WO2001072701A1 - Ceramide derivatives and method of use - Google Patents
Ceramide derivatives and method of use Download PDFInfo
- Publication number
- WO2001072701A1 WO2001072701A1 PCT/US2001/009894 US0109894W WO0172701A1 WO 2001072701 A1 WO2001072701 A1 WO 2001072701A1 US 0109894 W US0109894 W US 0109894W WO 0172701 A1 WO0172701 A1 WO 0172701A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- alkyl
- compound
- aryl
- ceramide
- och
- Prior art date
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- 150000001783 ceramides Chemical class 0.000 title abstract description 64
- 238000000034 method Methods 0.000 title description 15
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 66
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 60
- 125000003118 aryl group Chemical group 0.000 claims description 57
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 54
- 125000000217 alkyl group Chemical group 0.000 claims description 51
- 150000001875 compounds Chemical class 0.000 claims description 38
- 229910052794 bromium Inorganic materials 0.000 claims description 30
- 229910052801 chlorine Inorganic materials 0.000 claims description 27
- 229910052731 fluorine Inorganic materials 0.000 claims description 27
- 229910052740 iodine Inorganic materials 0.000 claims description 27
- 229910052739 hydrogen Inorganic materials 0.000 claims description 24
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 18
- CBOIHMRHGLHBPB-UHFFFAOYSA-N hydroxymethyl Chemical compound O[CH2] CBOIHMRHGLHBPB-UHFFFAOYSA-N 0.000 claims description 17
- 229910052736 halogen Inorganic materials 0.000 claims description 12
- 150000002367 halogens Chemical class 0.000 claims description 12
- 229910052799 carbon Inorganic materials 0.000 claims description 11
- 229910003849 O-Si Inorganic materials 0.000 claims description 9
- 229910003872 O—Si Inorganic materials 0.000 claims description 9
- MDFFNEOEWAXZRQ-UHFFFAOYSA-N aminyl Chemical compound [NH2] MDFFNEOEWAXZRQ-UHFFFAOYSA-N 0.000 claims description 6
- 125000003088 (fluoren-9-ylmethoxy)carbonyl group Chemical group 0.000 claims description 3
- LJCZNYWLQZZIOS-UHFFFAOYSA-N 2,2,2-trichlorethoxycarbonyl chloride Chemical compound ClC(=O)OCC(Cl)(Cl)Cl LJCZNYWLQZZIOS-UHFFFAOYSA-N 0.000 claims description 3
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- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 3
- 125000005228 aryl sulfonate group Chemical group 0.000 claims description 3
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- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 3
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- ZVEQCJWYRWKARO-UHFFFAOYSA-N ceramide Natural products CCCCCCCCCCCCCCC(O)C(=O)NC(CO)C(O)C=CCCC=C(C)CCCCCCCCC ZVEQCJWYRWKARO-UHFFFAOYSA-N 0.000 description 28
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Definitions
- the invention relates to ceramide derivatives, pharmaceutical compositions comprising the ceramide derivatives, and therapeutic uses of the ceramide derivatives as agents against cancer, metabolic diseases such as diabetes, inflammatory conditions and viral infections.
- Ceramides are a class of naturally occurring spliingolipids normally formed by intracellular hydrolysis of sphingomyelin, and are found in all animal cells. Sphingolipid metabolites participate in signal transduction and cell regulation possibly as first or second messengers. Although neither the direct targets nor the mechanisms of action of ceramides are fully understood, there are several pieces of evidence which suggest that ceramides play an important role as a regulatory component of apoptosis induced by tumor necrosis factor-alpha (TNF- ⁇ ), Fas ligand, ionizing radiation, and chemotherapeutic agents.
- TNF- ⁇ tumor necrosis factor-alpha
- Fas ligand Fas ligand
- ionizing radiation ionizing radiation
- Intracellular ceramide is elevated during the induction of apoptosis in a wide variety of cellular systems and addition of cell-permeable ceramide analogs induces apoptosis in many cell lines, providing evidence that ceramide generation plays a direct role in the apoptotic response.
- Apoptosis describes a programmed series of events resulting in cell death by fragmentation into membrane-bound particles; these particles are then phagocytosed by other cells (see, e.g., Stedman's Medical Dictionary ( " Illustrated ' )).
- Cells typically undergo apoptosis in physiologically determined circumstances such as the elimination of self- reactive T cells, the death of cells (e.g., neutrophils) with short half-lives, involution of growth factor-deprived cells, morphogenetic cell death during embryonic development and the deaths of cellular targets of cell-mediated cytotoxicity (see, e.g., J. Cohen, Immunol. Today, 14(3):126-130 (1993)).
- apoptotic bodies which are cellular fragments that retain their membranes and are able to regulate their osmotic pressures. Unlike necrotic cells, there is usually no leakage of cellular contents and hence, no invocation of an inflammatory response.
- Apoptotic cells typically have disrupted plasma membranes and condensed, disrupted nuclei. Nuclear chromatin in these cells is fragmented randomly between nucleosomes, as the result of endonuclease activation during apoptosis.
- C-myc protein is known to stimulate cell proliferation; however, it may also stimulate apoptosis in the absence of additional proliferative stimuli.
