NZ616960B2 - Prenylated hydroxystilbenes - Google Patents
Prenylated hydroxystilbenes Download PDFInfo
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- NZ616960B2 NZ616960B2 NZ616960A NZ61696012A NZ616960B2 NZ 616960 B2 NZ616960 B2 NZ 616960B2 NZ 616960 A NZ616960 A NZ 616960A NZ 61696012 A NZ61696012 A NZ 61696012A NZ 616960 B2 NZ616960 B2 NZ 616960B2
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- AYPZAZPOYROADP-UHFFFAOYSA-N 2-(2-phenylethenyl)phenol Chemical class OC1=CC=CC=C1C=CC1=CC=CC=C1 AYPZAZPOYROADP-UHFFFAOYSA-N 0.000 title abstract description 13
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- GVNVAWHJIKLAGL-UHFFFAOYSA-N 2-(cyclohexen-1-yl)cyclohexan-1-one Chemical compound O=C1CCCCC1C1=CCCCC1 GVNVAWHJIKLAGL-UHFFFAOYSA-N 0.000 claims description 118
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C37/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring
- C07C37/01—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring by replacing functional groups bound to a six-membered aromatic ring by hydroxy groups, e.g. by hydrolysis
- C07C37/055—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring by replacing functional groups bound to a six-membered aromatic ring by hydroxy groups, e.g. by hydrolysis the substituted group being bound to oxygen, e.g. ether group
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C39/00—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a six-membered aromatic ring
- C07C39/205—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a six-membered aromatic ring polycyclic, containing only six-membered aromatic rings as cyclic parts with unsaturation outside the rings
- C07C39/21—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a six-membered aromatic ring polycyclic, containing only six-membered aromatic rings as cyclic parts with unsaturation outside the rings with at least one hydroxy group on a non-condensed ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C39/00—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a six-membered aromatic ring
- C07C39/205—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a six-membered aromatic ring polycyclic, containing only six-membered aromatic rings as cyclic parts with unsaturation outside the rings
- C07C39/21—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a six-membered aromatic ring polycyclic, containing only six-membered aromatic rings as cyclic parts with unsaturation outside the rings with at least one hydroxy group on a non-condensed ring
- C07C39/215—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a six-membered aromatic ring polycyclic, containing only six-membered aromatic rings as cyclic parts with unsaturation outside the rings with at least one hydroxy group on a non-condensed ring containing, e.g. diethylstilbestrol
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C41/00—Preparation of ethers; Preparation of compounds having groups, groups or groups
- C07C41/01—Preparation of ethers
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C43/00—Ethers; Compounds having groups, groups or groups
- C07C43/02—Ethers
- C07C43/20—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring
- C07C43/23—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring containing hydroxy or O-metal groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C43/00—Ethers; Compounds having groups, groups or groups
- C07C43/02—Ethers
- C07C43/235—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring and to a carbon atom of a ring other than a six-membered aromatic ring
- C07C43/253—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring and to a carbon atom of a ring other than a six-membered aromatic ring containing hydroxy or O-metal groups
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/28—Preparation of carboxylic acid esters by modifying the hydroxylic moiety of the ester, such modification not being an introduction of an ester group
- C07C67/293—Preparation of carboxylic acid esters by modifying the hydroxylic moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/28—Preparation of carboxylic acid esters by modifying the hydroxylic moiety of the ester, such modification not being an introduction of an ester group
- C07C67/297—Preparation of carboxylic acid esters by modifying the hydroxylic moiety of the ester, such modification not being an introduction of an ester group by splitting-off hydrogen or functional groups; by hydrogenolysis of functional groups
Abstract
Disclosed are prenylated hydroxystilbene compounds of formula I where the substituents are as defined herein. Also disclosed are methods of synthesis of the compounds and the use of the compounds in the manufacture of medicaments for the treatment of cancer, immunosuppression, inflammation, bacterial or fungal infection and skin aging. l or fungal infection and skin aging.
Description
"Prenylated Hydroxystilbenes"
Technical Field
This invention relates to novel prenylated stilbene compounds and to the use of such
compounds in the treatment of diseases and medical disorders, for example cancer and
skin aging.
Background of the Invention
Propolis, or so called bee glue, is a complex resinous substance collected by worker
honey bees (Apis mellifera) from exudates and secretions of young shoots and buds
from certain trees and shrubs. It is used by the bees to seal cracks and holes in their
hives, and protect against microbial infections.
Propolis is a rich source of bioactive substances, and the medicinal use of propolis
dates back to ancient civilizations. Currently, propolis is extensively available as a
natural health product, and is widely used in cosmetics. However, its modern use in
medicine is limited, largely due to the wide variations in chemical compositions arising
from honey bees collecting from different or a mixture of plant sources. The
composition of propolis is dependent upon the surrounding flora to which the bees have
access, and as such, differences in flora may result in differences in propolis
compositions. For example, it is known that flavonoids are the major
pharmacologically active compounds in European propolis, polyprenylated
benzophenones are the main substances in Cuban and Venuzuelan propolis, and
prenylated cinnamic acid derivatives are predominant in Brazilian propolis.
Recognition of the botanical origin of the propolis produced by honey bees enables
beehives to be placed in favourable locations such that propolis from a single botanical
source may be produced to enable manufacture of medicines of high quality and
efficacy.
The medicinal uniqueness of propolis is determined by the selective collecting ability
of honey bees, as they can recognise natural materials that are relatively non-polar and
have antibiotic properties. As reported, the common source of propolis is leaf and
flower bud exudates, which are of high antibiotic character in order to protect the
delicate growing of plant tissue from attack by microorganisms. It has also been
reported that honey bees collect exudates from wounded or diseased plant tissues.
Such sources are potentially rich in antibiotic substances produced by plants in
response to wounding or attack from insects, microorganisms and viruses.
It is not clear from previous studies whether the bees simply collect a plant material
that is known as propolis, or if there is metabolic modification or addition from the
bees. However, there does not appear to be evidence of significant amounts of material
added from honey bees, or strong evidence for metabolic transformation.
Thus, a better understanding is required regarding the composition of propolis in
specific geographical locations to be able to utilize it to its full benefit.
