may each
be each excluded from the composition.
In some embodiments, a composition is provided consisting essentially of or
consisting of one or more compounds according to one or more of formulas (I), (11)
and/or (III), wherein each of the following compounds is excluded from the
ition in order to minimize selenium toxicity, remove inactive or inhibitory
compounds, and/or maximize the therapeutic index of the composition, wherein the
excluded compounds are y —glutamoyl selenocysteine-y—glutamoyl cysteine, y -
glutamoylcysteine-2,3—DHP—selenocysteine, di—y moylselenocysteine,
selenoglutathione-y-glutamoylcysteine, y -glutamoyl selenocysteine-y-glutamoyl
cysteine, y—glutamoylcysteine—2,3-DHP—selenocysteine, di—y —
glutamoylselenocysteine, glutathione-y-glutamoylcysteine, oxy 5'—
methylselenoadenosine, ethylselenoadenosine, seleno(hydroxyl)—selenophene—(3'—
deoxy—adenosine), allylselenoadenosyl homocysteine, seleno—adenosyl
homocysteine, seleno—hydroxy adenosyl steine, seleno ine, —
adenosyl—Se(methyl)—selenoxide, adenosyl—hydroxy selenoxide, ethyl
selenoadenosine, seleno—(hydroxy)—selenophene—(3'—desoxy—adenosine), adenosyl—
hydroxy selenoxide, and seleno—adenosyl—Se(methyl)—selenoxide.
In embodiments, any of the compounds described herein can be modified to
prolong half-life, to protect the compound against oxidation, to target the compound
to a tissue, to allow the compound to pass the blood brain barrier as described
herein.
2014/029542
In some embodiments, a ition is provided consisting ially of or
consisting of one or more compounds each according to formula (I). In some
s, the composition comprising one or more compounds each according to
formula (I) comprises 5'-methylselenoadenosine, or a pharmaceutically acceptable
salt, hydrate, or prodrug thereof; and 5'—selenoadenosyl homocysteine, or a
pharmaceutically acceptable salt, hydrate, or prodrug thereof.
In some embodiments, a composition is provided consisting essentially of or
consisting of one or more compounds each according to formula (I) and formula
(III). In some aspects, the composition comprising one or more compounds each
according to formula (I) and formula (III) comprises 5'-methylselenoadenosine, or a
pharmaceutically acceptable salt, hydrate, or prodrug thereof; 5'—selenoadenosyl
homocysteine, or a pharmaceutically acceptable salt, hydrate, or prodrug thereof;
and gamma-glutamyl-methylseleno-cysteine, or a pharmaceutically acceptable salt,
hydrate, or prodrug thereof
In some embodiments, the composition consisting essentially of or consisting
of one or more compounds each ing to formula (I) and formula (III)
comprises hylselenoadenosine, or a pharmaceutically able salt, hydrate,
or prodrug thereof; and gamma-glutamyl-methylseleno-cysteine, or a
pharmaceutically able salt, hydrate, or prodrug thereof.
In some embodiments, a composition is provided ting essentially of or
consisting of one or more compounds each according to a (II) and formula
(III). In some aspects, the composition comprising one or more compounds each
according to formula (II) and formula (III) comprises 5'—selenoadenosyl
homocysteine, or a pharmaceutically acceptable salt, hydrate, or prodrug thereof;
and gamma-glutamyl-methylseleno-cysteine, or a pharmaceutically acceptable salt,
hydrate, or prodrug thereof
According to another aspect, the present invention provides a pharmaceutical
composition, Which ts essentially of or consists of a therapeutically-effective
amount of one or more compounds of the present invention or a pharmaceutically—
acceptable salt, ester or g thereof, together with a pharmaceutically-acceptable
diluent or carrier. Pharmaceutically able carriers include : (l) sugars, such as
lactose, glucose and sucrose; (2) starches, such as corn starch and potato starch; (3)
cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl
cellulose and ose acetate; (4) ed tragacanth; (5) malt; (6) gelatin; (7)
talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as
peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and n
oil; (10) glycols, such as propylene glycol; (l l) polyols, such as glycerin, sorbitol,
mannitol and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate;
(l3) agar; (l4) buffering agents, such as ium hydroxide and aluminum
hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic ; (18)
Ringer's solution; (19) ethyl l; (20) phosphate buffer solutions; and (21) other
non—toxic compatible nces employed in pharmaceutical formulations.
The compositions may be formulated for any route of administration as
described herein.
Example I
Synthesis and Characterization of 5’—Methylselenoadenosine (“C”)
The synthesis scheme and methodology was:
“t”IKN N>\ NH2
H “t”KN | \
CI N>
NaBH4 HO
CH3Se-SeCH3 —> CHBSeNa —> H
Place sodium dride (227mg, 6.0mM, under Ar") in a 200mL round—bottom
flask containing 20mL of anhydrous ethyl alcohol, equipped in a magnetic r
and located in an ice cooling bath. Add from a syringe dimethyldiselenide (l90uL,
376mg, 2.0mM), with cooling, stirring and under Ar flow. After discoloration of a
yellowish solution add solid 5’—chloro—5’—deoxyadenosine (1,143 g, 4.0mM). The 5—
Cl—Ade is very poorly soluble in ethyl alcohol. lOOmL more ethyl alcohol was added
to dissolve the precipitate. Stirring of the mixture at r.t. was continued for the
following four days. MS was used to r the conversion. ~75% conversion
lished after 5 days. The solvents were evaporated and the product 3.22g
(with ~ 20% of SM) was collected and purified by the reverse phase (C—8)
preparative chromatography to yield 1. lg of pure product which molecular weight
was ed by mass spectrometry.
Example 2
sis and Characterization of nosyl-L-homocysteine (“D”)
The synthesis scheme and methodology was:
NH NH
2 2
I N\
> \
K 1 $002 N\>
N N LN |:>
2. Py/ACN anh.
o N—>H40H/MeOH
HO""
-°5/1h0° RT17h 00.50111
OH 5
HO HO
1 2 3
1. 3,MeOH N/ N
0 5002411
2. HCIto pH4 K
Na0/|iq. NH3 N N
NaSe 6
ONa —>
H2411 was to RT 0
HO"-'
‘ Se
4 5 0
HO 2
’—Chloro—5’—deoxyadenosine (63 9—62)
Place 89G (0.366mole, leq.) adenosine, 59.3ML (58G, 1.833mole, 2eq.)
anhydrous pyridine and IL anhydrous acetonitrile in an oven dried, 2L, 4 neck flask,
equipped in a dropping funnel, a stirrer, gas outlet and a thermometer. The
reaction set is placed in an ice/salt bath. Initiate agitation and when the temperature
of the solution drops below 3°C start a very slow addition of l chloride (strong
exotherml). The temperature of the reaction mixture needs to be maintained below
°C during thionyl chloride addition and for 4h more (at this time the on is
yellow with white-yellow precipitate on the bottom. Then the reaction is left
overnight at ambient temperature. The next morning the voluminous itate is
filtered off using sintered glass filter and washed on the filter with three lOOML
volumes of dry acetonitrile during which the precipitate color changes into white.
The wet precipitate is then transferred back into the 2L reaction fiask, containing a
mixture of 800ML of methanol and l60ML of water into which, 80ML of
concentrated ammonium hydroxide solution is added y-drop with mechanical
WO 37983
stirring and cooling with water bath. The mixture is agitated for 45min at ambient
ature and a white precipitate that is formed is separated from the liquid by
vacuum ion. The filtrate is concentrated to dryness using vacuum rotary—
evaporator, while the precipitate is crystallized from ~560ML hot water, cooled in
an ter bath, and the first crop of the crystals is filtered off and freeze—dried.
Then this filtrate is used as a solvent in the crystallization of solids resulted from the
rotary evaporation of the first filtrate to obtain second crop of the product which is
also freeze—dried (2 days). Both crops of crystals are finally dried for two days over
phosphorous pentoxide in a vacuum dessicator. 84G of white crystals, 80.5% yield
are obtained. MS (286—M+H), mp. 187°C.
Selenoadenosylhomocysteine 0)
9.806G (50mM, leq.) of L—selenomethionine are charged into a 2L, three
neck flask equipped in a thermometer, a large cooling finger (with -meter at
the outlet), ammonia gas inlet ing bottom of the flask) and a ic ng
bar and placed in a 2.5L duar vessel containing COz-Aceton cooling bath. Ar° is
passed through the flask before adding solid C02 to acetone bath and the cooling
finger. When the temperature inside the flask drops below —35°C the flow of
anhydrous ammonia (gas) is started and when liquid ammonia level reaches the
volume of 800ML the gas flow is d. At this time small pieces of metallic
sodium are added to a well stirred solution until blue—violet coloration of the
solution persists for ~30sec. Total of 2.645G (115mM, 2.3 eq.) of sodium are added
within 45min. Agitation and cooling is maintained for 30min more. At this time all
of the components are in the solution. 14.856G (52mM, 1.04 eq.) of anhydrous 5’—
chloro—5’—deoxyadenosine are added in a single portion and the reaction mixture is
left with stirring and very slow Ar0 flow overnight. The next morning (if all of
ammonia is gone) 350ML of anhydrous methanol are added to the white solids
which are present in the flask. The flask is placed in an oil bath, a reflux condenser
is installed, Ar" gas flow is maintained and an oil bath is heated to 50°C for the
subsequent 24h. At this time lML of the solution is acidified to pH 3.5 with few
drops of 0.1N HCl and the sample is analyzed for the presence of ates using
mass spectrometry. If they are below 5% the mixture can be acidified with 1N HCl
to pH 3.5, filtered from salts, concentrated to dryness using vacuum rotary—
evaporator and the crude product can be purified by crystallization from water-
ethanol mixture. 15.98G (74% yield) of the first crop of
2014/029542
Selenoadenosylhomocysteine crystals is ~95% clean, and can be used in biological
s without further purification.
Example 3
Synthesis and Characterization of Gamma-glutamyl-methylseleno-cysteine
The synthesis scheme and methodology was:
o o \
XOWOH >|\ o o
DCC, NHS 0 o
OYNH —> 0
Et20 OYNH
>(0 Se
1 X03 'Me
0 0 'Me
Se OH
0 0 'Me CF3C02H iO N
HOWNH H
O H E O NH O
60°C, 5h Y
N H2 0
>fO 5
Synthesis of N—Boc—(O—tBu)—L—Glu—OSu 0)
N—Boc—(O—tBu)—L—Glu—OH (303mg, 1.0Mmol), N—hydroxysuccinimide
(121mg, 1.05Mmol) and dicyclohexyl carbodiimide (227mg, 1. le01) were
suspended / ved in lSmL of anhydrous ethyl ether and lOuL of
dimethylethylbenzylamine was added from a syringe into the reaction mixture.