- p53 which is thought to suppress tumor growth, may also stimulate apoptosis.
- C-fas a transmembrane protein homologous to Tumor Necrosis Factor (TNF), can also induce apoptosis, as can TNF itself.
- TNF is a monokine protein produced by monocytes and macrophages.
- TNF- ⁇ and TNF- ⁇ both of which bind to the same cell surface receptors. Binding to these receptors by TNF leads to the activation of multiple signal transduction pathways, including the activation of sphingomyelinase (see, e.g., M. Raines et al., I. Biol. Chem. 268 (20): 14572 (1993); L. Obeid et al., Science 259:1769 (March 12, 1993); H. Morishige et al, Biochim. Biophys. Acta. 1151:59 (1993); J. Vilcek and T.
- apoptosis occurs in two phases, an initial commitment phase followed by an execution phase resulting in the condensation of nuclear chromatin, fragmentation of DNA, and alterations to the cell membrane.
- Caspases a family of cysteine proteases, play a critical role in the execution phase of apoptosis; they participate in a cascade that is triggered in response to proapoptotic signals and in cleavage of intracellular substrates, resulting in disassembling cells. Based on their function in the cascade, caspases can be grouped into two categories, initiators and effectors. Different initiator caspases such as caspase 8 and 9 mediate distinct sets of signals.
- Caspase 8 binds with the death effector domain DED of the Fas receptor and a cofactor FADD (Fas-associated protein with death domain).
- FADD Fas-associated protein with death domain
- the activation of caspase 9 requires several cofactors such as cytochrome c, dATP, and APAF-1 and through the caspase recruitment domain (CARD).
- CARD caspase recruitment domain
- Ceramides are a class of sphingolipids comprising fatty acid derivatives of a sphingoid, e.g., sphingosine, base (see, e.g., Stedman's Medical Dictionary (Illustrated). 24th edition (J. V. Basmajian et al., eds.), Williams and Wilkins, Baltimore (1982), p. 99). Different ceramides are characterized by different fatty acids linked to the sphingoid base.
- Shorter- or longer-chain fatty acids can also be linked to the sphingoid base.
- Applicants have previously reported that attachment of certain chemical groups to sphingolipids and ceramides so as to form analogs of such compounds can inhibit bioconversion of ceramides to sphingomyelins, and can thereby lead to an apoptosis stimulating increase in ceramide concentrations.
- Ceramides are found in all eukaryotic cell membranes, and are known to participate in a variety of critical cellular processes. Furthermore, certain sphingolipid compounds have been found to play a role in prevention of cellular proliferation. However, there has been no recognition in the prior art of the specific halogentated ceramides of the invention and their use in treating neoplastic diseases, metabolic conditions such as diabetes, inflammations and viral infections.
- Short-chain (C2-C 6 ), cell-permeable ceramides have been shown to directly affect endogenous ceramide levels, these short-chain ceramides mainly have been used for studying ceramide-mediated cellular functions. Further, though some reports have suggested that halogenated ceramides may be potentially useful as therapeutics for various pathologies of the nervous system, there has been no indication that halogenated ceramide derivatives would exhibit enhanced anti-neoplastic activity as compared to non-halogenated analogs, such as C2 and C6 ceramides.
- the invention involves a compound of the formula I:
- R is C n H 2n+1 , where n is an integer of from 1-18;
- M is C(O) or CH 2 ;
- Q is C, OC or S(O 2 )N;
- Y is H, OH, -Cg alkyl, C(O)OH, aryl, phenyl, NH 2 , NO 2 , C 6 H 5 , a halogen, NH-P l5 (O) or (S);
- Z is H, C 6 H 5 , alkyl, NH 2 , NH-Pi or C(O)OH, wherein when Y is (O) or (S), Z is not present, and wherein when X, Y and Z are present as different moieties, the compound has an R, an S, or any combination of the R and S configurations about the ⁇ -carbon;
- X is F, Cl, Br, I, C 6 H 5 , O-Si(CH 3 ) 3 , O-Si(C 4 H 9 ) 3 , O-Si(C 6 H 5 ) 3 , -C 17 alkyl, - CH O-X or
- k is integer from 0 to 6;
- Ri, R 2 , and R 3 are each independently H, -Ce alkyl, - alkenyl, C 2 -C 6 cycloalkyl, or aryl;
- Xi is H, OH, Ci-Cs alkyl, -C 6 O-alkyl, Q- S-alkyl, C 2 -C 6 cycloalkyl, aryl, phenyl, a halogen, NO 2 , CN, C(O)H, C(O)OH, C(O)OCH 3 , COCH 3 , CH 2 OH, NH 2 , N 3 , NHCH 3 , CONH 2 , N(CH 2 CH 2 ) 2 Cl2, B(OH) 2 , furyl or aryl sulfonate; X 2 is -O-CH 2 -, and X 3 is -O-CH 2 - or -O-, such that X 2 and X 3 taken together form a heterocyclic ring; and
- Pi is H or an amino protecting group.
- the ceramide derivative can be one or any combination of the O-erythro, D-threo, J ⁇ erythro and L-t ireo configurations, as well as one or any combination of (+) and (-) optical isomers.