In work leading up to the present invention the inventors have conducted a survey of
propolis samples isolated from Kangaroo Island (South Australia), and surprisingly
found that unlike other propolis which commonly contain flavonoids as active
constituents, Kangaroo Island propolis contain stilbenes, more particularly novel
prenylated polyhydroxystilbenes (pPHOS) which are similar in their core structure to
resveratrol (pictured below).
Resveratrol
Resveratrol is the constituent in red wine thought to contribute to the low incidence of
heart attack amongst the French despite high consumption of very rich food. In fact,
Resveratrol has been shown to inhibit LDL oxidation which leads to atherosclerosis
and coronary heart disease. Resveratrol is also a lead compound in preventative anti-
ageing medicine, and has also been found to possess anti-cancer and antioxidant
activities.
However, despite its therapeutic properties, resveratrol exhibits very poor oral
bioavailability and is rapidly metabolized in the intestines and liver into glucuronate
and sulfate conjugates. The in vivo effectiveness of resveratrol is only observed at high
concentrations (up to 5 g), or in the case of direct administration such as intravenous or
local application.
Recently, GlaxoSmithKline (GSK) Pharmaceutical conducted phase IIa clinical trials
of its proprietary formulation of resveratrol (3-5 g), SRT501 in the treatment of
multiple myeloma; however, the trials were halted as the formulation only offered
minimal efficacy, and several patients in the trial developed kidney failure.
Prenylated hydroxystilbenes have been reported in plants, mainly from the Moraceae
(Mulberry family, including Morus alba (mulberry), and various Artocarpus species)
and Fabaceae (Legume family, including Arachis hypogaea (peanut)) families. The
isolated compounds have reportedly exhibited anti-inflammatory, antimicrobial and
antioxidant activities, thus suggesting that the prenyl group does not adversely affect
the biological activities of hydroxystilbenes.
In fact, prenylated hydroxystilbenes could circumvent the problem of low
bioavailability of hydroxystilbenes, such as resveratrol, due to their lipophilic nature.
Owing to the presence of one or more prenyl groups, the compounds may be able to
cross cell membranes more readily and the formation of glucuronate and sulfate
conjugates may be avoided, thus improving the bioavailability of the compounds, and
more generally presenting superior drug candidates for the development of new
therapeutic agents. Previously, it has been demonstrated that a tetramethoxy derivative
of resveratrol was able to cross the blood-brain barrier in rats more easily than
resveratrol.
Thus, the novel pPHOS derivatives isolated from the propolis samples of Kangaroo
Island are strong candidates for the development of new therapeutic agents in the
treatment of diseases such as cancer.
Any discussion of documents, acts, materials, devices, articles or the like which has
been included in the present specification is not to be taken as an admission that any or
all of these matters form part of the prior art base or were common general knowledge
in the field relevant to the present invention as it existed before the priority date of each
claim of this application.
Summary of the Invention
In work leading up to the present invention the inventors have isolated and synthesised
a number of novel prenylated polyhydroxystilbenes (pPHOS) derivatives, and carried
out in vitro experiments in which these novel compounds have exhibited high potency
and selectivity in a panel of cancer cell lines, particularly in leukemia and melanoma
cell lines. In other preliminary experiments, a number of the novel pPHOS derivatives
were found to modulate activity of the SIRT1 enzyme which indicate that the novel
pPHOS compounds of the present invention may be lead therapeutic agents for the
treatment of a range of diseases.
Accordingly, in a first aspect of the present disclosure, there is provided a method for
treating cancer comprising administering a therapeutically effective amount of a
compound of formula (I),
wherein:
R is independently H, OH, OR , CH CH=C(CH ) , OCH CH=C(CH ) ,
2 3 2 2 3 2
CH=CHCH(CH ) , CH=CHC(CH )=CH , OCH=CHCH(CH ) , or
3 2 3 2 3 2
OCH=CHC(CH )=CH , wherein at least one of R is CH CH=C(CH ) ,
3 2 2 3 2
OCH CH=C(CH ) , CH=CHCH(CH ) , CH=CHC(CH )=CH ,
2 3 2 3 2 3 2
OCH=CHCH(CH ) , or OCH=CHC(CH )=CH ;
3 2 3 2
R is selected from OH, OR , CH CH=C(CH ) , OCH CH=C(CH ) ,
2 3 2 2 3 2
CH=CHCH(CH ) , CH=CHC(CH )=CH , OCH=CHCH(CH ) , or
3 2 3 2 3 2
OCH=CHC(CH )=CH ;
R is selected from H, OH, OR , CH CH=C(CH ) , OCH CH=C(CH ) ,
2 3 2 2 3 2
CH=CHCH(CH ) , CH=CHC(CH )=CH , OCH=CHCH(CH ) , or
3 2 3 2 3 2
OCH=CHC(CH )=CH ;
R is selected from, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl or
benzyl;
n is an integer selected from the group consisting of 1, 2, 3 or 4;
and A----B is selected from CH=CH, CH -CH , CH=CHX, or CH -CH X,
2 2 2 2
where X=(CH )pCH , and p is an integer selected from the group consisting of
0, 1, 2 or 3; provided that when R is OH, R is H or OH, A----B is CH=CH, n is
3 and two of the R groups are OH, then the third R group is not
CH=CHCH(CH ) ;
or a pharmaceutically acceptable salt, solvate, or pharmaceutical composition
including said compounds, to a patient in need thereof.
In a second aspect of the present disclosure, there is provided a method for treating
cancer comprising administering a therapeutically effective amount of a compound of
formula (I),
wherein:
R is independently H, OH, OR , CH CH=C(CH ) , OCH CH=C(CH ) ,
2 3 2 2 3 2
CH=CHCH(CH ) , CH=CHC(CH )=CH , OCH=CHCH(CH ) , or
3 2 3 2 3 2
OCH=CHC(CH )=CH , wherein at least one of R is CH CH=C(CH ) ,
3 2 2 3 2
OCH CH=C(CH ) , CH=CHCH(CH ) , CH=CHC(CH )=CH ,
2 3 2 3 2 3 2
OCH=CHCH(CH ) , or OCH=CHC(CH )=CH ;
3 2 3 2
R is selected from OH, OR , CH CH=C(CH ) , OCH CH=C(CH ) ,
2 3 2 2 3 2
CH=CHCH(CH ) , CH=CHC(CH )=CH , OCH=CHCH(CH ) , or
3 2 3 2 3 2
OCH=CHC(CH )=CH ;
R is selected from H, OH, OR , CH CH=C(CH ) , OCH CH=C(CH ) ,
2 3 2 2 3 2
CH=CHCH(CH ) , CH=CHC(CH )=CH , OCH=CHCH(CH ) , or
3 2 3 2 3 2
OCH=CHC(CH )=CH ;
R is selected from, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl or
benzyl;
n is an integer selected from the group consisting of 1, 2, 3 or 4;
and A----B is selected from CH=CH, CH -CH , CH=CHX, or CH -CH X,
2 2 2 2
where X=(CH )pCH , and p is an integer selected from the group consisting of
0, 1, 2 or 3;
or a pharmaceutically acceptable salt, solvate, or pharmaceutical composition
including said compounds, to a patient in need thereof.