Stirring at ambient temperature (22°C) was ined for 48h. The mixture was
d and the precipitate was washed 10 x lOmL of ethyl ether. The filtrate was
concentrated and dried under high vacuum yielding white crystalline product
(570mg, ~90% yield). MS (M+Na+) = 423.17;
Synthesis of N—Boc—(O—tBu)—L—Glu—MeSe—Cys—OH (655—90)
N—Boc—(O—tBu)—L—Glu—OSu (570mg, 0.9Mmol), methylselenocysteine
(175mg, 0.8Mmol), triethylamine (152mg, 209uL, 1.5Mmol) were added into a
mixture of 6mL of l,4-Dioxane and 2mL of water. Magnetic stirring of the reaction
WO 37983
mixture was maintained for 100h. After this time 1.21N HCl (1.65mL) were added
and the post-reaction e was extracted with3x 20mL of ethyl ether and the
extract was concentrated to dryness using vacuum rotary—evaporator yielding 649mg
of waxy product that was submitted to preparative HPLC. 283mg of the product
were collected (75.6%Yield). The mass spectrum confirmed the molecular weight of
the product and the presence of a single Se atom in it. Calcd. Ms for C18H32N207Se
=468.42; Found 469.24 m/e (M+H+) and 491.24 m/e (M+Na+).
sis of Gamma—glutamyl-methylseleno—cysteine (655—92)
A mixture of 283mg (0.6Mmol) of N—Boc—(O—tBu)—L—Glu—MeSe—Cys—OH,
2mL of thioanisol and 5mL of trifluoroacetic acid were heated with magnetic
stirring in an oil bath, for 6h and at 63°C and left over night at ambient temperature
(22°C). After this time the reaction mixture was added (drop—by—drop) into
vigorously stirred ethyl ether (20mL). The precipitate that formed was washed with
2x 20mL of ethyl ether ng 138.3mg of creamy precipitate which was then
purified by preparative HPLC.
Example 4
Three synthetic selenoorganic compounds were tested alone or in
combination in cell culture for s on mitochondrial function, cell survival and
gene expression. Cells tested ed liver cells, kidney cells, neuronal cells and
skeletal .
Materials and Methods
Cell lines and AT compounds
Human embryonic kidney HEK293T cells were generously provided by Dr.
Qiutang Li (University of Louisville). The mouse skeletal muscle myoblast C2Cl2
cell line was a gift from Dr. Xiao (University of Kentucky). Human neuroblast IMR-
32 cells and mouse liver cell line AML-l2 were sed from American Type
Culture tion (ATCC, Manassas, Virginia). All these cells were amplified in
the ATCC recommended culture media.
Compound C(5’—Methylselenoadenosine), D(Se—Adenosyl—L—homocysteine)),
and E(Gamma-glutamyl-methylseleno-cysteine)), and their sulfur analogs H(5’-
Methylthioadenosine) ), enosyl-L-homocysteine), and J (Gamma-glutamylmethyl-cysteine
) were identified as individual compounds of selenized yeast having
less than 2% inorganic selenium and were either synthesized or obtained (where
WO 37983
available) from commercial sources . The purities of all tested compounds were
verified to be 2 99%, as determined by Mass—Spectrometry.
Fluorescence analysis of mitochondrial ial in HEK293T cells
HEK293T cells were cultured in 8—chamber glass slides (1X104
cells/chamber) for 24 hours, and then treated with various concentrations of
compounds or its respective sulfur analogs (dissolved in sterilized water) for 4.5 hr.
These compound—treated cells were rinsed twice with PBS, and incubated with
Mitotracker Orange Fluorescence Dye (Invitrogen) at 37°C for 30 min, and then
replaced with fresh PBS according to the Manufacturer’s protocol. Then fluorescent
signals hondrial potential) in these living cells were recorded using a Zeiss
Axio Vert.Al fluorescence microscope (Thomwood, NY). At least three samples in
each ent group were ed under the cent microscope.
Quantitative analysis of mitochondrial potential in C2C12, IMR-32 and AML-
12 cells
For C2C12 cells, equal number of cells (1X104) were seeded on Corning 96—
well clear-bottom and dark-wall cell culture plates (VWR), cultured in 10%FBS
DMEM media for 24 hr., and then treated with vehicle (sterilized , compound
C and D and their sulfur analogs for 24 and 48 hrs. These vehicle— or nd—
treated cells were rinsed twice with PBS, incubated with Mitotracker Orange
fluorescence dye at 37°C for 30 min, and then replaced with PBS. Mitotracker
Orange fluorescence intensities (mitochondrial potential) in these living cells were
determined by a Bio-TeK Synergy HT Multi-Mode Fluorescence Microplate Reader
ski, VT). Eight samples per each treatment were examined for the above
analysis, and data are presented as mean :: sem of eight samples.
For AML-l2 liver cells, cells were amplified in 10% FBS Dulbecco's
modified Eagle's medium and Ham's F12 medium (l:l) (DMEM/F12) media
supplemented with 1X Insulin/Transferin/Selenium (ITS, Sigma). Then equal
number of cells (1X104 cells/well) were seeded on Corning 96—well clear—bottom and
dark-wall cell culture plates (VWR, Radnor, PA), cultured in ITS-free 10% FBS
DMEM/F12 media for 24 hr., and then subjected to the treatments of various
compounds or combination of compounds for 6, 24, and 48 hr. Mitochondrial
potential in living cells was determined by tative analysis of fluorescence
intensities using the Mitotracker orange dye as described above. In addition, the
above treated cells were also incubated with Hoechst 33342 dye (Invitrogen, Grand
Island, NY) to stain cell nuclei according to the Manufacturer’s protocol. The
fluorescent intensities of stained cell nuclei by t 33342 dye were also
determined by the fluorescence microplate reader. The mitochondrial potential per
cell in living cells was obtained by normalizing the fluorescence intensities of
Mitotracker orange dye to the fluorescence intensities of Hoechst 33342 dye in each
well. Eight samples per each treatment were examined for the above analysis and
data are presented as mean :: sem of eight samples.
Similar to the above studies on AML-12 cells, the ondrial potential
per cell in living IMR-32 cells was ined using the Bio-TeK Synergy HT
Multi—Mode fluorescence late reader with the following modifications. To
improve the attachment of IMR—32 cells to culture dishes, cell culture plates were
precoated with 0.1% gelatin (Sigma, St. Louis, MO). 2X104 cells per a 96—well were
seeded on gelatinized 96—well plates for the above studies. To reduce the cell
dislodgment, Mitotracker orange and Hoechst 33342 fluorescent dyes (diluted in
culture media) were directly added to each well after vehicle— or compound—
treatments. After dye incubation, cell culture media were carefully ed with 1X
PBS for the quantitation analysis of fluorescence on the microplate reader. Eight
s per each treatment were examined for the above analysis, and the
experiments were repeated at least five times. Data are presented as mean :: sem of
eight samples.
Cell ity assay
Cell viability in cultured cells was determined using Promega’s CellTiter96®
AQueous One Solution Cell Proliferation Assay kits, ing to the
Manufacturer’s protocol. In brief, equal number of C2C12 (1X104 cells/well), AML-
12 (1X104 cells/well) and IMR—32 (2X104 cells/well) were seeded on 96—well clear
plates (VWR) and treated with vehicle or compounds for 24, 28 and/or 72 hr. Then,
cultured cells were incubated with s One solution (100 ul/per well) at 37° C
for 1 hr, and the absorbance of OD490 nm in each sample was determined by the
Bio—Tek microplate reader. Cell ity in culture cells were determined by the
subtraction of OD490 nm in cultured cells with the OD490 nm in plain culture
media (without g of . Eight samples per each treatment were examined
for the above analysis. Data are presented as Mean :: sem of eight samples.
RNA isolation and Real-time PCR analysis
Human IMR—32 cells were seeded on gelatinized 6—well (6.5 X 105
cells/well) or 24—well (1.3 X 105 cells/well) plates, while mouse liver AML-l2 cells
were ed on uncoated 6—well (3.33 X 105 cells/well) or 24—well (6.7 X104
cells/well) plates. Cells were treated with vehicle (control) or various compounds
for 6, 24 or 48 hr. Total RNA from these cells was using Trizol (Invitrogen)
according to the cturer’s protocol, and then incubated with DNase I to
remove any potential contaminated genomic DNA. Then RNA samples were
subjected to ime PCR analysis using the Applied-Bioscience’s RT kit and
igned Taqman probes (Invitrogen), as described previously (Lan et al EMBO
J 2003). Three to six samples were analyzed in each treatment group. Data were
normalized by Actin B (Actb) or Glyceraldehyde Phosphate Dehydrogenase
(Gapdh) levels in each sample, and are presented as mean :: sem of 3—6 samples.
Protein preparation and Western blot analysis
IMR—32 and AML12 cells were seeded on 6-well plates, and then d
with vehicle and various compounds for 6 and 24 hr, as described above. After
treatments, cells were rinsed with ice-cold PBS, and lysed in the ice-cold RIPA
buffer containing te proteinase and phosphotase tors (Themo-Fisher
Scientific, Waltham, MA) on ice for 30 min. Cell lysates were collected using a cell
scraper and transfer pipette, and then centrifuged at 12000 g for 30 min at 4°C to
remove the DNA pellet and obtain the protein extract. Protein levels in the
supernatant of these cell lysates were determined using the Pierce Micro-BCA
protein assay kit (Themo Scientific-Piece Biotechnology, Rockford, IL) according to
the manufacturer’s protocol.
For Western blot analysis, five micrograms of total proteins from e-
and compound(s)—treated cells were subjected to SDS—PAGE gel separation, and
then transferred to PVDF membranes, as described usly (Reddy, Liu et al.
2008 e). Membranes were blocked in a phosphate-buffered saline (PBS)
containing 5% (w/v) of bovine serum albumin (Sigma, St. Louis, MO), and
incubated with specific primary antibodies followed by the incubation with HRP -
conjugated anti—mouse or anti—rabbit secondary antibodies 0 on, Cell
ing Inc.). All primary antibodies except G6PC (Santa Cruz), Actb (Li—COR ,
Lincoln, Nebraska), Elf2b8 and pElf2b8 (Abcam, Cambridge, MA) were purchased
from Cell Signaling Inc. Positive signals on the membrane blots were detected using
the Amersham’s enhanced chemiluminescence Western Blotting Prime Detection
reagents (GE healthcare Lifescience, urgh, PA). Images of these luminescence
signals on the membrane blots were captured using the LI—COR y Fc Image
system (Lincoln, ka). The same membrane blot was striped and re—blotted
with another antibody as described in the GE WB ECL—prime—detection protocol
(GE healthcare Lifescience, Pittsburgh, PA). n band densities in the Western
blots were determined using the Li—COR Image studio software or NIH ImageJ
software, and then normalized by Actb level in each sample. Data are presented as
mean :: sem of three samples per each group.