- Each of Y and Z is independently H or C 6 H 5 .
- M is C(O)
- X is Br or a Ci-C ⁇ alkyl group
- Q is C
- Z is H, C 6 H 5 , an alkyl group or C(O)OH.
- M is C(O), and X is
- M is C(O)
- X v ⁇ X ⁇
- Xi is H, Ci-C ⁇ alkyl, F, Cl, Br, I, OH, OCH 3 , NO 2 , CN, C(O)OH, C(O)OCH 3 , Ci-Q; O- alkyl, - 5-alkyl, phenyl or aryl; Y is H, CH 3 , NH 2 , or NO 2 ; and Z is H.
- M is C(O)
- X is
- Y is H, CH 3 , NH 2 , or NO 2 ; and ZisH.
- Y is H, CH 3 , NH 2 , or NO 2 ; and ZisH.
- M is C(O)
- X is
- Xi is H, Q-C 6 alkyl, F, Cl, Br, I, OH, OCH 3 , NO 2 , CN, C(O)OH, C(O)OCH 3 , -C 6 O- alkyl, - S-alkyl, phenyl or aryl;
- X 4 is H, a halogen, OH, OCH 3 , NO 2 , CN, C ⁇ -C 6 alkyl or C 2 -C 6 cycloalkyl;
- Y is H, CH 3 , NH 2 , or NO 2 ;
- M is C(O)
- X is
- Xi is H, Ci-Q alkyl, F, Cl, Br, I, OH, OCH 3 , NO 2 , CN, C(O)OH, C(O)OCH 3 , - O- alkyl, C ⁇ -C 6 5-alkyl, phenyl or aryl;
- Y is H
- Z is H, -C 6 alkyl or C 2 -C 6 cycloalkyl.
- M is C(O)
- X is
- X ! is H, Ci- alkyl, F, Cl, Br, I, OH, OCH 3 , NO 2 , CN, C(O)OH, C(O)OCH 3 , - O- alkyl, C ⁇ -C 6 S-alkyl, phenyl or aryl;
- Y is H
- Z is H, Ci-Q alkyl or C 2 -C 6 cycloalkyl.
- M is C(O)
- X is
- Xi is H, d-C 6 alkyl, F, Cl, Br, I, OH, OCH 3 , NO 2 , CN, C(O)OH, C(O)OCH 3 , - O- alkyl, C ⁇ -C 6 S-alkyl,. phenyl or aryl;
- Y is H
- Z is H, Ci- alkyl or C 2 -C 6 cycloalkyl.
- M is C(O)
- X is
- X! is H, Ci-C ⁇ alkyl, F, Cl, Br, I, OH, OCH 3 , NO 2 , CN, C(O)OH, C(O)OCH 3 , C C 6 O- alkyl, - S-alkyl, phenyl or aryl;
- Y is H, C ⁇ -C 6 alkyl, aryl, phenyl, OH, C(O)OH, NH 2 , NO 2 , (O) or (S);
- Z is H or C(O)OH, wherein when Y is (O) or (S), Z is not present.
- M is C(O)
- X is Xi is H, Cj-Cs alkyl, F, Cl, Br, I, OH, OCH 3 , NO 2 , CN, C(O)OH, C(O)OCH 3 , C!-C 6 O- alkyl, Q-C 6 S-alkyl, phenyl or aryl;
- Y is H, C C 6 alkyl, aryl, phenyl, OH, C(O)OH, NH 2 , NO 2 , (O) or (S);
- Z is H or C(O)OH, wherein when Y is (O) or (S), Z is not present.
- X is H, C ⁇ -C 6 alkyl, F, Cl, Br, I, OH, OCH 3 , NO 2 , CN, C(O)OH, C(O)OCH 3 , C C 6 O- alkyl, -C ⁇ 5-alkyl, phenyl or aryl;
- Y is H, C C 6 alkyl, aryl, phenyl, OH, C(O)OH, NH 2 , NO 2 , (O) or (S);
- Z is H or C(O)OH, wherein when Y is (O) or (S), Z is not present.
- M is C(O)
- X is
- X ! is H, C C 6 alkyl, C C 6 0-alkyl, Ci-C 6 S-alkyl, COCH 3 , CH 2 OH, phenyl or aryl; Y is H, -Qs alkyl, aryl, phenyl, OH, C(O)OH, NH 2 , NO 2 , (O) or (S); Z is H or C(O)OH, wherein when Y is (O) or (S), Z is not present.
- Xi is H, Q-C 6 alkyl, C r C 6 O-alkyl, C C 6 S-alkyl, COCH 3 , CH 2 OH, phenyl or aryl; and ZisNH 2 orNH-P ⁇ .
- M is C(O)
- X is
- X is H, C-i- alkyl, Ci-C 6 O-alkyl, Q- S-alkyl, COCH 3 , CH 2 OH, phenyl or aryl;
- Y is H, OH, a halogen, NH 2 , NH-P 1; (O) or (S).
- M is C(O)
- X is
- Xi is H, -C 6 alkyl, -C 6 O-alkyl, - S-alkyl, COCH 3 , CH 2 OH, phenyl or aryl.