In a third aspect, there is provided a compound of formula (I) according to the first or
second aspects, or pharmaceutical composition thereof, for use as a medicament.
In a fourth aspect, there is provided a compound of formula (I) according to the first or
second aspects, or pharmaceutical composition thereof, for use in therapy.
In a fifth aspect of the invention there is provided a compound of formula (I) according
to the first or second aspects, or pharmaceutical composition thereof, for use in the
treatment of cancer.
In a sixth aspect of the invention, there is provided a method for treating
immunosuppression comprising administering a therapeutically effective amount of a
compound of formula (I) according to the first or second aspects, or a pharmaceutical
composition including said compounds to a patient in need thereof.
In a seventh aspect of the invention, there is provided a method for treating
inflammation comprising administering a therapeutically effective amount of a
compound of formula (I) according to the first or second aspects, or a pharmaceutical
composition including said compounds to a patient in need thereof.
In an eighth aspect of the invention, there is provided a method for treating a bacterial
or fungal infection comprising administering a therapeutically effective amount of a
compound of formula (I) according to the first or second aspects, or a pharmaceutical
composition including said compounds to a patient in need thereof.
In a ninth aspect of the invention, there is provided a method for treating skin aging
comprising administering a therapeutically effective amount of a compound of formula
(I) according to the first or second aspects, or a pharmaceutical composition including
said compounds to a patient in need thereof.
In a tenth aspect of the invention, there is provided a use of a compound of formula (I)
according to the first or second aspects, or a pharmaceutical composition thereof in the
preparation of a medicament for the treatment of cancer.
In an eleventh aspect of the invention, there is provided a use of a compound of
formula (I) according to the first or second aspects, or a pharmaceutical composition
thereof in the preparation of a medicament for the treatment of immunosuppression.
In a twelfth aspect of the invention, there is provided a use of a compound of formula
(I) according to the first or second aspects, or a pharmaceutical composition thereof in
the preparation of a medicament for the treatment of inflammation.
In a thirteenth aspect of the invention, there is provided a use of a compound of formula
(I) according to the first or second aspects, or a pharmaceutical composition thereof in
the preparation of a medicament for the treatment of a bacterial or fungal infection.
In a fourteenth aspect of the invention, there is provided a use of a compound of
formula (I) according to the first or second aspects, or a pharmaceutical composition
thereof in the preparation of a medicament for the treatment of skin aging.
In further aspects of the invention, there is provided combinations comprising a
compound or pharmaceutical composition as defined above, and at least one further
therapeutic agent for the methods and uses as described herein.
According to a fifteenth aspect of the invention, there is provided a compound of
formula (Ia)
or a pharmaceutically acceptable salt or solvate thereof, wherein:
1a 1b 1c 1d 4
R R , R and R are each independently H, OH, OR , CH CH=C(CH ) ,
, 2 3 2
OCH CH=C(CH ) , CH=CHC(CH )=CH , OCH=CHCH(CH ) , or
2 3 2 3 2 3 2
1a-1d
OCH=CHC(CH )=CH , wherein at least one of R is CH CH=C(CH ) ,
3 2 2 3 2
OCH CH=C(CH ) , CH=CHC(CH )=CH , OCH=CHCH(CH ) , or
2 3 2 3 2 3 2
OCH=CHC(CH )=CH ;
R is selected from OH, OR , CH CH=C(CH ) , OCH CH=C(CH ) ,
2 3 2 2 3 2
CH=CHC(CH )=CH , OCH=CHCH(CH ) , or OCH=CHC(CH )=CH ;
3 2 3 2 3 2
R is selected from H, OH, OR , CH CH=C(CH ) , OCH CH=C(CH ) ,
2 3 2 2 3 2
CH=CHC(CH )=CH , OCH=CHCH(CH ) , or OCH=CHC(CH )=CH ;
3 2 3 2 3 2
R is selected from, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl or
benzyl;
and A----B is selected from CH=CH, CH -CH , CH=CHX, or CH -CH X,
2 2 2 2
where X=(CH )pCH , and p is an integer selected from the group consisting of
0, 1, 2 or 3; provided that:
3 2 1b 1d
(i) when R is H and R is OH or OCH CH=C(CH ) , then R and R are
2 3 2
independently not OH or OCH CH=C(CH ) ;
2 3 2
3 1a-1d 1a-1d
(ii) when R is H, one of R is H and at least one of R is
CH CH=C(CH ) , then A---B is not CH=CH.
2 3 2
In a sixteenth aspect of the invention, there is provided a compound of formula (Ia)
or a pharmaceutically acceptable salt or solvate thereof, wherein:
1a 1b 1c 1d 4
R R , R and R are each independently H, OH, OR , CH CH=C(CH ) ,
, 2 3 2
OCH CH=C(CH ) , CH=CHC(CH )=CH , OCH=CHCH(CH ) , or
2 3 2 3 2 3 2
1a-1d
OCH=CHC(CH )=CH , wherein at least one of R is CH CH=C(CH ) ,
3 2 2 3 2
OCH CH=C(CH ) , CH=CHC(CH )=CH , OCH=CHCH(CH ) , or
2 3 2 3 2 3 2
OCH=CHC(CH )=CH ;
2 3 4
R and R are each independently selected from OH, OR , CH CH=C(CH ) ,
2 3 2
OCH CH=C(CH ) , CH=CHC(CH )=CH , OCH=CHCH(CH ) , or
2 3 2 3 2 3 2
OCH=CHC(CH )=CH ;
R is selected from, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl or
benzyl;
and A----B is selected from CH=CH, CH -CH , CH=CHX, or −CH -CH X,
2 2 2 2
where X=(CH )pCH and p is an integer selected from the group consisting of 0,
1, 2 or 3.