Statistical analysis
If applicable, a t’s t-test was performed to determine the statistical
difference between two groups. P value less than 0.05 was considered significant.
s and Discussion: Mitochondrial Function
To test if compound C or D can enhance the mitochondrial (“MT”) potential
in cultured human kidney cells, HEK293T cells were d with 37.5 and 75 ppb
of compound C or D. These amounts were based on work with the se assay
where the effective dose was found to be 100—150ppb. Compound C as well as its
sulfur analog H were ted with HEK293T cells for 4.5 hour (hr), and subjected
to fluorescent analysis under the microscope. As shown in Fig. 1, compound C at the
lower dose (37.5 ppb) enhanced MT ial while there were less effects on MT
potential in kidney cells treated with a higher dose (75 ppb) of compound C for 4.5
hr. In contrast, compound D at all tested doses did not affect MT potential (Figure
Our results clearly demonstrate that compound C enhanced MT potential in
kidney cells while compound D was ineffective. Considering that um is
present in both compound C and D and that their sulfur analogs, H and J,
respectively, proved incapable of stimulating mitochondrial activity, one must
conclude that the stimulatory effect of compound C in kidney cells is due to a
combined effect of um and the molecular structure surrounding selenium in
this organoselenium compound. The stimulatory activity is not due to a selenium
effect alone.
The importance of being able to increase mitochondrial ty in kidney
cells may have very significant health benefits, especially in diabetic subjects. Very
recent research (Sharma et al., I AM Soc Nephrol, 2013: 1901—12) concluded from a
metabolomic analysis of urine from a diabetic population that diabetic kidney
disease is clearly linked to a decrease in mitochondrial on. Diabetic kidney
e (DKD) is the leading cause of end-stage renal disease and the authors
concluded that therapeutic approaches that restore or increase mitochondrial
function could ameliorate or even arrest DKD. Of added interest is the fact that the
authors link mitochondrial dysfunction in these cases to a decrease in the expression
of a riptional co-activator called PGCla. As discussed later, PGCla is a target
of the synthetic um compounds described in this application.
Mitochondrial potential enhanced by compound C and D in mouse C2C12 cells
To test whether compound C and D affect MT potential in skeletal muscle
cells, C2C12 cells were treated with vehicle (water, control) or various
concentrations of selenium and sulfur compounds, and then subjected to quantitative
analysis of MT potentials.. As shown in Figure 2, MT potential was decreased in
C2C12 cells after treatment with sulfur analogs for 24 hr (when compared to
control), indicating that sulfur compounds displayed some MT toxicity in skeletal
muscle cells. In st, selenium compounds C and D significantly ed MT
potential (Fig 2).
Two aspects of this result are particularly surprising and unanticipated.
Firstly, compound D, while inactive in kidney cells was highly effective in
stimulating ondrial activity in muscle cells (some two—fold over control levels
at its most effective dose). Moreover, at lower doses (37.5 and 75 ppb, Fig. 2), it
proved more potent than compound C which (as shown above) was the only
effective tested compound in kidney cells.
Secondly, the sulfur analogs of C and D, rather than just having no effect,
ve to e-treated control cells, were inhibitory to mitochondrial activity
(reducing it by 2/3 in some . This effect has not been reported in the past but
may help explain why some s using selenium enriched yeast preparations have
ed pro—diabetic effects in subjects receiving these supplements. While
selenium replaces sulfur in what are normally sulfur-containing molecules in yeast
during the selenium enrichment process, there will always be a preponderance of
sulfur-containing molecules in the final ation (sulfur is a macro element and is
impossible to remove completely from any growth or fermentation process). Thus,
the presence of certain sulfur-containing molecules in um-enriched yeast may,
in some cases, inhibit mitochondrial activity and lead, over time, to a pro-diabetic
state. It is well documented in the literature that adult-onset diabetes is linked to a
l decline in mitochondrial activity over a period of several years. This is
particularly important in the case of skeletal muscle which, it is estimated, uses 75—
80% of daily ingested glucose. Even modest es in the y of muscle
mitochondria to efficiently utilize glucose can, over time, lead to serious health
problems. The two-fold stimulation of mitochondrial activity noted in C2C12
muscle cells in response to compound D, for example, may ent a way to avoid
or delay mitochondrial decline in the muscle tissue of abetic or diabetic
To investigate whether the observed increase of MT potential by compound
C and D is simply caused by an increase in viable cell number, we performed a cell
viability assay. It was found that compound C and D did not affect cell viability in
C2C12 cells after treatments with these nds at the same doses for 24 hr and
48 hr (data not shown). Together, our results suggest that compound C and D did not
have a negative effect on cell survival, but can transiently enhance MT potential in
C2C12 cells.
MT potential transiently enhanced by compound C, D, and E in IMR-32 cells
To investigate whether selenium compounds can regulate MT function in
al cells, human IMR32 cells were treated with various compounds for 6, 24
and 48 hr, and then subjected to mitochondrial potential assays. As shown in Fig 3
(top panel), treatment of compound D or E or a combination of both for 6 hr
icantly enhanced MT potential when ed to control normal cells (with
water vehicle treatment) while a trend towards elevated MT potential was also
observed in compound C—treated IMR—32 cells. Increased MT potential was also
observed in cells treated with compound H or I and J (when compared to control,
Figure 3 top panel). However, the enhanced MT potential was more pronounced in
cells treated with compound D or E or a DB combination than their respective sulfur
analog(s) (Figure 3 top panel).
At 24 hr after compound treatment, a significant increase in MT potential
was ed in all selenium nd—treated cells (when compared to control). In
general, enhanced MT potential was more pronounced in cells treated with selenium
compound C, D, E or a combination of CDE than their sulfur analogs H, I, J, or a
combination of HIJ. It should be noted that in one instance at the 24 hr time point
the combination of I and J elicited the highest mitochondrial se. However at
48 hr, there was no significant change in MT potential among all tested groups.
Together, these results suggest that selenium compound C, D, E or a combination of
these compounds can transiently enhance the MT ial in IMR-32 cells, and the
effects of these selenium nds are more evident than their sulfur analogs.
Once again, there is a marked pecific and compound—specific response
evident in this experiment which underscores the differential response of cell types
to these specific selenium compounds and their combinations. Moreover, instead of
being inhibitory to mitochondrial activity as in the case of muscle cells, sulfur
compounds stimulated mitochondrial activity in IMR-32 cells — albeit to a generally
lesser extent that selenium compounds. The transient or al effect noted in this
case indicates that these compounds or their combinations would have to be
repeatedly administered to a treated subject in order to in an effect on
ondrial activity; in essence, a daily dose might be required.
MT potential elevated by repeated D or E treatments in IMR-32 cells for a total
of 48 hrs.
The above observed transient effects of compound C, D and E on MT
potential prompted us to test whether repeated treatments can enhance the MT
potential. Thus, IMR-32 cells were first treated with compound C, D or E for 24 hr,
and then re-treated with freshly prepared compound C, D or E for another 24 hr. As
a negative control, IMR—32 cells were treated only once with compound C, D, or E
for 48 hr. Then, MT potential assays were performed on these cells. As anticipated,
prolonged single treatments of compound C, D, or E for 48 hr (continuous 48 hr
single ent) did not affect MT potential in IMR-32 (Figure 4 top panel).
However, repeated treatments of compound D (at both 15 and 150 ppb) or E (at the
dose of 150 ppb) icantly enhanced MT potential (when compared to control or
the sulfur analogs I or J).
No toxic effects of nd C, D, E on the cell survival of IMR—32 cells
To test whether there is any toxic effect of selenium compounds on the
survival of IMR-32 cells, cell viability assays were performed on cells after
ent with various compounds for 24, 48 and 72 hr. As shown in Figure 5,
treatment of all compounds for the tested time points did not cause a significant
decrease of viable cells in IMR-32. In fact, there was a small but significant increase
of cell viability in cells after selenium compound ents for 48 and 72 hr (Fig. 5
middle and bottom ). These data suggest that selenium compounds did not
have a toxic effect on the survival of IMR-32 cells, but instead, had a small but
significant beneficial effect on neuronal cell survival. It should be noted, however,
that any observed increases in cell viability in this experiment are too slight to
account for the increases in MT potential observed in the IMR—32 cell line in
response to certain selenium compounds or their analogs.
Experimental data to demonstrate the y of selected synthetic selenium
compounds to se or decrease mitochondrial activity on isolated
mitochondrial from rat .
A water soluble t was obtained from selenized yeast. The water—soluble
extract accounts for up to 25% of the total selenium present in the preparation. We
reasoned that these selenium species would be the first to be ted/digested from
selenized yeast in its passage h the intestinal tract. Following identification of
the selenium containing compounds in the extract by mass spectroscopy, we
synthesized a number of selenium ning compounds and peptides, Accordingly,
this round of synthesis and purification resulted in a panel of nine (9) selenium-
ning species for further testing. Given the small quantities of the materials thus
generated (low milligram quantities) it was deemed impractical to conduct feeding
studies in live animals. Because we were ily interested in the potential s
of these selenium species on mitochondrial bioenergetics, it was decided to test these
selenium molecules directly using mitochondria.
Selenium concentration ranges low (50ppb), mid (500 ppb) and high (lppm)
were initially tested as a possible range for the compounds. Based on no observable
toxicity against mitochondria in the nge, we selected 500ppb (5uM)
concentration for performing our compound screens using mitochondrial
bioenergetics as the primary outcome measure. Adult rat brain ficoll purified
mitochondria were incubated with the 9 nds for 30 min at 37°C prior to
being loading into the Seahorse Biosciences flux analyzer in triplicate. We measured
OCR (Oxygen Consumption Rates) ters in three respiratory states including
ATP synthesis (State 111), Complex 1 dependent (NADH-driven) Maximum
Respiratory Capacity (State V FCCP) and Complex II (FADH-driven) dependent
Maximum Respiratory Capacity (State Vsucc).
The results show that ent selenium compounds derived from the water
t had differential activity in being able to increase mitochondrial potential.