- Pi is Boc, Fmoc, Troc, silyl, sulfonyl, acetyl or benzyl.
- the invention also encompasses a pharmaceutical composition comprising the ceramide derivative described above, and a liposome having a lipid bilayer that comprises a lipid and the ceramide derivative described above.
- the invention encompasses methods of treating an animal afflicted with cancer, an inflammatory disease or a viral infection by administering an anti-cancer, anti-inflammatory or anti- viral effective amount of the ceramide derivative to the animal.
- Figs. 1A-1H are a series of fluorescence micrographs showing 2-Br C2 ceramide induced apoptosis in human tumor cell lines.
- Control untreated
- U937 Fig. 1 A
- MCF7 Fig. IE
- MCF7/ADR Fig IG
- 2-Br C2 ceramide treated cells U937, with 2 ⁇ M for 2 hr (Fig IB), 5 ⁇ M for 2 hr (Fig. 1C), 5 ⁇ M for 3 hr (Fig. ID), MCF7, with 25 ⁇ M for 20 hr (Fig. IF), MCF7/ADR, with 1 ⁇ M for 20 hr (Fig.
- Figs. 2A-2D are a series of graphical depictions of 2-Br C2 ceramide induced apoptosis in U937 cells.
- Fig. 2A cells were treated with 0, 2, or 5 ⁇ M of 2-Br C2 ceramide for the indicated hours and then processed using TUNEL assay.
- the dUTP-biotin labeled (apoptotic) cells were distinguished from unlabeled ones and quantified using flow cytometry.
- Mean values ⁇ SE from at least three independent experiments are shown in 5 ⁇ M treated samples. Histograms shown are from a representative experiment, in which cells were either untreated (Fig. 2B), treated with 100 ⁇ M C2 ceramide (Fig.
- Figs. 3A and 3B are plots showing caspase inhibitors preventing U937 cells from undergoing 2-Br C2 ceramide induced apoptosis.
- various peptide inhibitors were incubated with cells an hour prior to drug treatment. Cells were further treated with 2-Br C2 ceramide for additional 3 hrs and processed using TUNEL assay as described previously.
- Fig. 3B indicates ZBETD-FMK inhibition of 2-Br C2 ceramide induced apoptosis in a dose-dependent manner. Increasing doses of ZIETD-FMK were added to cells prior to 2-Br C2 ceramide treatment. Data shown are representative of two independent experiments.
- Figs. 4 A and 4B are graphs showing caspase activation by 2-Br C2 ceramide treatment.
- U937 cells were treated with 5 ⁇ M 2-Br C2 ceramide for indicated times were processed for cytosolic extract as described in materials and methods. 50 ⁇ g of total protein from the extracts were used in all samples and the volume was normalized with lysis buffer.
- IETDase (Fig 4A) and DEVDase (Fig. 4B) activity in extracts was measured with the fluorogenic substrate, Ac-IETD- AFC and Ac-DEVD-AFC, respectively.
- the present invention comprises novel ceramide derivatives that show significant anti-neoplastic activity.
- the ceramide derivatives are of the formula I:
- R is C n H 2n+1 , where n is an integer of from 1-18;
- M is C(O) or CH 2 ;
- Q is C, OC or S(O 2 )N;
- Y is H, OH, Cj- alkyl, C(O)OH, aryl, phenyl, NH 2 , NO 2 , C 6 H 5 , a halogen, NH-P l5 (O) or (S);
- Z is H, C 6 H 5 , alkyl, NH 2 , NH-Pi or C(O)OH, wherein when Y is (O) or (S), Z is not present, and wherein when X, Y and Z are present as different moieties, the compound has an R, an S, or any combination of the R and S configurations about the ⁇ -carbon;
- X is F, Cl, Br, I, C 6 H 5 , O-Si(CH 3 ) 3 , O-Si(C 4 H 9 ) 3 , O-Si(C 6 H 5 ) 3 , C X -C X1 alkyl, -CH 2 -O-X ! , or
- k is an integer from 0 to 6;
- Ri, R 2 , and R 3 are each independently H, C C 6 alkyl, Ci-C 6 alkenyl, C 2 -C 6 cycloalkyl, or aryl;
- Xi is H, OH, Ci-C ⁇ alkyl, Q-C 6 0-alkyl, Q-C6 S-alkyl, C 2 -C 6 cycloalkyl, aryl, phenyl, a halogen, NO 2 , CN, C(O)H, C(O)OH, C(O)OCH 3 , COCH 3 , CH 2 OH, NH 2 , N 3 , NHCH 3 , CONH 2 , N(CH 2 CH 2 ) 2 C1 2 , B(OH) 2 , furyl or aryl sulfonate;
- X 2 is -O-CH 2 -, and X 3 is -O-CH 2 - or -O-, such that X 2 and X 3 taken together form a heterocyclic ring;
- Pi is H or an amino protecting group.
- the ceramide derivative can be one or any combination of the O-erythro, D-threo, L-erythro or L-threo confirmations, but is preferably D-erythro. Additionally, the ceramide derivatives can consist of a (+) optical isomer exclusively, a (-) optical isomer exclusively, or any combination of (+) and (-) optical isomers.