In a seventeenth aspect of the invention, there is provided a pharmaceutical
composition comprising a compound of formula (Ia) according to the fifteenth or
sixteenth aspects, or a pharmaceutically acceptable salt or solvate thereof, and a
pharmaceutically acceptable excipient.
According to an eighteenth aspect, there is provided a method for treating cancer,
immunosuppression, inflammation, bacterial infection, fungal infection or skin aging
comprising administering a therapeutically effective amount of a compound of formula
(Ia) according to the fifteenth or sixteenth aspects, or a pharmaceutical composition
including said compounds to a patient in need thereof.
In a nineteenth aspect of the invention, there is provided a use of a compound of
formula (Ia) according to the fifteenth or sixteenth aspects, or a pharmaceutical
composition thereof in the preparation of a medicament for the treatment of cancer,
immunosuppression, inflammation, bacterial infection, fungal infection or skin aging.
According to the twentieth aspect of the invention, there is provided a method of
preparing compounds of formula (Ib) which comprises the following steps:
(i) treating the carboxylic acid with a suitable agent to provide the acid chloride as
follows;
(ii) condensation of the corresponding acid chloride with an aryl alkene as follows;
(iii) deprotection of the acetate group and alkylation as follows;
4 5 6
wherein, R , R and R are each independently selected from the group OMe, OEt,
i i t
OPr, O Pr, OBu, O Bu, O Bu, OBn.
In one embodiment, the method comprises the additional step as follows:
(iv) a hydrogenation reaction as follows:
4 5 6 4 5
wherein, R , R and R are as previously defined, provided that at least one of R , R or
R is OBn;
7 8 9
R , R and R are each independently selected from the group OH, OMe, OEt,
i i t
OPr, O Pr, OBu, O Bu, O Bu.
In another embodiment the method comprises two additional steps as follows:
(v) rearrangement of the prenyl group as follows:
(vi) and a hydrogenation reaction as follows:
(Ie)
(If)
4 5 6 4 5
wherein, R , R and R are as previously defined, provided that at least one of R , R or
R is OBn;
7 8 9
R , R and R are each independently selected from the group OH, OMe, OEt, OPr,
i i t
O Pr, OBu, O Bu, O Bu.
In a twenty first aspect of the invention, there is provided a compound according to
USYDS15 as identified below
USYDS15
There is also provided a pharmaceutical composition comprising the compound
USYDS15 according to the twenty first aspect, or a pharmaceutically acceptable salt or
solvate thereof, and a pharmaceutically acceptable excipient.
In a twenty third aspect of the invention, there is provided use of the compound
according to the twenty first aspect or the composition of the twenty second aspect, in
the preparation of a medicament for the treatment of cancer, immunosuppresion,
inflammation, fungal or bacterial infection, or for the treatment of skin aging.
Specific embodiments:
Specific embodiments of the disclosure are defined in the following items:
1. Use of a compound of formula (Ia),
or a pharmaceutically acceptable salt, solvate, or pharmaceutical composition
including said compounds,
wherein:
1a 4
R is selected from the group consisting of, OH, OR , CH CH=C(CH ) ,
2 3 2
OCH CH=C(CH ) , CH=CHCH(CH ) , CH=CHC(CH )=CH ,
2 3 2 3 2 3 2
OCH=CHCH(CH ) , or OCH=CHC(CH )=CH ,
3 2 3 2
1b 4
R is selected from the group consisting of H, OH, OR ,
CH CH=C(CH ) , OCH CH=C(CH ) , CH=CHCH(CH ) ,
2 3 2 2 3 2 3 2
CH=CHC(CH )=CH , OCH=CHCH(CH ) , or OCH=CHC(CH )=CH ,
3 2 3 2 3 2
1c 4
R is selected from the group consisting of H, OH, OR ,
CH CH=C(CH ) , OCH CH=C(CH ) , CH=CHCH(CH ) ,
2 3 2 2 3 2 3 2
CH=CHC(CH )=CH , OCH=CHCH(CH ) , or OCH=CHC(CH )=CH ,
3 2 3 2 3 2
1d 4
R is selected from the group consisting of H, OH, OR ,
CH CH=C(CH ) , OCH CH=C(CH ) , CH=CHCH(CH ) ,
2 3 2 2 3 2 3 2
CH=CHC(CH )=CH , OCH=CHCH(CH ) , or OCH=CHC(CH )=CH ,
3 2 3 2 3 2
1a-1d 1a-1d
wherein at least one of R is OH and at least one of R is
CH CH=C(CH ) , OCH CH=C(CH ) , CH=CHCH(CH ) ,
2 3 2 2 3 2 3 2
CH=CHC(CH )=CH , OCH=CHCH(CH ) or OCH=CHC(CH )=CH ;
3 2 3 2 3 2
R is selected from OH, OR , CH CH=C(CH ) , OCH CH=C(CH ) ,
2 3 2 2 3 2
CH=CHC(CH )=CH , OCH=CHCH(CH ) , or OCH=CHC(CH )=CH ;
3 2 3 2 3 2
R is selected from OH, OR , CH CH=C(CH ) , OCH CH=C(CH ) ,
2 3 2 2 3 2
CH=CHC(CH )=CH , OCH=CHCH(CH ) , or OCH=CHC(CH )=CH ;
3 2 3 2 3 2
R is selected from, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl or
benzyl;
and A----B is selected from CH=CH, CH -CH , CH=CHX, or CH -CH X,
2 2 2 2
where X=(CH )pCH , and p is an integer selected from the group consisting of
0, 1, 2 or 3
in the preparation of a medicament for treating cancer, immunosuppression,
bacterial or fungal infection, or skin aging.