Compound 5 :Valine—Selenomethionine-Arginine
Compound 6:Leucine—Valine—Selenomethionine—Arginine
Compound 7 :Leucine—Threonine—Glycine—Selenomethionine—Alanine—
Phenylalanine-Arginine
Compound 8 : Selenoglutathione dimer
Compound 9:MethylSelenoadenosine
Compound l0:Glutamylselenocysteine
Compound 25: Total water extract of yeast at pH 6.0
Compound 28:Glutathione oxidized
Compound 3 0:Glutamylcysteine
Table 1
um compounds effects on mitochondrial bioenergetics (rat brain
purified mito 5uglwell)
STATE % STATE % STATE %
Ill change V change Vsucc change
CTRL 432.6 182.1 350.1
R\\§ 445.9 3.0 187.8 3.2 292.5 -16.4
#6 477.5 10.3 220.6 21.2 376.4 7.6
372.5 —14.0 147.1 —19.2 288.0 —17.7
424.0 —2.1 192.3 5.7 371.0 6.0
#9 507.8 17.3 210.3 15.6 437.1 24.9
§\§‘ 352.1 —18.7 112.7 —38.1 254.4 —27.3
419.0 —3.2 136.2 —25.2 309.3 -11.6
§\\\ 451.6 4.3 149.6 -17.8 319.3 —8.8
s \\\ 423.2 —2.3 153.8 —15.5 305.4 —12.7
“05‘
\. \x
In ular, compounds 6 and 9 increased mitochondrial potential while
compounds 7, 10, and 25 inhibited mitochondrial potential. These results show that
compounds derived for a water t of zed yeast have very different effects
on mitochondrial potential and led us to isolate, screen, and synthesize candidate
compounds with a view to selecting only those which elicit positive ses on
biological processes.
Experimental data to demonstrate the ability of synthetic selenium compounds
to restore stressed mitochondria to normal activity in isolated mitochondrial
from rat brains.
The following e describes an experiment performed in the SeaHorse
al flux analyzer; an instrument for measuring the respiration rate of
mitochondria expressed as the oxygen consumption rate, or OCR. The experiment in
question used mitochondria from the brain cortex of normal rats, ined on
normal laboratory chow which had not been fortified with any additional selenium
sources. Figure 6 shows the respiration chart of normal mitochondria (top line) with
the final OCR being the measured distance between the end of the graph line and the
X—axis.
An identical sample of the same mitochondrial preparation was treated in
exactly the same manner as the control sample except that calcium (10 micromolar
final concentration) was added to stress or damage the mitochondria by depolarizing
them. As shown m line) the OCR dropped from a value of 1,677 to 1,066
pMoles/min 02.
Again, identical samples of rat brain cortex mitochondria were incubated as
above except that they contained calcium (lOuM) and 150 ppb of compounds D and
E, respectively. C was not tested. It is evident that the OCR of the compound—
treated, calcium-stressed mitochondria were restored to near control levels, i.e. 1,564
pMoles/min 02 in the case of compound D and 1,531 pMoles/min 02 in the case of
compound E.
Based on this result and those of repeat experiments using rat brain
mitochondria, we de that the synthetic selenium compounds not alone have
the y to increase the mitochondrial activity of normal ondria (see
examples using ssed cells of various types) but can also e the respiratory
capacity of stressed or damaged mitochondria.
MT ial enhanced by the combination of C, D, and E, but not by
individual nds in mouse liver AML-12 cells
To investigate whether selenium nds can regulate MT function in
liver cells, mouse AML—l2 cells were treated with various compounds for 6 and 24
hr, and then subjected to mitochondrial potential assays. As shown in Fig 7,
separate treatments with compounds C, D, or E at 150 ppb or their respective sulfur
analogs at the same concentration did not significantly affect MT potential when
compared to control normal cells (with water vehicle treatment). However, the
combination of C, D and E caused a highly significant increase of MT potential
when compared to both vehicle— or HIJ-treated groups (Figure 7). Thus, in liver
cells, a specific combination of compounds C, D and E is required to elicit an
increase in MT ial while the individual compounds and their sulfur analogs
have no effect. This effect is totally different from that observed in neuronal cells
and has never been documented before in the literature.
UCP2 expression is downregulated by the combination of compound C, D and
E in AML-12 cells
One candidate family of genes which have the ability to increase or
decrease ondrial activity are the so-called Uncoupling Protein Genes or
UCPs. The elevated MT potential observed in response to treatment with the CDE
combination led us to test r there is differential regulation of these genes in
vehicle-, HIJ- and CDE-treated AML-12 cells. In normal AML-12 cells, Ucp2
mRNA sion levels were four hundred sixteen—fold higher than Ucpl, while
Ucp3 mRNA was undetected by real—time RT—PCR (Fig. 8A, Ucp3 data not shown).
Treatment of AML-12 cells with CDE nds did not affect Ucpl expression
(Fig. 8B). However, there was a icant se of Ucp2 mRNA expression in
AML-12 cells after treatment with CDE but not HIJ (Fig. 8C). As Ucp2 can inhibit
MT potential, reduced Ucp2 sion may be at least a partial cause of the
ed MT potential elicited by CDE compounds in AML—l2 cells. Since obese
patients generally have high levels of Ucp2 in the liver, d Ucp2 expression by
CDE indicates that CDE compounds may be beneficial for the treatment of obesity.
No toxic effects of CDE compounds on the survival of AML-12 cells
To test whether there is any toxic effect of selenium compounds on the
survival of AML-12 cells, cell viability assays were performed on cells after
treatment with various nds for 48 hr. We found that no treatment (both
single compounds and their combinations) caused a significant decrease of cell
viability in AML—12 cells e 9) which confirms that selenium compounds did
not have the toxic effect on the survival of AML-12 cells.
Downregulation of UCP2/3 by the combination of compounds C, D and E in
IMR-32 cells
As mentioned earlier, UCPs such as Ucpl, 2 and 3 are critical genes for the
regulation of MT potential. The elevated MT potential observed in IMR-32 cells in
response to CDE (Fig. 3 top two panels) ed us to test whether there is
differential expression of these three genes in response to the combination treatment.
It was found that Ucpl mRNA was undetectable in normal IMR-32 cells by real-
time RT-PCR analysis (data not shown). Treatment of IMR-32 cells with CDE
compounds but not HIJ for 6 hour caused a icant decrease of both Ucp2 and
Ucp3 expression (Fig. lOA-B). At 24 hr. treatment, Ucp2 expression was
icantly decreased in both HIJ- and CDE-treated groups (Fig. 10A), while a
significant decrease of Ucp3 expression was also observed in CDE—treated IMR—32
cells (Fig. 10B). These results suggest that the downregulation of Ucp2/3 may be at
least one reason for the enhanced MT potential observed in IMR—32 cells in response
to CDE nds.
Discussion
Thus, we have presented evidence that three tic organoselenium
compounds have the ability, either singly or in various combinations, to significantly
increase mitochondrial activity in diverse cell types; namely, kidney cells, skeletal
muscle cells, neuronal cells and liver cells. Mechanistically, we note that modulation
of UCPs may offer one explanation for this increase and present evidence below that
the expression of other proteins, critical to mitochondrial function and biogenesis,
may also be favorably affected by these compounds. Regardless of mechanism of
action, r, the fact that these compounds can stimulate mitochondrial activity
in a cross-tissue manner means that they may be particularly valuable in
ameliorating the onset and progress of seemingly diverse diseases; for example,
Alzheimer’s e (AD) and Type2Diabetes (T2DM).
In the case of Alzheimer’s disease, there has been a rapid growth in the
literature supporting the idea that AD originates from ed e import,
defective energy metabolism, ondrial dysfunction, chronic oxidative stress
and DNA damage in the brain (reviewed by de la Monte and Wands, 2008). For
example, many s have concluded that insulin deficiency and insulin resistance
can mediate many of the effects noted in AD-degeneration. Furthermore, it has been
found that T2DM causes brain insulin ance, oxidative stress and cognitive
impairment. Extensive disturbances in brain insulin and Insulin-like Growth Factor
signaling mechanisms can account for a number of the molecular,
biochemical and histopathological effects seen in AD.
A nown tic, published by the Alzheimer’s Association of
America, states that some 80% of AD sufferers also have T2DM. These, and other
reasons, have led to many researchers using the term “Type-3 Diabetes” to reflect
the fact that AD represents a form of diabetes that selectively involves the brain and
has molecular and biochemical features that overlap with both Typel and Type 2
diabetes.
The link between AD and Type—2 diabetes is becoming very solid in the
scientific literature but what is the link n these diseases and mitochondrial
dysfunction? It is that T2DM, which combines defects in insulin ion by the
pancreas and insulin resistance in peripheral tissues, most notably liver and skeletal
muscle, is caused by a modest and gradual loss of mitochondrial respiratory function
over a prolonged period (Lowell and Shulman, 2005). Any agent, therefore, which
can increase mitochondrial function in diverse tissues may be extremely valuable as
an intervention for conditions tracing their origins to mitochondrial decline.
s and Discussion of Alzheimer’s Disease pathogenesis
Downregulation of PSEN by the ation of compounds C, D and E in
IMR-32 cells
IMR—32 cells have been reported to be an appropriate in vitro model
system for the study of the pathogenesis of Alzheimer’s disease (AD). (Neill et al., J.
cience Res. 1994 39:482). One of the key pathological features of AD are
Amyloid Plaques which occur between neurons and which contribute to brain
atrophy and cell death. The mechanisms ed in the production of amyloid
plaques are complicated but chiefly rely on the action of an enzyme called beta-
secretase (BACE) which acts in concert with a multi-enzyme complex called
gamma-secretase. Together, in AD, these enzymes act to aberrantly process a brain
protein called amyloid precursor protein (APP). The resulting product is an
abnormal d beta peptide which clumps together to form plaques.
As , the gamma-secretase enzyme is ly a multimeric complex
composed of four known members: Presenilin-l (PSENl or PSEN), Nicastrin, APH—
rior Pharynx Defective l) and PEN2 (Presenilin Enhancer 2). The other
paralog of PSEN is ilin2 or PSEN2. While all four components are important
for the correct functioning of gamma-secretase, two components in particular have
become the focus for pipeline therapeutic drugs. These are Presenilinl and Nicastrin.
This is because ilin l is the actual catalytic component of the gamma-
2014/029542
ase — the component that physically cleaves the amyloid precursor protein.
Furthermore the gene for Presenilin 1 is the most frequently mutated gene in familial
AD. ve to PSEN2, PSENl is much more nt and is functionally better
defined. Nicastrin is of st, not because it is catalytic but because it binds to and
orients APP so that Presenilin can cleave it. PSEN 1 and Nicastrin are, therefore,
the targets of greatest interest for gamma-secretase-focused AD interventions.
It should also be noted that AD is thought by several research groups to
have its origins in a gradual e in mitochondrial function, as a person ages. In
this regard, it is also of interest to note that one of the first physiological s
measureable in the AD e s is a defective uptake and utilization of
glucose by brain cells; clearly, both these phenomena may be linked. Accordingly,
we examined the expression of the genes encoding the PSENs in IMR32 cells
treated with a combination of compounds C, D, and E (CDE), alongside a
combination of their sulfur analogs (HIJ).
We found that the expression of PSEN was almost eight-fold higher than
PSEN2 in normal IMR32 cells (Fig. 10C). More importantly, PSENl expression
was significantly decreased in CDE-treated cells when compared to control or HIJ
group (Fig. 10D). In contrast, there was no obvious change in PSEN2 expression
among control, HIJ and CDE groups (Fig. 10E). These results suggest that selenium
compounds can selectively down—regulate PSEN but not PSEN2 expression in IMR—
32 cells and there may exist a lead substance among CDE compounds against
amyloid plaque formation.