- Each of Y and Z is independently H or C 6 Hs.
- M is C(O)
- X is Br or a -C 17 alkyl group
- Q is C
- Z is H, C 6 H 5 , an alkyl group or C(O)OH.
- M is C(O), and X is
- M is C(O)
- X is -°- y Xl
- X ⁇ is H, Q-C 6 alkyl, F, Cl, Br, I, OH, OCH 3 , NO 2 , CN, C(O)OH, C(O)OCH 3 , Q-Qs O- alkyl, C ⁇ -C 6 5-alkyl, phenyl or aryl;
- Y is H, CH 3 , NH 2 , or NO 2 ; and Z is H.
- M is C(O)
- X is
- Y is H, CH 3 , NH 2 , or NO 2 ; and Z is H.
- M is C(O)
- X is
- Y is H, CH 3 , NH 2 , or NO 2 ; and Z is H.
- M is C(O)
- X is
- X ! is H, d-C 6 alkyl, F, Cl, Br, I, OH, OCH 3 , NO 2 , CN, C(O)OH, C(O)OCH 3 , C C 6 O- alkyl, - S-a ⁇ kyl, phenyl or aryl;
- X t is H, a halogen, OH, OCH 3 , NO 2 , CN, - alkyl or C 2 -C 6 cycloalkyl;
- Y is H, CH 3 , NH 2 , or NO 2 ;
- M is C(O)
- X is
- Xi is H, C ⁇ -C 6 alkyl, F, Cl, Br, I, OH, OCH 3 , NO 2 , CN, C(O)OH, C(O)OCH 3 , C r C 6 O- alkyl, C ⁇ -C 6 S-alkyl, phenyl or aryl;
- Y is H
- Z is H, C ⁇ -C 6 alkyl or C 2 -C 6 cycloalkyl.
- M is C(O)
- X is
- Xi is H, C C 6 alkyl, F, Cl, Br, I, OH, OCH 3 , NO 2 , CN, C(O)OH, C(O)OCH 3 , - O- alkyl, - S-alkyl, phenyl or aryl; Y is H; and
- Z is H, Ci-Q alkyl or C 2 -C 6 cycloalkyl.
- Xi is H, Ci-Q alkyl, F, Cl, Br, I, OH, OCH 3 , NO 2 , CN, C(O)OH, C(O)OCH 3 , - O- alkyl, - S-alkyl, phenyl or aryl;
- Y is H
- Z is H, Ci- alkyl or C 2 -C 6 cycloalkyl.
- M is C(O)
- X is
- Xi is H, C ⁇ -C 6 alkyl, F, Cl, Br, I, OH, OCH 3 , NO 2 , CN, C(O)OH, C(O)OCH 3 , -C 6 O- alkyl, C ⁇ -C 6 S-alkyl, phenyl or aryl;
- Y is H, C ⁇ -C 6 alkyl, aryl, phenyl, OH, C(O)OH, NH 2 , NO 2 , (O) or (S);
- Z is H or C(O)OH, wherein when Y is (O) or (S), Z is not present.
- M is C(O)
- X is
- Xi is H, C ⁇ -C 6 alkyl, F, Cl, Br, I, OH, OCH 3 , NO 2 , CN, C(O)OH, C(O)OCH 3 , C C 6 O- alkyl, C ⁇ -C 6 S-alkyl, phenyl or aryl;
- Y is H, Ci-Q; alkyl, aryl, phenyl, OH, C(O)OH, NH 2 , NO 2 , (O) or (S);
- Z is H or C(O)OH, wherein when Y is (O) or (S), Z is not present.
- M is C(O);
- X is -CH 2 -O-X ! ;
- Xi is H, Q-Q alkyl, F, Cl, Br, I, OH, OCH 3 , NO 2 , CN, C(O)OH, C(O)OCH 3 , Q-Q O- alkyl, Q-Q S-alkyl, phenyl or aryl;
- Y is H, Q-Q alkyl, aryl, phenyl, OH, C(O)OH, NH 2 , NO 2 , (O) or (S);
- Z is H or C(O)OH, wherein when Y is (O) or (S), Z is not present.
- M is C(O)
- X is
- Xi is H, C ⁇ -C 6 alkyl, Q-Q O-alkyl, Q-Q 5-alkyl, COCH 3 , CH 2 OH, phenyl or aryl; Y is H, Q-Q alkyl, aryl, phenyl, OH, C(O)OH, NH 2 , NO 2 , (O) or (S); Z is H or C(O)OH, wherein when Y is (O) or (S), Z is not present.
- M is C(O)
- X is
- Xi is H, Q-Q alkyl, Q-C 6 O-alkyl, C ⁇ -C 6 S-alkyl, COCH 3 , CH 2 OH, phenyl or aryl; and Z is NH 2 or NH-P ⁇ .
- M is C(O)
- X is
- Xi is H, Q-C 6 alkyl, Q-C 6 O-alkyl, Q-Q S-alkyl, C ⁇ CH 3 , CH 2 ⁇ H, phenyl or aryl; Y is H, ⁇ H, a halogen, NH 2 , NH-Pi, (O) or (S).