2. Use of a compound of formula (Ia),
or a pharmaceutically acceptable salt, solvate, or pharmaceutical composition
including said compounds,
wherein:
1a 4
R is selected from the group consisting of, OH, OR , CH CH=C(CH ) ,
2 3 2
OCH CH=C(CH ) , CH=CHCH(CH ) , CH=CHC(CH )=CH ,
2 3 2 3 2 3 2
OCH=CHCH(CH ) , or OCH=CHC(CH )=CH ,
3 2 3 2
1b 4
R is selected from the group consisting of H, OH, OR ,
CH CH=C(CH ) , OCH CH=C(CH ) , CH=CHCH(CH ) ,
2 3 2 2 3 2 3 2
CH=CHC(CH )=CH , OCH=CHCH(CH ) , or OCH=CHC(CH )=CH ,
3 2 3 2 3 2
1c 4
R is selected from the group consisting of H, OH, OR ,
CH CH=C(CH ) , OCH CH=C(CH ) , CH=CHCH(CH ) ,
2 3 2 2 3 2 3 2
CH=CHC(CH )=CH , OCH=CHCH(CH ) , or OCH=CHC(CH )=CH ,
3 2 3 2 3 2
1d 4
R is selected from the group consisting of H, OH, OR ,
CH CH=C(CH ) , OCH CH=C(CH ) , CH=CHCH(CH ) ,
2 3 2 2 3 2 3 2
CH=CHC(CH )=CH , OCH=CHCH(CH ) , or OCH=CHC(CH )=CH ,
3 2 3 2 3 2
1a-1d 1a-1d
wherein at least one of R is OH and at least one of R is
CH CH=C(CH ) , OCH CH=C(CH ) , CH=CHCH(CH ) ,
2 3 2 2 3 2 3 2
CH=CHC(CH )=CH , OCH=CHCH(CH ) or OCH=CHC(CH )=CH ;
3 2 3 2 3 2
R is selected from OH, OR , CH CH=C(CH ) , OCH CH=C(CH ) ,
2 3 2 2 3 2
CH=CHC(CH )=CH , OCH=CHCH(CH ) , or OCH=CHC(CH )=CH ;
3 2 3 2 3 2
R is selected from OH, OR , CH CH=C(CH ) , OCH CH=C(CH ) ,
2 3 2 2 3 2
CH=CHC(CH )=CH , OCH=CHCH(CH ) , or OCH=CHC(CH )=CH ;
3 2 3 2 3 2
R is selected from, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl or
benzyl;
and A----B is selected from CH=CH, CH=CHX, or CH -CH X, where
X=(CH )pCH , and p is an integer selected from the group consisting of 0, 1, 2
or 3
in the preparation of a medicament for treating inflammation.
3. Use according to item 1 or 2 wherein
R is selected from OH, OR , CH CH=C(CH ) , OCH CH=C(CH ) ,
2 3 2 2 3 2
CH=CHC(CH )=CH , OCH=CHCH(CH ) , or OCH=CHC(CH )=CH .
3 2 3 2 3 2
4. Use according to item 1 wherein A----B is selected from CH=CH or
CH -CH .
. Use of a compound of formula (Ia),
wherein:
1a 1c 1b
R is CH CH=C(CH ) and R is H or CH CH=C(CH ) ; R is selected from
2 3 2 2 3 2
1d 1a 1c
OH, OCH or OCH CH=C(CH ) ; R is OH; wherein at least one of R or R
3 2 3 2
1b 2
is CH CH=C(CH ) and/or R is OCH CH=C(CH ) ; R is selected from OH or
2 3 2 2 3 2
OCH ; R is selected from OH or OCH ;
and A----B is CH=CH;
or a pharmaceutically acceptable salt, solvate, or pharmaceutical composition
including said compounds,
in the preparation of a medicament for treating cancer, immunosuppression,
inflammation, bacterial or fungal infection, or skin aging.
6. Use according to any one of items 1 to 5, wherein the compound is selected
from the group consisting of:
7. Use of a compound or a pharmaceutically acceptable salt or pharmaceutical
composition including said compounds, in the preparation of a medicament for
treating cancer, immunosuppression, inflammation, bacterial or fungal infection,
or skin aging,
wherein the compound is:
USYDS18
8. Use of a compound according to any one of items 1, 3, 5, or 7 or a
pharmaceutical composition thereof in the preparation of a medicament for the
treatment of cancer.
9. Use of a compound according to item 8 wherein the cancer is leukemia, non-
small cell lung cancer, colon cancer, CNS cancer, melanoma, ovarian cancer,
renal cancer, prostate cancer or breast cancer.
. Use of a compound according to item 9 wherein the cancer is leukemia.
11. Use of a compound according to item 9 wherein the cancer is melanoma.
12 Use of a compound according to any one of items 1, 3, 5, or 7 or a
pharmaceutical composition thereof in the preparation of a medicament for the
treatment of immunosuppression.
13. Use of a compound according to any one of items 2, 5, , or 7, or a
pharmaceutical composition thereof in the preparation of a medicament for the
treatment of inflammation.
14. Use of a compound according to any one of items 1, 3, 5, or 7, or a
pharmaceutical composition thereof in the preparation of a medicament for the
treatment of a bacterial or fungal infection.
. Use of a compound according to any one of items 1, 3, 5, or 7, or a
pharmaceutical composition thereof in the preparation of a medicament for the
treatment of skin aging.
16. A compound of formula (Ia)
or a pharmaceutically acceptable salt or solvate thereof,
wherein:
R is selected from, CH CH=C(CH ) , OCH CH=C(CH ) , CH=CHCH(CH ) ,
2 3 2 2 3 2 3 2
CH=CHC(CH )=CH , OCH=CHCH(CH ) , or OCH=CHC(CH )=CH ;
3 2 3 2 3 2
1b 4
R is selected from, H, OH, OR , CH CH=C(CH ) , OCH CH=C(CH ) ,
2 3 2 2 3 2
CH=CHCH(CH ) , CH=CHC(CH )=CH , OCH=CHCH(CH ) , or
3 2 3 2 3 2
OCH=CHC(CH )=CH ;
1c 4a
R is selected from H, OH, OR , CH CH=C(CH ) , OCH CH=C(CH ) ,
2 3 2 2 3 2
CH=CHCH(CH ) , CH=CHC(CH )=CH , OCH=CHCH(CH ) , or
3 2 3 2 3 2
OCH=CHC(CH )=CH ;
R is selected from H, OH, CH CH=C(CH ) , OCH CH=C(CH ) ,
2 3 2 2 3 2
CH=CHCH(CH ) , CH=CHC(CH )=CH , OCH=CHCH(CH ) , or
3 2 3 2 3 2
OCH=CHC(CH )=CH ;
1b-1d 1a-1d
wherein at least one of R is OH and at least one of R is \
CH CH=C(CH ) , OCH CH=C(CH ) , CH=CHCH(CH ) ,
2 3 2 2 3 2 3 2
CH=CHC(CH )=CH , OCH=CHCH(CH ) , or OCH=CHC(CH )=CH ;
3 2 3 2 3 2
R is selected from OH, OCH CH=C(CH ) , CH=CHC(CH )=CH ,
2 3 2 3 2
OCH=CHCH(CH ) , or OCH=CHC(CH )=CH ;
3 2 3 2
R is selected from OH, OR , OCH CH=C(CH ) , CH=CHC(CH )=CH ,
2 3 2 3 2
OCH=CHCH(CH ) , or OCH=CHC(CH )=CH ;
3 2 3 2
R is selected from, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl or
benzyl;
R is selected from, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl or benzyl;
and A----B is selected from CH=CH, CH=CHX, or −CH -CH X, where
X=(CH )pCH and p is an integer selected from the group consisting of 0, 1, 2
or 3.