Compound C, a lead compound for preventing the cleavage of APP for plaque
formation in AD by targeting the gamma-secretase complex genes PSEN and
Nicastrin in IMR-32 cells
As shown above (Fig. 10D), nd CDE mixtures inhibited PSEN
expression, indicating that there exists a biological lead among these three
compounds against gamma-secretase components for the production of amyloid beta
peptide. That study was limited to PSEN expression but, because gamma secretase is
a enzyme x, another important component protein, Nicastrin, was
included in this particular example. In order to fy the lead compound, IMR-32
cells were treated with individual compounds and subjected to Western blot and RT—
PCR analyses.
As shown in Figure llA, PSEN and Nicastrin, but not PEN2 and beta-
secretase BACE proteins were attenuated in IMR-32 cells after 24 hr of treatment by
compound C. Quantitative analysis showed that there was a significant reduction of
both PSEN and Nicastrin n levels only by C, while the D and E compounds
also elicited a trend towards reduced Nicastrin n expression (Fig. llB-C).
Consistent with attenuated PSEN expression, PSEN mRNA expression was
significantly reduced by compound C not only at 6 hr but also at 24 hr. of treatment
(Fig. 11 D—E). Similarly, compound C treatment also caused a trend s reduced
rin mRNA expression in IMR-32 cells after 6 hr. treatment, (Fig. 11F), and,
more importantly, a significant decrease in Nicastrin mRNA expression in IMR-32
cells after 24 hr treatment (Fig. 11G). In st, compounds D and E ents
did not inhibit, but instead stimulated PSEN and Nicastrin mRNA expression in
IMR-32 cells (Fig. 11E and 11G).
Together, our data suggested that nd C can inhibit both PSEN and
Nicastrin expression at both mRNA and protein levels. These results suggest that
compound C is an anti-AD compound of the three candidates and achieves this by
targeting gamma-secretase complex ents, more specifically PSEN and
Nicastrin, which are known to be responsible for plaque formation in AD.
Compound C, a cell-specific GSK3b gulator against the
hyperphosphorylation of Tau protein in IMR-32 cells
The second main pathology, besides amyloid plaques, in AD is called the
Neurofibrillary tangle, NFT or tangle for short. It has been well characterized that
tangle formation in AD is caused by hyperphosphorylation of a protein called Tau
and that this phosphorylation is caused by kinase enzymes such as DYRKlA (Dual
specificity tyrosine-phosphorylation-regulated kinase 1A) and mainly Gsk3b
(Glycogen synthase kinase 3 beta). To explore whether the selenium compounds C,
D or E can potentially contribute to diminished tangle formation in AD, we first
investigated the phosphorylation status of two AD biomarkers, pTau S396 and
00/T403/S404, as well as the total Tau protein concentration in IMR32 cells.
Phosphorylation of Tau at the sites indicated has been associated with ilization
of the Tau protein and the eventual formation of tangles. For this purpose, cells were
treated with compound C, D, and E for 6 and 24 hr, and then subjected to Western
blot analysis.
As shown in Figure 12A, protein levels of all tested Tau protein species
were not affected at 6 hr treatment. However after 24 hr treatment, protein levels of
pTauS396, 00/T403/S404 and/or total Tau in IMR-32 cells were
significantly downregulated by compound C and/or E. Quantitative analysis showed
that compound C did not affect total Tau protein level, but significantly inhibited
the phosphorylation of Tau at 403/S404 but not at S396 (Fig. .
Compound D had no effect on Tau phosphorylation at all tested serine/threonine
residues, or on total Tau protein level, while the phosphorylation of Tau at S396 and
S400/T403/S404, and total Tau protein were significantly down-regulated by E
compound (Fig. l2B—C).
Analysis of the ratio of total pTauS396 and pTauS400/T403/S404 to total
Tau proteins showed that only compound C, but not D or E, significantly attenuated
total phosphorylation of Tau protein in IMR-32, even though there was a trend of
d Tau phosphorylation at all tested serine/threonine residues by compound E
(Fig. 12E).
Together, our data showed that compound C can markedly inhibit Tau
phosphorylation but does not affect total Tau protein in IMR32 cells, while
compound D did not have any effect in the process. Compound E may also play a
role in the regulation of Tau phosphorylation but the effect of this compound is
likely through the down-regulation of total Tau protein in IMR-32 cells. Given that
hyperphosphorylation of Tau is a cause of tangle ion in AD, our data suggest
that C ts Tau hyperphosphorylation that butes to tangle formation in
To investigate whether the downregulation of Tau phosphorylation by
compound C is due to Gsk3 and DYRKlA (two key kinases for Tau
phosphorylation in AD), Western blot analysis was performed to examine their
protein levels. As shown in Fig. 12A, phosphorylation of Gsk3b, total Gsk3a and
DYRKlA proteins were not affected by any of the three compounds in IMR-32
cells. However, Gsk3b protein levels were visibly decreased in IMR—32 cells after
treatment with compound C, but not D or E, for 24 hr but not 6 hr (Fig. 12A).
Quantitative analysis showed that there was a statistically significant decrease of
Gsk3b n levels in nd C, but not D or E, treated IMR—32 cells (when
compared to control cells) (Fig. 12F).
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To further confirm that Gsk3b expression is inhibited by compound C,
quantitative RT-PCR was performed to examine its mRNA level. As shown in Fig.
12G, Gsk3b mRNA levels were significantly decreased in IMR32 cells after
treatment with compound C for 6 hr. A trend of decreased Gsk3b mRNA expression
was also ed in IMR—32 cells after treated with compound C for 24 hr (Fig.
12H). In contrast, compound D and E treatments for 6 hr did not significantly inhibit
Gsk3b mRNA expression in IMR-32 cells (Fig. 12G). Instead, there was a
significant increase of Gsk3b mRNA expression in IMR-32 cells after treated with
compound D or E for 24 hr (Fig. 12H). Together, these data t that compound
C can inhibit Gsk3b expression at both the mRNA and protein levels and that down-
regulation of GSK3b by Compound C is likely the cause of reduced Tau
phosphorylation indicated above.
To investigate whether the inhibitory effect of compound C on Gsk3b
expression is al cell—specific, we examined its protein levels in mouse liver
cells. Protein extracts were prepared from liver cells at the same time and the same
experimental conditions as the above IMR-32 cells. It was found that Gsk3b protein
levels were not affected by compound C in liver cells (Fig. 16). Thus, the
downregulation of Gsk3b sion is al cell—specific. The lack of a GSK3b
response to compound C in liver cells could be of icant value from a
therapeutic perspective. It means that compound C could be used as a therapeutic in
neuronal tissue without running the risk of causing serious disturbances to liver
carbohydrate metabolism.
er, our results suggest that Compound C is a neuronal pecific
Gsk3b down-regulator and can inhibit orylation of Tau in neuronal cells,
which will be beneficial against tangle formation in AD. These data provide further
in vitro evidence that compound C may be a le therapeutic in the field of AD.
Neuronal-specific downregulation of FOXO phosphorylation and upregulation
of PGCla protein by CDE in IMR32 cells
Given the observed effects of CDE nds on mitochondrial activity in
IMR-32 cells, we wished to examine if these compounds can regulate key factors
responsible for cellular growth and metabolism, mitochondrial function and
energetics. The FOXO (Forkhead box) proteins are a family of key nuclear
transcription factors, having diverse roles in cell proliferation, differentiation and
longevity. They partially control key functions in the cell, such as gluconeogenesis
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(glucose tion from non—carbohydrate substrates). Their entry into the cell
nucleus is controlled by phosphorylation; phosphorylated FOXO is excluded from
the s while dephosphorylated FOXO can enter.
PGCla (Peroxisome proliferator-activated receptor gamma coactivator 1-
alpha) is a potent riptional activator that regulates genes involved in energy
metabolism and is also the chief regulator of mitochondrial biogenesis and growth. It
es a direct link between external stimuli (such as exercise) and the regulation
of mitochondrial biogenesis. It performs its diverse functions by teaming with
different transcription factors to co-activate genes. In the context of neuronal-
specif1c mitochondrial activity and AD ssion, it is of interest to note that
PGCla expression decreases in the Alzheimer’s disease brain as on of
dementia (Qin et al., 2009. Arch Neurol; 66:352—361).
Accordingly, we were interested to study if any of the CDE compounds
could influence the expression of these potent ing factors. As shown in Figure
13, phosphorylation of Foxo4 and Foxo3 were downregulated in IMR-32 cells after
treatment of CDE for both 6 and 24 hr, while PGCla protein was increased in IMR-
32 cells after 24 hr treatment. There were little or no effects on the protein
expression of other tested signaling molecules. ed PGCla protein may
promote MT biogenesis which may offer another explanation why MT potential was
ed by the combination of CDE in IMR-32 cells (Fig. 3, top and middle
panels). It is well characterized that dephosphorylation of FOXOs, such as Foxo 4 at
T28 and 8193, leads to nuclear localization of FOXO proteins. This result strongly
suggests that the combination of CDE compounds likely will enhance nuclear
FOXO action. Together our data suggest that CDE contain one or more Foxo
activator(s) and positive PGCla regulator(s) in neuronal cells.
This result may be very significant from a therapeutic perspective in
neuronal cells, such as brain. It is well established that co-localization of certain
FOXO proteins and PGCla in the nucleus can lead to a potent activation of
gluconeogenesis se production). While such a situation would be undesirable
in, say, the liver of a diabetic t, it could be viewed as extremely favorable in
the situation of a subject in early stage AD — where glucose import into the neuron is
impaired and, consequently, the brain cell is starved of its primary fuel source. An
enhanced ability to produce e from the carbon skeletons of other molecules
would be very beneficial, in such circumstances.
To test whether the ed activation of FOXO and PGCla (above) is
neuronal cell—specific, we also examined their protein levels in mouse liver AML-l2
cells. Protein ts were prepared from liver cells at the same time and the same
experimental conditions as IMR—32 cells. However, the effects noted in liver cells
(Fig. 15) described in a later section were quite te those obtained for IMR—32
cells and certainly suggest that the dephosphorylation of FOXO and the upregulation
of PGCla by CDE is not a tissue—wide enon and may be restricted to
neuronal cells.
Compound C, a neuronal-specific FOXO activators and a PGCla upregulator
As described above, CDE compounds together t about the
dephosphorylation of FOXOs and stimulated PGCla protein expression (Fig. 13).