- M is C(O)
- X is
- X! is H, Q-C 6 alkyl, Q-C 6 O-alkyl, Q-C 6 S-alkyl, COCH 3 , CH 2 OH, phenyl or aryl.
- Pi is Boc, Fmoc, Troc, silyl, sulfonyl, acetyl or benzyl.
- the invention also encompasses a pharmaceutical composition comprising the novel ceramide derivatives.
- the pharmaceutical composition may include a pharmaceutically acceptable carrier.
- the invention also comprises a method of treating an animal afflicted with cancer, an inflammatory disease or a viral infection by administering an anti-cancer, anti-inflammatory or anti- viral effective amount of the ceramide derivative to the animal.
- An "anti-cancer effective amount” is an amount that slows or stops the proliferation of cancer cells or other abnormally-proliferating cells, or causes cancer cell death.
- An “anti-inflammatory effective amount” is an amount that slows or stops an inflammatory response in a patient.
- An “anti-viral effective amount” is an amount that slows or stops the proliferation of a virus, or causes the death of a virus.
- Sphingosines and ceramides are formed in animal cells by the combination of palmitoyl CoA (CH3(CH2)i4-CO-S-CoA) and serine to give dehydrosphinganine
- Sphingomyelinase can catalyze the hydrolytic removal of the phosphorylcholine from the sphingomyelin to give rise to a ceramide. Reverse hydrolysis of the ceramide can give rise to a sphingomyelin.
- the growth inhibitory data collected on the inventive ceramides and presented below suggest that there is a structure-activity relationship depending upon the nature of the X, Y, and Z groups attached. Since variations in potency are found with changes in short-chain residues (as is the case with 2-Bromo Cx, 2 or 3-Methyl Cx, 2 or 3-Phenyl Cx ceramide series), it is likely that hydrophobicity plays a key role in distinguishing the cellular targets. Those targets may have active sites that could accommodate only smaller size hydrophobic moieties.
- hydrophilic moiety tethered to the hydrophobic moiety may assist in enhancing cytotoxicity.
- N- Tyrosine (4-0- ) ⁇ N-Boc-Phenylalanine (4-N,N-dichloroethyl), and N-Boc- Phenylalanine (4-CH 2 NH-/ ' Propyl ceramide compounds) may assist in enhancing cytotoxicity.
- compositions comprising the compound of this invention and a pharmaceutically acceptable carrier; the composition can also comprise an additional bioactive agent.
- pharmaceutically acceptable carriers as used herein are generally intended for use in connection with the administration of lipids and liposomes, including liposomal bioactive agent formulations, to animals, including humans.
- Pharmaceutically acceptable carriers are generally formulated according to a number of factors well within the purview of the ordinarily skilled artisan to determine and account for, including without limitation: the particular liposomal bioactive agent used, its concentration, stability and intended bioavailability; the disease, disorder or condition being treated with the liposomal composition; the subject, its age, size and general condition; and the composition's intended route of administration, e.g., nasal, oral, ophthalmic, topical, transdermal, vaginal, subcutaneous, intramammary, intraperitoneal, intravenous, or intramuscular (see, for example, Nairn, J.G., Pharmaceutical Sciences, Mack Publishing Co. (1985)).
- Typical pharmaceutically acceptable carriers used in parenteral bioactive agent administration include, for example, D5W, an aqueous solution containing 5% weight by volume of dextrose, and physiological saline.
- Pharmaceutically acceptable carriers can contain additional ingredients, for example those which enhance the stability of the active ingredients included, such as preservatives and anti-oxidants.
- sphingosine synthetic and swine brain
- Avanti Polar Lipids Alaster, AL
- Matreya, Inc. Matreya, Inc.
- All other reagents used in the synthesis were obtained either from Aldrich (Milwaukee, WI) or from Fluka (Ronkonkoma, NY). Solvents used for the reactions and purification, unless stated otherwise, were obtained from Aldrich.
- sphingosine 200 mg, 0.67 mmol, Avanti Polar Lipids
- 15 ml of anhydrous dichloromethane solution containing 2- bromoacetic acid 111 mg, 0.80 mmol; Aldrich Chemicals
- 1,3- dicyclohexylcarbodiimide 165 mg, 0.8 mmol, Aldrich Chemicals.
- the reaction mixture was brought to 0° C with the aid of an ice-water bath and then triethylamine (73 mg, 100 ⁇ l, 1 mmol, Fluka) was added.
- ceramides varying in acyl chain length from Q to Qo were prepared by the same procedure as described above except the corresponding 2-bromo carboxylic acids were used. The resulting products were characterized by TLC and IH NMR. 2-chloro and 2-iodo Q ceramides were prepared by the same procedure as described above except 2-chloro acetic acid and 2-iodo acetic acid were used, respectively, and characterized by TLC and 1H NMR.
- ceramides were prepared as described above and evaluated for anti- neoplastic activity against several established tumor cell lines using Sulforhodamine B (SRB) assays (described below). The anti-neoplastic activity of the ceramides against particular leukemia lines was also evaluated as described below.