17. A compound of formula (Ia)
or a pharmaceutically acceptable salt or solvate thereof,
wherein:
R is selected from, CH CH=C(CH ) , OCH CH=C(CH ) ,
2 3 2 2 3 2
CH=CHC(CH )=CH , OCH=CHCH(CH ) , or OCH=CHC(CH )=CH ;
3 2 3 2 3 2
1b 4
R is selected from, H, OH, OR , CH CH=C(CH ) , OCH CH=C(CH ) ,
2 3 2 2 3 2
CH=CHC(CH )=CH , OCH=CHCH(CH ) , or OCH=CHC(CH )=CH ;
3 2 3 2 3 2
1c 4a
R is selected from H, OH, OR , CH CH=C(CH ) , OCH CH=C(CH ) ,
2 3 2 2 3 2
CH=CHC(CH )=CH , OCH=CHCH(CH ) , or OCH=CHC(CH )=CH ;
3 2 3 2 3 2
1d 4a
R is selected from H, OH, OR ,CH CH=C(CH ) , OCH CH=C(CH ) ,
2 3 2 2 3 2
CH=CHC(CH )=CH , OCH=CHCH(CH ) , or OCH=CHC(CH )=CH ;
3 2 3 2 3 2
1b-1d 1a-1d
wherein at least one of R is OH and at least one of R is
CH CH=C(CH ) , OCH CH=C(CH ) , CH=CHC(CH )=CH ,
2 3 2 2 3 2 3 2
OCH=CHCH(CH ) , or OCH=CHC(CH )=CH ;
3 2 3 2
2 3 4a
R and R are each independently selected from OH, OR , OCH CH=C(CH ) ,
2 3 2
CH=CHC(CH )=CH , OCH=CHCH(CH ) , or OCH=CHC(CH )=CH ;
3 2 3 2 3 2
R is selected from, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl or
benzyl;
R is selected from, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl or benzyl;
and A----B is selected from CH=CH, CH=CHX, or −CH -CH X, where
X=(CH )pCH and p is an integer selected from the group consisting of 0, 1, 2
or 3.
18. A compound of formula (Ia)
or a pharmaceutically acceptable salt or solvate thereof,
wherein:
1a 1c
R is CH CH=C(CH ) or CH=CHCH(CH ) , R is selected from H or
2 3 2 3 2
CH CH=C(CH ) or CH=CHCH(CH ) ; R is selected from OH, OCH or
2 3 2 3 2 3
1d 1a 1c
OCH CH=C(CH ) ; R is OH; wherein at least one of R or R is
2 3 2
1b 2
CH CH=C(CH ) and/or R is OCH CH=C(CH ) ; R is selected from OH or
2 3 2 2 3 2
OCH ; R is OCH ;
and A----B is CH=CH.
19. A compound of formula (Ia)
or a pharmaceutically acceptable salt or solvate thereof,
wherein:
1a 1b
R is CH CH=C(CH ) or CH=CHCH(CH ) ; R is selected from OH, OCH
2 3 2 3 2 3
or OCH CH=C(CH ) ; R is selected from H or CH CH=C(CH ) or
2 3 2 2 3 2
1d 1a 1c
CH=CHCH(CH ) ,; R is OH; wherein at least one of R or R is
1b 2
CH CH=C(CH ) and/or R is OCH CH=C(CH ) ; R is selected from OH or
2 3 2 2 3 2
OCH ; R is selected from OH or OCH ;
and A----B is CH=CH.
1b-1d
. A compound according to item 16 or 17 wherein two of R are H.
1b-1d
21. A compound according to item 16 or 17 wherein one of R is H.
1b-1d
22. A compound according to item 16 or 17 wherein none of R are H.
1a-1d
23. A compound according to item 16 or 17 wherein at least one of R is
CH CH=C(CH ) .
2 3 2
1a-1d
24. A compound according to item 16 or 17 wherein at least one of R is
OCH CH=C(CH ) .
2 3 2
1b-1d
. A compound according to item 16 or 17 wherein at least two of R are OH.
1b-1d 4
26. A compound according to item 16 or 17 wherein at least one of R is OR
and R is methyl.
1b-1d 4
27. A compound according to item 16 or 17 wherein at least one of R is OR or
4a 4 4a
OR and R or R is benzyl.
28. A compound according to item 16 or 17 wherein at least one of R or R is OH.
3 4 4
29. A compound according to item 16 or 17 wherein R is OR and R is methyl.
. A compound according to item 16 or 17 wherein both R and R are OH.
3 4 4
31. A compound according to item 16 or 17 wherein R is OR and R is benzyl.
32. A compound according to item 16 or 17 wherein A----B is CH=CH or
CH=CHX, where X=(CH )pCH , and p is an integer selected from the group
consisting of 0, 1, 2 or 3.
33. A compound according to item 16 or 17 wherein A----B is
CH -CH X, where X=(CH ) pCH , and p is an integer selected from the group
2 2 2 2
consisting of 0, 1, 2 or 3.
34. A compound with the formula of (Ib):
wherein,
i i t 6
R is selected from the group OEt, OPr, O Pr, OBu, O Bu, O Bu, OBn; and R
and R are each independently selected from the group OMe, OEt, OPr, O Pr,
OBu, O Bu, O Bu, OBn.