To identify which compound in the CDE mixture has these effects, we examined the
expression of the aforementioned proteins in C-, D- and E-treated IMR32 cells. As
shown in Fig. 14A, pFOXO4 levels were decreased ically in IMR32 cells
after 6 hr treatments of all three compounds. After 24 hr treatment, decreased
pFOXO4 T28 levels were also observed in C- and E—, but not D—, treated IMR—32
cells. Quantitative is showed that the decrease of pFoxo4 levels in IMR-32
cells by C, D, and E at 6 hr treatment, and by C and E at 24 hr treatment was
statistically significant (Fig. l4B-C).
It is important to note that neither the CDE ation nor the individual
C, D or E treatments brought about any change in total FOXO levels (Fig 13 and
14), but rather just changed the control of FOXO action by dephosphorylating it.
Reduced FOXO phosphorylation was unlikely due to the down—regulation of AKT
phosphorylation, as pAKT protein levels were not visibly decreased in C,—, D— or E—
treated cells (Fig.14A). Also, pElf2beSS39 protein level was also not affected by C,
D or E, indicating that these compounds likely did not affect protein translation in
neuronal cells (Fig. 14A). In contrast, PGCla n levels were markedly elevated
after 24 hr treatment of all three compounds (Fig. 14A, 14D), which may explain
why MT potential was lated by these compounds in IMR—32 cells (Fig. 3 top
and middle panels). Together, our data suggest that compound C and E are FOXO
activators and PGCla upregulators, while nd D is a PGCla upregulator and
have mixed effects in the regulation of FOXO phosphorylation.
Discussion
When viewed in their totality, our results in neuronal cells put compound C
as the favored agent for eliciting beneficial effects in these cells. While the results
described directly above show that all three compounds are capable of bringing
about dephosphorylation of FOXO and upregulation of PGCla — very desirable
effects from an energetic standpoint in neuronal cells, it should be recalled that
compound C is the only candidate which elicits these FOXO/PGCl effects and, at
the same time, significantly s PSEN and Nicastrin levels (Fig. 11).
Furthermore, it was the nd which demonstrated a favorable response in
terms of reducing o—Tau levels and GSK3b levels in IMR—32 cells (Fig. 12).
As such, Compound C appears to be the compound of choice for eliciting a
triad of cial effects in neuronal cells, as follows; 1) a beneficial impact on
mitochondrial activity and function, by ating overall mitochondrial potential,
increasing PGCl levels and decreasing FOXO phosphorylation — thus allowing it
nuclear access an implied effect in reducing amyloid build—up by decreasing the
, 2)
sion of PSENl and Nicastrin and, 3) an implied effect of reduced Tau tangle
formation by reducing levels of phosphorylated Tau and the enzyme (GSK3b) which
is thought to be responsible for Tau phosphorylation.
Once again, to test the cell-specificity of these effects, n extracts
from a combination of CDE-treated liver AML-12 cells were probed with the same
antibodies to detect ences in FOXO phosphorylation and PGCla levels. As
shown in Figure 15 and 16, and discussed in more detail in a later n, the effects
seen with the three respective compounds confirmed that the IMR—32 cell effects
were certainly not observed in liver. In fact, one could say that directly opposing
effects were noted; namely, increased FOXO phosphorylation (nuclear exclusion),
no change in PGCla levels and no change in GSK3b levels. As will become clear,
however, these are the type of s one would wish to see happening in liver,
especially in the case of a diabetic subject where hepatic glucose output needs to be
controlled. Most importantly, it was found that, completely unlike neuronal cells,
liver AML-12 cells did not respond to ent with the individual compounds and,
instead, only responded to the C,D,E mixture. Once again, this points to very
definite cell-specif1cities and unanticipated cellular responses in on to the mode
of action of these compounds.
Results and Discussion: Liver cells
Liver cell-specific and PDKl/AKT-independent upregulation of FOXO
orylation by Compound CDE in ation but not by individual
compounds or their sulfur analogs
As was the case with lMR-32 neuronal cells, the observations that
selenium compounds (CDE combination, in this case) enhanced MT activity and
modulated the expression of a key gene controlled in ar energetic (UCP2)
prompted us to look for s which this combination of selenium compounds
might have on other critical genes involved in liver energy metabolism, insulin
signaling and cell proliferation. Accordingly, Western blot analyses were performed
on CDE-treated AML-12 cells.
As described previously, FOXOs are major signaling molecules for
gluconeogenesis and insulin sensitivity in the liver. It will be recalled that the
functionality of FOXO proteins is ed by their state of phosphorylation.
Phosphorylation of FOXOs excludes them from the nucleus, thereby essentially
inactivating them. Dephosphorylation allows entry of FOXO proteins into the
nucleus where they can ipate in transcriptional regulation of several key genes
ned with energy metabolism. As shown in Figure 15A, the phosphorylated
forms of FOXO3 and 4 3 and pFOXO4 protein levels) were found to be
significantly elevated in AML-12 cells after treatment of CDE, but not HIJ, for 6 hr.
Quantitative analysis showed there was approximately a 2.5-fold increase of pFoxo3
and about a 3.2-fold increase of pFoxo4 in CDE-treated AML-12 cells (Fig. lSB-C).
As phosphorylation of FOXOs causes r exclusion to inactivate FOXO in the
s, our results t that CDE will function as FOXO inactivators in liver
cells. As increased FOXO phosphorylation was not observed in CDE—treated lMR—
32 neuronal cells in analyses that were performed at the same time and under the
same experimental conditions (see the above Figure 13), we can conclude that the
inactivation of FOXO by CDE is liver—cell specific.
Together, our results suggest that the combination of CDE will function as
novel liver cell-specific FOXO vators. In fact, in lMR-32 neuronal cells, a
marked and highly significant activation (dephosphorylation) of FOXO proteins
occurred in response to the single or combination of selenium compounds C, D and
E. Thus, what we have in the case of these particular compounds is the ability to
selectively te FOXO proteins in neuronal cells and inactivate them in liver
cells. The overall importance and novelty of this finding becomes apparent when
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one considers it in the context of glucose handling in Type-2 diabetes and
Alzheimer’s disease.
As a brief background, in its activated or unphosphorylated state FOXO
resides in the nucleus where it binds to the promoter region for glucose 6—
phosphatase and, together with other factors such as PGC—la, increases transcription
of e—6—phosphatase, thereby sing the rate of glucose production. Glucose
6—phosphatase catalyzes the last step in gluconeogenesis and glycogenolysis causing
the release of glucose from the liver. It is, therefore, critically important in the
control of glucose homeostasis, particularly in diabetic ts. Normally, the
process of FOXO phosphorylation is controlled directly by another kinase enzyme
called AKT (Protein Kinase B). AKT phosphorylates FOXO and drives it from the
nucleus, thereby decreasing glucose production via a decreased rate of transcription
of e 6—phosphatase. AKT itself is under upstream control by a mini molecular
e reaction, which starts with insulin binding to its receptor at the cell surface.
This tes a series of events involving two other kinase enzymes,
Phosphatidylinositol 3-kinase (PI3K) and Phosphoinositide-dependent protein
kinase 1 . The overall pathway is known as the Insulin/PI3K/PDKl/Akt
pathway and it has the job controlling glucose homeostasis via insulin signaling. In
the context of FOXO control, PDKl orylates and activates Akt which, in
turn, phosphorylates and inactivates FOXO.
Since PI3K/PDKl/AKT is the major signaling pathway upstream of FOXO
for the insulin —mediated l of glucose production in the liver, we asked
whether enhanced FOXO phosphorylation by CDE is due to the activation of
PI3K/Pdk/Akt signaling pathway in liver cells. To test this, we ed the protein
levels of pPDKl, pAKT T308 and S473 and total AKT in eated liver cells.
Surprisingly, CDE did not affect the phosphorylation of PDKl, AKT, or total AKT
levels (Fig. 15A). We also examined levels of two other downstream signaling
molecules pGSk3a and pGSK3b which are directly controlled by AKT, and did not
observe any change in their protein levels (Fig. 15A), which is consistent with no
change of pAKT in CDE-treated cells. The levels of p4Ebp (a downstream
molecular target of AKT/mTor signaling) and pElf2be S539 (a ream
molecular target of Gsk3) that are key for insulin-driven protein synthesis or
translation were also not affected (Fig. 15A). This provides additional direct
molecular evidence that CDE did not have a toxic effect in affecting liver cell
proliferation/survival as described earlier.
As described in the context of neuronal IMR—32 cells, PGCla is a critical
gene for MT biogenesis and carbohydrate metabolism. In liver cells, it also acts in
concert with FOXO to drive the transcription of genes involved in gluconeogensis,
but cannot do this in the nuclear absence of FOXO. We examined PGCla protein
expression, and did not observe a significant change of PGC protein level in liver
cells after the combination of CDE treatment by quantitative analysis (Fig 15A and
D). However, due to the robust effect noted on FOXO phosphorylation in response
to CDE, it is almost certain that it would be excluded from the nucleus and, hence,
the level of PGCla becomes of low importance because it requires FOXO to initiate
the gluconeogenic process. Together, these results suggest that CDE did not affect
DKl/AKT signaling and several other AKT direct or indirect downstream
signaling les, except the above described but critical FOXOs. In other words,
CDE can selectively inactivate FOXOs and this action appears to be ndent on
the PI3K/PDKl/AKT signaling in the liver cells.
In essence, therefore, the mode of action of CDE in liver cells may be totally
independent of the insulin-driven DKl/AKT signaling pathway, i.e. it may be
insulin—independent. The importance of this becomes immediately s to
anyone d in the art of metabolic ing pathways because it s the
physiological uences of a liver cell becoming insulin—resistant, in the context
of controlling hepatic glucose output. Bypassing insulin signaling while still being
able to l glucose homeostasis through FOXO regulation opens up many
therapeutic possibilities for the treatment of diabetes in general; making it less
dependent on the administration of exogenous insulin.
In addition, the importance of finding a potentially AKT-independent FOXO
inhibitor in liver should not be underestimated from a broader health perspective. It
is well established that the PI3k/PDKl/AKT pathway is the prototypic pathway that
promotes cell growth and is constitutively active in many cancers. AKT, when
activated, ms al roles in diverse cellular processes — not just e
homeostasis through FOXO inactivation. Chief among these other pathways is
cancer progression. In this respect, it is of interest to note that AKT was ally
identified as the oncogene in the transforming retrovirus AKT8. Thus, any
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compound which can m a key role of AKT, but do it in an AKT-independent
fashion is both very novel and le.