- SRB Sulforhodamine B
- HT29 human colon carcinoma
- DCT Tumor Repository Ferick, MD
- MCF7 human breast tumor MCF7/ADR (MCF7 adriamycin resistant subline)
- A549 human non small cell lung cancer P388 murine leukemia
- P388/ADR P388 adriamycin resistant subline
- U937 human promyelocytic leukemia All lines were grown in Complete Medium (RPMI 1640 medium containing 10% fetal bovine serum (GIBCO)) in an atmosphere of 5% CO 2 at 37 9 C.
- GEBCO fetal bovine serum
- SRB assays were performed as described by Monk, A. et al., Natl Cancer Inst, 83:757-766 (1991), (incorporated herein by reference), with minor modifications. Following incubation with experimental ceramide derivatives or control compounds (i.e., without drug), cells were fixed with 50 ⁇ l of cold 50% (wt/vol) trichloroacetic acid (TCA) for 60 minutes at 4 Q C. The supernatant was discarded, and the plates were washed six times with deionized water and air dried.
- TCA trichloroacetic acid
- the precipitate was stained with 100 ⁇ l SRB solution (0.4% wt/vol in 1% acetic acid) for 10 minutes at room temperature, and free SRB was removed by washing three times with 1% acetic acid, and the plates were air dried.
- Bound SRB was solubilized with Tris buffer (10 mM), and the optical densities (ODs) were read using an automated plate reader (Bio-Rad, Model 3550- UV) at 490 nm. Background values were subtracted from the test data, and the data were calculated as % of control.
- the GI 50 represents the concentration of test agent resulting in 50% of net growth compared to that of the control untreated samples.
- GI 50 represents the concentration of test agent resulting in 50% of net growth compared to that of the untreated control samples.
- Tables 1 and 2 were the average of three samples of duplicates (total of six data points) from a single experiment. Those marked by * were the average of two independent experiments (total of twelve data points), while results presented as mean ⁇ S.E. were from three or more independent experiments. Numbers containing > or ⁇ were an estimated values based on % control in the prescreening test rather than from a full scale Gl 50 study, nd: not determined. (+): Cell death observed (when the OD of the test samples is less than the time 0 sample) at 50 ⁇ M, the maximum test concentration. (-): Cell death not observed.
- 2-Br C2 ceramide a cell-permeable synthetic ceramide
- C2 ceramide a cell-permeable synthetic ceramide
- this modification greatly enhanced growth inhibition compared to the parent compound.
- 2-Br C2 ceramide is 5 to 50 times more potent compared to C2 parent ceramide. While the GIso's for C2 ceramide ranged from 20 to 30 ⁇ M, the GIso's for 2-Br C2 ceramide were from 0.2-6 ⁇ M.
- 2-Br-C2 ceramide was more potent in leukemia ( ⁇ 1 ⁇ M) than in solid tumor lines (1- 6 ⁇ M) and also active in drug resistant lines (MCF7/ADR vs. MCF7 and P388 vs. P388/ADR). While not limiting our by theory, we believe that the enhanced potency of 2-Br-C2 ceramide compared to C2 ceramide could result from changes in cell permeation, compartmentalization and cell metabolism, due to the altered structure and conformation of the ceramide. The 2-Cl- and 2-1- C2 ceramides showed less activity than the 2-Br C2 ceramide against tumor cell growth, though the 2-1 was surprisingly much better than the 2-Cl.
- the 2-Br-C6 ceramide surprisingly showed more potency than the C6 ceramide, though the differences were not as dramatic as those between the 2-Br-C2 and C2 ceramides. Potency decreased in the 2-Br-C8 ceramide, and the 2-Br-C10 to C16 ceramides were relatively inactive in these in vitro tests.
- Table 4 results were the average of three samples of duplicates (total of six data points) from a single experiment. Numbers containing > or ⁇ were an estimated values based on % control in the prescreening test rather than from a full scale GI 50 study. (+) Cell death observed (when the OD of the test samples is less than the time 0 sample) at 50 ⁇ M, the maximum test concentration.
- the D-erythro isomer showed higher anti-tumor activity against the HT-29 and A-549 cell lines than the L-threo isomer. Both isomers were similarly effective against the MCF-7 and MCF-7/ADR lines.
- TUNEL Terminal transferase mediated dUTP nick end labeling
- Fig. 1 Photographs were taken using a fluorescence microscope with a 40X lens, and are shown in Fig. 1 ((A) control (untreated) U937; (B) U937 treated with 2 ⁇ M 2-Br C2 ceramide for 2 hr; (C) U937 treated with 5 ⁇ M 2-Br C2 ceramide for 2 hr; (D) U937 treated with 5 ⁇ M 2-Br C2 ceramide for 3 hr; (E) control (untreated) MCF7; (F) MCF7 treated with 25 ⁇ M 2-Br C2 ceramide for 20 hr; (G) control (untreated) MCF7/ADR; (H) MCF7/ADR treated with 1 ⁇ M 2-Br C2 ceramide for 20 hr).
- Fig. 1 The results shown in Fig. 1 reveal that 2- Br C2 ceramide induces apoptosis in U937 cells and in other solid tumor lines.