. A compound with the formula of (Ic) or (Id):
wherein,
8 i i t 9
R is selected from the group OH, OEt, OPr, O Pr, OBu, O Bu, O Bu; and R and
i
R are each independently selected from the group OH, OMe, OEt, OPr, O Pr,
OBu, O Bu, O Bu.
36. A compound with the formula of (Ie) or (If):
wherein,
8 9 10
R , R and R are each independently selected from the group OH, OMe, OEt,
i i t
OPr, O Pr, OBu, O Bu, O Bu.
37. A compound according to item 16 or 17, selected from the group consisting of:
or pharmaceutically acceptable salt or solvate thereof.
38. A compound according to structure USYDS18:
USYDS18
39. A compound according to any one of items 16 to 37 wherein the compound is
chemically synthesised.
40. A compound according to any one of items 16 to 37 isolated from propolis,
wherein the propolis originates from plants of the Lepidosperma genus.
41. A compound according to anyone of items 16 to 37 isolated from the resin, gum
or exudate of the Lepidosperma genus.
42. A pharmaceutical composition comprising a compound according to any one of
items 16 to 37, or a pharmaceutically acceptable salt or solvate thereof, and a
pharmaceutically acceptable excipient.
43. A method of preparing the compound according to item 34 which comprises:
(i) treating the carboxylic acid with a suitable agent to provide the acid chloride as
follows:
(ii) condensation of the corresponding acid chloride with an aryl alkene as follows:
(iii) deprotection of the acetate group and alkylation as follows:
i i t
wherein, R is selected from the group OEt, OPr, O Pr, OBu, O Bu, O Bu, OBn;
R and R are each independently selected from the group OMe, OEt, OPr,
i i t
O Pr, OBu, O Bu, O Bu, OBn.
44. A method according to item 43 for preparing compounds of formula (Ic) and
(Id) according to item 34, comprising the additional step:
(iv) a hydrogenation reaction as follows:
(Ic)
(Id)
6 7
wherein, R , R and R are as defined in item 43, provided that at least one of
6 7
R , R or R is OBn;
8 i i t
wherein, R is selected from the group OH, OEt, OPr, O Pr, OBu, O Bu, O Bu;
9 10
R and R are each independently selected from the group OH, OMe, OEt, OPr,
i i t
O Pr, OBu, O Bu, O Bu.
45. A method according to item 43 for preparing compounds of formula (Ie) and
(If) according to item 36, comprising the additional steps:
(v) rearrangement of the prenyl group as follows:
(vi) and a hydrogenation reaction as follows:
6 7 5
wherein, R , R and R are as defined in item 43, provided that at least one of R ,
R or R is OBn;
8 9 10
R , R and R are each independently selected from the group OH, OMe, OEt,
i i t
OPr, O Pr, OBu, O Bu, O Bu.
46. A method according to any one of items 43 to 45 wherein the condensation
reaction in step (ii) is carried out in the presence of a palladium catalyst.
47. A method according to item 46 in which the palladium catalyst is palladium (II)
acetate.
48. A method according to any one of items 43 to 45 wherein the alkylation reaction
in step (iii) is carried out in the presence of a metal hydride and a halogenated
prenyl reagent.
49. A method according to item 48 wherein the metal hydride is sodium hydride.
50. A method according to item 48 or 49 wherein the halogenated prenyl reagent is
BrCH CH=C(CH ) .
2 3 2
51. A method according to item 43 or 45 wherein the hydrogenation in step (iv) or
(vi) is carried out in the presence of a palladium catalyst in a mixture of
solvents.
52. A method according to item 51 wherein the palladium catalyst is palladium on
carbon.
53. A method according to item 51 or 52 wherein the mixture of solvents comprises
1,4-cyclohexadiene and ethanol.
54. A method according to item 45 wherein the rearrangement in step (v) is carried
out in the presence of magnesium silicate particles, silica or alumina particles.
55. A method according to item 45 or 54 wherein the rearrangement in step (v) is
carried out in the presence of microwave radiation or light.
56. A compound according to structure USYDS15:
USYDS15
57. Use of the compound according to item 56 in the preparation of a medicament
for the treatment of cancer, immunosuppresion, inflammation, fungal or
bacterial infection or of skin aging.
Description of the preferred embodiments of the Invention
Throughout this specification the word "comprise", or variations such as "comprises" or
"comprising", will be understood to imply the inclusion of a stated element, integer or
step, or group of elements, integers or steps, but not the exclusion of any other element,
integer or step, or group of elements, integers or steps.
While it is possible that, for use in therapy a therapeutically effective amount of the
compounds as defined herein, or a pharmaceutically acceptable salt or solvate thereof,
may be administered as the raw chemical; in one aspect of the present invention the
active ingredient is presented as a pharmaceutical composition. Thus, in a further
embodiment the invention provides a pharmaceutical composition comprising a
compound of formula (I) or (Ia) according to the first, second, fifteenth and sixteenth
aspects, or a pharmaceutically acceptable salt or solvate thereof, in admixture with one
or more pharmaceutically acceptable carriers, diluents, or excipients. The carrier(s),
diluent(s) or excipient(s) must be acceptable in the sense of being compatible with the
other ingredients of the formulation and not deleterious to the recipient thereof.
When applicable, the compounds of the present invention, including the compounds of
formula (I) or (Ia) may be in the form of and/or may be administered as a
pharmaceutically acceptable salt.
As used herein the term “pharmaceutically acceptable salt” refers to salts which are
toxicologically safe for systemic administration. The pharmaceutically acceptable salts
may be selected from alkali or alkaline earth metal salts, including, sodium, lithium,
potassium, calcium, magnesium and the like, as well as non-toxic ammonium,
quaternary ammonium, and amine cations, including, but not limited to ammonium,
tetramethylammonium, tetraethylammonium, methylamine, dimethylamine,
trimethylamine, triethylamine, ethylamine, triethanolamine and the like.
As used herein the term “pharmaceutically acceptable excipient” refers to a solid or
liquid filler, diluent or encapsulating substance that may be safely used in systemic
administration. Depending upon the particular route of administration, a variety of
carriers, well known in the art may be used. These carriers or excipients may be
selected from a group including sugars, starches, cellulose and its derivatives, malt,
gelatine, talc, calcium sulfate, vegetable oils, synthetic oils, polyols, alginic acid,
phosphate buffered solutions, emulsifiers, isotonic saline, and pyrogen-free water.