Once again, to complete our investigations into compound specificity, we
wished to determine if the single compounds in CDE had the ability to inactivate
FOXOs in liver cells, AML-12 cells were d with individual compounds under
the same experimental conditions. Western blot analysis showed that the inactivation
of FOXO (indicated by increased pFOXOs) was not observed in individual
compound-treated liver cells after 6 or 24 hr treatment (Fig. 16). We also examined
a number of other signaling molecules and did not observed the increased
phosphorylation of AKT, Gsk3a/b and Elf2be in the liver cells after treatment with
C, D, or E for 6 or 24 hr (Fig. 16). The only effects noted had to do with compound
E which appeared to slightly reduce the levels of pAKT and pElf2b8 $539 in AML-
12 cells after 6 hr treatment (Fig. 16). The effect on AKT by compound E, however,
must be marginal since this was not ed by a compound ated decrease in
phosphorylation of FOXOs (the immediate downstream target of AKT). As such,
this does not indicate a significant change in gluconeogenic potential in E-treated
cells. Dephosphorylation of EIF2b8 may signify an increased level of
mRNA/Protein translation, but this has not been thoroughly explored. However, it is
clear that the protein expression of the species tested in these Western blots was not
altered by any of these three selenium compounds (Fig. 16). Regardless, our results
suggest that the individual selenium compounds C, D or E alone did not increase
FOXO orylation in liver cells. Therefore, there exists a synergistic effect
among C, D and E compounds to inactivate FOXO in liver cells.
Together, our results suggest that CDE, but not individual nds, will
function as liver cell-specific and PI3K/PDK/AKT-independent FOXO inactivators.
Downregulation of the expression of G6pc, a FOXO downstream target for
glucose production, in AML-lZ cells after treatment with nd CDE
um compounds
As ned above, Glucose 6—Phosphatase, Catalytic subunit (G6PC) is a
direct ream target of FOXO which enhances glucose production, especially in
the liver. Enhanced levels of pFOXOs (inactive) in CDE—treated liver cells suggests
that CDE can play a role in controlling glucose production and in improving n
sensitivity in liver cells. The real proof that the selenium compound combination,
CDE, can modulate gluconeogenesis or glycogenolysis through FOXO
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phosphorylation, would be to see a decreased expression of G6PC in a hepatic
environment. To test this hypothesis, we examined G6pc expression in liver cells by
quantitative RT-PCR analysis.
As shown in Figure 17, treatment of AML-12 liver cells with the CDE
ation, but not the HIJ sulfur analog ation caused a very significant
45% decrease in G6pc expression in liver cells. In on, we also examined G6pc
expression in AML-12 cells after treatment with all of the individual compounds,
and did not observed any significant alteration (increase or decrease) in G6pc
expression (Fig 17); a finding consistent with the unchanged FOXO
phosphorylation levels noted in compound-, D- or E- treated liver cells, as
determined by Western blot is (Fig. 16). The effect of decreased G6pc
expression in response to the CDE combination was observed in three repeat
experiments using different s of cells (data not shown).
Together, our s demonstrate that CDE, but not the individual
compounds, can significantly attenuate G6pc expression, thereby representing a
novel way to reduce hepatic glucose output. Our tive findings further point to
the mode of action of these compounds being mediated by an AKT—independent
se in FOXO phosphorylation. These data provide strong in vitro evidence that
CDE has cant potential in a therapeutic capacity for controlling hepatic
glucose output in obese and type—2 diabetic subjects.
Overall Summary and sion
We have identified that compound C, but not D, enhanced MT potential
in kidney cells, and that both compound C and D enhanced MT potential in mouse
skeletal muscle st C2C12 cells. These results suggest that compound C may
be useful against progressive kidney failure, and C and D against sarcopenia caused
by progressive loss of MT function in the kidney or skeletal muscle. In the case of
skeletal muscle, we also expect C and D to be potentially useful in the area of T2DM
research and control, given that skeletal muscle utilizes 75—80% of daily ingested
glucose and that mitochondrial dysfunction in skeletal muscle is believed to be a key
initiator of T2DM.
In addition, our experiments using human neuronal IMR-32 cells indicate
that one of these compounds in particular (compound C) may be uniquely t
AD pathogenesis. This conclusion is based on the following key findings:
(1) MT potential transiently enhanced by C (Fig. 3)
2014/029542
(2) Improved neuronal cell survival by compound C (Fig. 5)
(3) al cell—specif1c downregulation of FOXO phosphorylation (key for cell
metabolism) and upregulation of PGCla (key for MT biogenesis) (Fig. 14 vs
liver cell data in Fig. 16);
(4) Selective targeting of the gamma-secretase complex genes PSEN and Nicastrin
to inhibit their expression for APP cleavage (Fig. 11);
(5) Inhibition of Tau orylation likely against tangle formation in AD
(Fig.12); and
(6) Neuronal cell—specif1c GSK3b downregulation which, again indicates
reduces Tau phosphorylation potential and reduced tangle formation in AD
ions (Fig. 12 vs liver cell data Fig. 16).
We have identified a novel liver cell-specific and PI3K/PDKl/AKT-independent
FOXO inactivation compound combination (CDE) (i.e., the combination of CDE,
but not the individual compounds). This combination of nds dramatically
downregulates G6pc expression in liver cells through the nuclear exclusion of
FOXO proteins. We envisage that this combination may be particularly useful in the
research and amelioration of symptoms and pathologies arising from metabolic
syndrome, obesity and T2DM. Our reasoning is based on the following findings:
(1) MT potential is significantly enhanced in liver cells by a combination of CDE
only; not any other compound or their combinations. (Fig. 7);
(2) There was no toxic effect on the survival of liver cells or neuronal cell (Fig. 5,
Fig.9)
(3) The Uncoupling Protein 2 (Ucp2) gene was specifically and significantly
gulated by CDE (Fig. 8); Of particular note in this regard are the gs
from recent studies that inhibition of UCP2 expression es diet—induced
es by affecting both insulin secretion and action.
(4) Liver cell-specific FOXO was inactivated ((phosphorylated) by CDE (Fig. 15
vs neuronal cell data Fig. 13);
(5) No effect on FOXO inactivation by individual compounds was noted (Fig. 16)
(6) No effect on phosphorylation of PI3K/PDK/Akt signaling by CDE was noted
(Fig. 15). This indicates that CDE represents a novel AKT-independent FOXO
inactivator.
(7) icant downregulation of the critical FOXO target gene G6pc by CDE (Fig.
17) but not by any of the individual compounds (Fig. 17). It will be recalled that
hepatic glucose output is controlled by FOXO—mediated activation of G6pc
transcription.
Based on the above experimental data, we believe that the CDE combination can
specifically act as a potent FOXO inactivator in liver cells to reduce G6pc
expression and lower hepatic glucose output. Furthermore, we have shown that this
action is ndent of PI3K/PDK/Akt signaling. A depiction of how this process
may work is shown in Figure 18. Whereas, ly, FOXO phosphorylation and its
subsequent entry or ion from the nucleus is governed by the
n/PI3K/PDKl/AKT pathway, we show that the specific combination of
compounds C, D and E brings about the orylation of FOXO by an as yet
unidentified kinase enzyme. orylated FOXO, excluded from the s, is
unable to transcriptionally activate G6PC which leads, in turn, to d glucose
output from the liver. Reduced hepatic glucose output and the associated decrease in
blood glucose concentration will lead to an insulin—sparing effect, i.e. reduced
demand on the pancreas to secrete insulin in response to high blood glucose.
It is also quite reasonable to expect that the lower level of blood glucose
may lead to both enhanced insulin sensitivity in peripheral tissues and a more
lled release of insulin by the beta-cells of the pancreas. That is to say, insulin
output by the as will be less likely to be overtaxed, due to lower circulating
glucose levels overall. From the experiments conducted and presented in this
application, we have been unable to identify any negative effects on either the
growth of all cell types tested or activation of pathways which may signal initiation
of uncontrolled proliferation and growth, i.e. cancer causing. In fact, the ability of
these compounds to bypass the AKT—signaling pathway (at least in liver) makes
them ularly interesting from a reduced toxic potential viewpoint.
Based on the findings presented above, we also believe that we can
hypothesize a plausible model for the effect of compound C, in particular, on
ameliorating the impacts of the AD pathologies (Amyloid plaques and Tau tangles).
As shown in Figure l9A—C, the key AD—related genes whose expression is reduced
or altered in IMR-32 cells have the binding motifs (sites) for FOXOs l, 3 or 4 in
their gene promoter regions. This is true for Gsk3b (Fig. 19A), Psenl (Fig. 19B) and
Nicastrin (Fig. 19C). This means that nuclear-localized FOXO proteins could bind to
and vely regulate transcription from these gene promoters. With this
knowledge, it is thus quite easy to visualize a situation (Fig. 19D) where compound
C dephosphorylates FOXO proteins and allows them into the nucleus. Here, the
active FOXO proteins bind to and inhibit transcription from the promoter regions of
the genes mentioned above. Lower levels of GSK3b in IMR cells (Fig. 12) will
result in decreased phosphorylation of Tau, followed by decreased microtubule
stabilization and decreased tangle formation as a direct .
Likewise, binding of FOXO proteins to the promoter regions of PSEN and
Nicastrin inhibits transcription from these genes which results in lower amounts of
these critical gamma-secretase ents being produced in neuronal cells. The
natural implication of this would be lower levels of aberrant APP processing, lower
amyloid-beta peptide tration and decreased amyloid plaque burden as a result.
All publications and patents mentioned in the t application are herein
incorporated by reference. Various modification and ion of the described
s and compositions of the present application will be apparent to those
skilled in the art without departing from the scope and spirit of the present
application. gh the present application has been described in connection with
specific preferred embodiments, it should be understood that the present application
as claimed should not be unduly d to such ic embodiments. Indeed,
various modifications of the described modes for carrying out the present
application that are obvious to those skilled in the relevant fields are intended to be
within the scope of the following claims.