- the apoptotic (brighter) cells and condensed chromatin were observed in U937 cells as early as 2 hr following 2 ⁇ M 2-Br C2 ceramide treatment (Fig. IB), and the number of apoptotic cells increased in a dose- and time- dependent manner (Fig.lB-D).
- Fig.lB-D the number of apoptotic cells increased in a dose- and time- dependent manner
- chromatin granules were present within the nuclear membrane, however, by 3 hr of drug treatment, many cells seemed to have lost their integrity and the nuclei had disintegrated.
- ZVAD- FMK a general inhibitor
- ZDEVD- FMK a inhibitor for Group It caspases and, to a lesser extent 8
- ZIETD- FMK a specific inhibitor for caspase 8
- ZLEHD- FMK a specific inhibitor for caspase 9
- ZFA- FMK a negative control
- Cytosolic extracts were prepared cell cytosolic extracts were prepared according to Tamm et al., Cancer Res, 58:5315-5320 (1998), and reactions were carried out in 96 well plates as described by Cuvillier et al., I Biol Chem, 273:2910-2916 (1998).
- reaction buffer 2X containing 100 ⁇ M of Z-DEVE-AFC or Z-IETD-AFC (Enzyme System Products, CA), 20 mM Hepes (pH 7.4), 200 mM NaCl, 1 mM EDTA, 0.2% CHAPS, 10 mM DTT, and 20% Sucrose was add to an equal volume of buffer A (20 mM Hepes, 10 mM KC1, 1.5 mM MgC12, 1 mM EDTA, and 1 mM DTT) containing 50 ⁇ g total protein.
- Enzymatic hydrolysis of substrates was measured by release of AFC (amino-trifluoromethyl coumarin) induring a 30-min period using a Cytofluor 4000 multi plate reader (PerSeptive Biosystems, MA) (excitation at 395 nm and emission at 490 nm). Caspase activity was measure as arbitrary fluorescence units and converted to fold increase over basal level in untreated (control) cells. Background fluorescence of substrate alone was subtracted in each coordinated sample. The accumulation of IETD- and DEVD-specific protease activity from untreated and treated U937 cells was determined (Fig. 4A & B).
- C2 ceramide acts at the level of mitochondria, which is upstream of caspase 8 in the apoptosis pathway.
- ceramide could act upstream of caspase 8 in U937 cells.
- the GI50 values were determined by the SRB assay as described above. A “+” indicates that cell death was observed (when the OD of the test samples is less than the time 0 sample) at 50 ⁇ M, the maximum test concentration. "-" indicates that cell death was not observed at 50 ⁇ M.
- Table 8 Screening against MCF-7 and A549 tumor cell lines; the "+” sign indicates the activity at 50 ⁇ M concentration, whereas the "-" sign indicates relatively inactive.
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AU2001255199A AU2001255199A1 (en) | 2000-03-28 | 2001-03-28 | Ceramide derivatives and method of use |
CA002402769A CA2402769A1 (en) | 2000-03-28 | 2001-03-28 | Ceramide derivatives and method of use |
JP2001570614A JP2003528851A (en) | 2000-03-28 | 2001-03-28 | Ceramide derivatives and methods of use |
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Cited By (22)
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FR2839310A1 (en) * | 2002-05-03 | 2003-11-07 | Pasteur Institut | NOVEL PROCESS FOR THE PREPARATION OF ALPHA-GLYCOSYLCERAMIDES, NOVEL ALPHA-GLYCOSYLCERAMIDE DERIVATIVES AND THEIR APPLICATIONS |
WO2004064823A1 (en) * | 2003-01-21 | 2004-08-05 | Aston University | Ceramide derivatives for the treatment of inflammation |
US6858383B2 (en) | 2000-12-22 | 2005-02-22 | Medlyte, Inc. | Compositions and methods for the treatment and prevention of cardiovascular diseases and disorders, and for identifying agents therapeutic therefor |
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EP1576894A1 (en) * | 2004-03-16 | 2005-09-21 | Nederlandse Organisatie voor toegepast-natuurwetenschappelijk Onderzoek TNO | The use of sphingolipids in the treatment and prevention of type 2 diabetes mellitus, insulin resistance and Metabolic Syndrome |
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WO2010093615A2 (en) * | 2009-02-10 | 2010-08-19 | Tulane University | Compounds, their syntheses, compositions, and methods to treat cancer |
US7829674B2 (en) | 2006-10-27 | 2010-11-09 | Lpath, Inc. | Compositions and methods for binding sphingosine-1-phosphate |
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US10045953B2 (en) | 2006-07-06 | 2018-08-14 | Case Western Reserve University | Ceramide composition and method of use |
US10273208B2 (en) | 2014-05-23 | 2019-04-30 | Northwestern University | Screening methods for the binding affinity of chemical entities to biological molecules and NEDD4-1 inhibitors identified by the screening methods |
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CA2402769A1 (en) | 2001-10-04 |
EP1268414A1 (en) | 2003-01-02 |
JP2003528851A (en) | 2003-09-30 |
AU2001255199A1 (en) | 2001-10-08 |
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