Claims (14)
1. Use of a composition in the manufacture of a medicament for enhancing mitochondrial function in one or more cells selected from the group consisting of skeletal muscle cell, neuronal cell, and combinations thereof, for treating a e or condition associated with mitochondrial dysfunction, wherein said composition comprises: at least one of 5’-Methylselenoadenosine, Se-Adenosyl-L-homocysteine, and Gamma-glutamyl-methylseleno-cysteine, and, optionally, at least one of a compound of formula (I) other than 5’-Methylselenoadenosine, a compound of formula (II) other than Se-Adenosyl-L- homocysteine, a compound of formula (III) other than Gamma-glutamyl-methylseleno-cysteine, n formula (I) is: or a pharmaceutically acceptable salt, hydrate, or prodrug thereof, wherein R1 is H, acyl, alkyl, alkenyl, alkynyl, aralkyl, carboxyl, cycloalkyl, , or C(O)OR’, wherein R’ is alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, or heterocyclyl; or R1 together with R2 form a heterocyclic ring having 4 to 8 ring s with at least one heteroatom ed from nitrogen; R2 is H, acyl, alkyl, alkenyl, alkynyl, aralkyl, carboxyl, lkyl, C(O)R‴, or C(O)OR‴, wherein R‴ is selected from alkyl, cycloalkyl, aryl, aralkyl, or heterocyclyl; or R1 er with R2 form a heterocyclic ring having 4 to 8 ring members with at least one heteroatom selected from nitrogen; R3 is H, acyl, alkyl, alkenyl, alkynyl, aralkyl, cycloalkyl, carboxyl, or C-amido; or R3 er with R4 and the atoms to which they are attached form a heterocyclic ring having 4 to 8 ring members with at least two heteroatoms selected from oxygen; R4 is H, acyl, alkyl, alkenyl, alkynyl, aralkyl, cycloalkyl, carboxyl, or C-amido; or R3 together with R4 and the atoms to which they are attached form a heterocyclic ring having 4 to 8 ring members with at least two heteroatoms ed from oxygen; R5 is oxo, hydroxyl, alkyl, alkenyl, alkynyl, OR”, or is absent; n R” is selected from alkyl, alkenyl, alkynyl, cycloalkyl, aryl, and aralkyl; R6 is oxo, hydroxyl, alkyl, alkenyl, alkynyl, OR”, or is absent; wherein R” is selected from alkyl, alkenyl, alkynyl, cycloalkyl, aryl, and aralkyl; R7 is a C3-C16 alkyl, alkenyl, alkynyl, ketone, amino alcohol, amino acid, ORa, Se- Rb, or S-Rb, wherein Ra for ORa is selected from the group consisting of H, alkyl, lkyl, aryl, aralkyl, and heterocyclyl, where Rb for Se-Rb is selected from the group consisting of H, C3-C16 alkyl, cycloalkyl, aryl, aralkyl, and cyclyl, wherein Rb for S-Rb is selected from the group consisting of H, C3-C16 alkyl, cycloalkyl, aryl, aralkyl, and heterocyclyl, and wherein the amino acid is selected from the group consisting of arginine, histidine, lysine, ic acid, ic acid, , threonine, asparagine, glutamine, cysteine, selenocysteine, glycine, proline, alanine, valine, isoleucine, leucine, methionine, phenylalanine, tyrosine, and tryptophan; and R8 is hydrogen, azido, alkyl, alkenyl, or alkynyl, with the proviso that formula (I) is not 5’-Methylselenoadenosine, wherein Formula (II) is: or a pharmaceutically acceptable salt, hydrate, or prodrug f, wherein R1 is H, acyl, alkyl, alkenyl, alkynyl, aralkyl, carboxyl, cycloalkyl, C(O)R’, or C(O)OR’, wherein R’ is alkyl, alkenyl, l, cycloalkyl, aryl, aralkyl, or cyclyl; or R1 together with R2 form a heterocyclic ring having 4 to 8 ring members with at least one heteroatom selected from nitrogen; R2 is H, acyl, alkyl, alkenyl, alkynyl, aralkyl, carboxyl, cycloalkyl, C(O)R‴, or C(O)OR‴, wherein R‴ is selected from alkyl, lkyl, aryl, aralkyl, or heterocyclyl; or R1 together with R2 form a heterocyclic ring having 4 to 8 ring members with at least one heteroatom selected from nitrogen; R3 is H, acyl, alkyl, alkenyl, alkynyl, aralkyl, cycloalkyl, carboxyl, or C-amido; or R3 together with R4 and the atoms to which they are attached form a heterocyclic ring having 4 to 8 ring members with at least two heteroatoms selected from oxygen; R4 is H, acyl, alkyl, alkenyl, alkynyl, aralkyl, cycloalkyl, carboxyl, or C-amido; or R3 er with R4 and the atoms to which they are attached form a heterocyclic ring having 4 to 8 ring members with at least two heteroatoms selected from oxygen; R5 is oxo, hydroxyl, alkyl, alkenyl, alkynyl, OR”, or is absent; wherein R” is selected from alkyl, alkenyl, alkynyl, cycloalkyl, aryl, and l; R6 is oxo, yl, alkyl, alkenyl, alkynyl, OR”, or is absent; wherein R” is ed from alkyl, alkenyl, alkynyl, cycloalkyl, aryl, and aralkyl; R8 is hydrogen, azido, alkyl, alkenyl, or alkynyl; R9 is H, acyl, alkyl, alkenyl, alkynyl, aralkyl, carboxyl, cycloalkyl, C(O)Rc, or C(O)ORc, where Rc is alkyl, cycloalkyl, aryl, aralkyl, or heterocyclyl; or R9 together with R10 form a heterocyclic ring having 4 to 8 ring members with at least one heteroatom selected from nitrogen; R10 is H, acyl, alkyl, alkenyl, alkynyl, aralkyl, carboxyl, cycloalkyl, , or C(O)ORc, where Rc is selected from alkyl, cycloalkyl, aryl, aralkyl, or heterocyclyl; or R9 together with R10 form a heterocyclic ring having 4 to 8 ring members with at least one heteroatom selected from nitrogen; and R11 is OR, alkoxy, aralkoxy, or amino, where R is selected from alkyl, cycloalkyl, aryl, aralkyl, and heterocyclyl, with the proviso that formula (II) is not Se-Adenosyl-L-homocysteine, and wherein formula (III) is: or a pharmaceutically acceptable salt, hydrate, or prodrug thereof, wherein R1 is H, acyl, alkyl, alkenyl, alkynyl, aralkyl, carboxyl, cycloalkyl, C(O)R’, or C(O)OR’, wherein R’ is alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, or heterocyclyl; or R1 together with R2 form a heterocyclic ring having 4 to 8 ring members with at least one heteroatom selected from nitrogen; R2 is H, acyl, alkyl, alkenyl, alkynyl, aralkyl, carboxyl, cycloalkyl, C(O)R‴, or C(O)OR‴, wherein R‴ is selected from alkyl, lkyl, aryl, aralkyl, or heterocyclyl; or R1 er with R2 form a cyclic ring having 4 to 8 ring s with at least one heteroatom ed from en; R3 is OH, OR, alkoxy, aralkoxy, or amino, where R is selected from alkyl, lkyl, aryl, aralkyl, and heterocyclyl; R4 is alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, or heterocyclyl, or a ceutically acceptable salt; R5 is oxo, hydroxyl, alkyl, alkenyl, alkynyl, OR”, or is absent; wherein R” is selected from alkyl, l, alkynyl, cycloalkyl, aryl, and aralkyl; R6 is oxo, hydroxyl, alkyl, alkenyl, alkynyl, OR”, or is absent; wherein R” is ed from alkyl, alkenyl, alkynyl, cycloalkyl, aryl, and aralkyl; and R7 is a C3-C16 alkyl, alkenyl, alkynyl, ketone, amino alcohol, amino acid, ORa, Se- Rb, or S-Rb, wherein Ra for ORa is selected from the group consisting of H, alkyl, cycloalkyl, aryl, aralkyl, and heterocyclyl, where Rb for Se-Rb is selected from the group consisting of H, C3-C16 alkyl, cycloalkyl, aryl, aralkyl, and heterocyclyl, wherein Rb for S-Rb is selected from the group consisting of H, C3-C16 alkyl, lkyl, aryl, aralkyl, and heterocyclyl, and wherein the amino acid is selected from the group consisting of arginine, histidine, lysine, aspartic acid, glutamic acid, serine, threonine, asparagine, glutamine, ne, selenocysteine, e, proline, alanine, , isoleucine, leucine, methionine, phenylalanine, tyrosine, and tryptophan, with the proviso that formula (III) is not Gamma-glutamyl-methylseleno-cysteine, wherein, when present, 5’-Methylselenoadenosine is present in an amount from 15 ppb to 500 ppb, wherein, when present, Se-Adenosyl-L-homocysteine is present in an amount from 15 ppb to 500 ppb, and wherein, when t, Gamma-glutamyl-methylseleno-cysteine is present in an amount from 15 ppb to 500 ppb.
2. Use of the composition of claim 1, wherein the compound or combination of compounds is isolated.
3. Use of the ition of claim 1, wherein the compound or combination of compounds is purified.
4. Use of the composition of any one of claims 1-3, wherein the composition comprises 5’-Methylselenoadenosine.
5. Use of the composition of any one of claims 1-4, wherein the composition excludes glutamyl selenocysteine, nine or selenomethionine.
6. Use of the composition of any one of claims 1-5, wherein the composition comprises 200 micrograms of at least one of hylselenoadenosine, Se-Adenosyl-L- steine, and Gamma-glutamyl-methylseleno-cysteine, and, optionally, at least one of a compound of formula (I) other than 5’-Methylselenoadenosine, a compound of formula (II) other than Se-Adenosyl-L-homocysteine, and a compound of formula (III) other than Gamma-glutamylmethylseleno-cysteine.
7. Use of the ition of any one of claims 1-6, wherein the composition is formulated for administration once daily.
8. Use of the ition of claim 1, comprising a compound of formula (I) other than 5’-Methylselenoadenosine, a compound of formula (III) other than Gamma-glutamylmethylseleno-cysteine , or a combination of two or more of 5’-Methylselenoadenosine, Se-Adenosyl- L-homocysteine, Gamma-glutamyl-methylseleno-cysteine, the compound of formula (I) other than 5’- Methylselenoadenosine, and the nd of formula (III) other than Gamma-glutamylmethylseleno-cysteine.
9. Use of the composition of claim 1, comprising 5’-Methylselenoadenosine, Se-Adenosyl-L-homocysteine, and Gamma-glutamyl-methylseleno-cysteine.
10. Use of the composition of claim 9, also sing insulin or an analog or derivative thereof.
11. Use of the composition as claimed in claim 9, also comprising a carrier.
12. Use of the composition of claim 1, wherein, when present, 5’- selenoadenosine is present in an amount of from 100 ppb to 500 ppb, wherein, when present, Se-Adenosyl-L-homocysteine is t in an amount of from 100 ppb to 500 ppb, and wherein, when present, Gamma-glutamyl-methylseleno-cysteine is present in an amount of from 100 ppb to 500 ppb.
13. Use of the composition of claim 1, wherein, when present, 5’- Methylselenoadenosine is present in an amount of from 37.5 ppb to 500 ppb, wherein, when present, Se-Adenosyl-L-homocysteine is present in an amount of from 37.5 ppb to 500 ppb, and wherein, when present, Gamma-glutamyl-methylseleno-cysteine is present in an amount of from 37.5 ppb to 500 ppb.
14. Use of the composition of claim 1, wherein the composition comprises from 15 ppb to 75 ppb hylselenoadenosine or from 15 ppb to 75 ppb Se-Adenosyl-L-homocysteine.
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
PCT/US2014/029542 WO2015137983A1 (en) | 2014-03-14 | 2014-03-14 | Compositions of selenoorganic compounds and methods of use thereof |
Publications (2)
Publication Number | Publication Date |
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NZ723233A NZ723233A (en) | 2020-10-30 |
NZ723233B2 true NZ723233B2 (en) | 2021-02-02 |
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