As used herein, the term "solvate" refers to a complex of variable stoichiometry formed
by a solute (in this invention, a compound of formula (I) or (Ia) or a salt or
physiologically functional derivative thereof) and a solvent. Such solvents for the
purpose of the invention may not interfere with the biological activity of the solute.
Examples of suitable solvents include, but are not limited to, water, methanol, ethanol
and acetic acid. In particular the solvent used is a pharmaceutically acceptable solvent.
Examples of suitable pharmaceutically acceptable solvents include, without limitation,
water, ethanol, acetic acid, glycerol, liquid polyethylene glycols and mixtures thereof.
A particular solvent is water.
Administration of compounds of the formula (I) or (Ia) may be in the form of a
“prodrug”. A prodrug is an inactive form of a compound which is transformed in vivo
to the active form. Suitable prodrugs include esters, phosphonate esters etc, of the
active form of the compound.
It should be understood that in addition to the ingredients particularly mentioned above,
the formulations may include other agents conventional in the art having regard to the
type of formulation in question.
The compounds of the present invention may be suitable for the treatment of diseases
in a human or animal patient. In one embodiment, the patient is a mammal including a
human, horse, dog, cat, sheep, cow, or primate. In one embodiment the patient is a
human. In a further embodiment, the patient is not a human.
As used herein, the term "effective amount" means that amount of a drug or
pharmaceutical agent that will elicit the biological or medical response of a tissue,
system, animal or human that is being sought, for instance, by a researcher or clinician.
Furthermore, the term "therapeutically effective amount" means any amount which, as
compared to a corresponding subject who has not received such amount, results in
improved treatment, healing, prevention, or amelioration of a disease, disorder, or side
effect, or a decrease in the rate of advancement of a disease or disorder. The term also
includes within its scope amounts effective to enhance normal physiological function.
As used herein the term "treatment" refers to defending against or inhibiting a
symptom, treating a symptom, delaying the appearance of a symptom, reducing the
severity of the development of a symptom, and/or reducing the number or type of
symptoms suffered by an individual, as compared to not administering a
pharmaceutical composition comprising a compound of the invention. The term
treatment encompasses the use in a palliative setting
Those skilled in the art will appreciate that in the preparation of the compounds of the
invention it may be necessary and/or desirable to protect one or more sensitive groups
in the molecule to prevent undesirable side reactions. Suitable protecting groups for use
according to the present invention are well known to those skilled in the art and may be
used in a conventional manner. See, for example, "Protective groups in organic
synthesis" by T. W. Greene and P. G. M. Wuts (John Wiley & sons 1991 ) or
"Protecting Groups" by PJ. Kocienski (Georg Thieme Verlag 1994). Examples of
suitable amino protecting groups include acyl type protecting groups (e.g. formyl,
trifluoroacetyl, acetyl), aromatic urethane type protecting groups (e.g.
benzyloxycarbonyl (Cbz) and substituted Cbz), aliphatic urethane protecting groups
(e.g. 9-fluorenylmethoxycarbonyl (Fmoc), t-butyloxycarbonyl (Boc),
isopropyloxycarbonyl, cyclohexyloxycarbonyl) and alkyl type protecting groups (e.g.
benzyl, trityl, chlorotrityl).
According to the first, second or eighteenth aspects of the invention, the cancers to be
treated are leukemia, non-small cell lung cancer, colon cancer, CNS cancer, melanoma,
ovarian cancer, renal cancer, prostate cancer or breast cancer. Most preferably, the
cancer to be treated is leukemia or melanoma.
In a preferred embodiments of the first to ninth aspects, the compound according to
formula (I) has the formula (Ia).
According to the tenth or nineteenth aspect of the invention, preferably the medicament
is used to treat the following cancers; leukemia, non-small cell lung cancer, colon
cancer, CNS cancer, melanoma, ovarian cancer, renal cancer, prostate cancer or breast
cancer. Most preferably, the medicament is used to treat leukemia or melanoma.
In preferred embodiments of the tenth to fourteenth aspects, the compound according to
formula (I) has the formula (Ia).
The antitumor effect of the compounds of the present invention may be applied as a
sole therapy or may involve, in addition, one or more other substances and/or
treatments. Such conjoint treatment may be achieved by way of the simultaneous,
sequential or separate administration of the individual components of the treatment. In
the field of medical oncology it is normal practice to use a combination of different
forms of treatment to treat each patient with cancer such as a combination of surgery,
radiotherapy and/or chemotherapy. In particular, it is known that irradiation or
treatment with antiangiogenic and/or vascular permeability reducing agents can
enhance the amount of hypoxic tissue within a tumour. Therefore the effectiveness of
the compounds of the present invention may be improved by conjoint treatment with
radiotherapy and/or with an antiangiogenic agent.
The individual components of such combinations can be administered separately at
different times during the course of therapy or concurrently in divided or single
combination forms. The present invention is therefore to be understood as embracing
all such regimes of simultaneous or alternating treatment and the term "administering"
is to be interpreted accordingly. It will be understood that the scope of combinations of
the compounds of this invention with other anti-neoplastic agents includes in principle
any combination with any pharmaceutical composition useful for treating cancer.
When combined in the same formulation it will be appreciated that the two compounds
must be stable and compatible with each other and the other components of the
formulation and may be formulated for administration. When formulated separately
they may be provided in any convenient formulation, conveniently in such a manner as
are known for such compounds in the art.
Pharmaceutical compositions of the invention may be formulated for administration by
any appropriate route, for example by the oral (including buccal or sublingual), rectal,
nasal, topical (including buccal, sublingual or transdermal), vaginal or parenteral
(including subcutaneous, intramuscular, intravenous or intradermal) route. Therefore,
the pharmaceutical compositions of the invention may be formulated, for example, as
tablets, capsules, powders, granules, lozenges, creams or liquid preparations, such as
oral or sterile parenteral solutions or suspensions. Such pharmaceutical formulations
may be prepared by any method known in the art of pharmacy, for example by bringing
into association the active ingredient with the carrier(s) or excipient(s). Such
pharmaceutical formulations may be prepared as enterically coated granules, tablets or
capsules suitable for oral administration and delayed release formulations.
When a compound is used in combination with a second therapeutic agent active
against the same disease, the dose of each compound may differ from that when the
compound is used alone. Appropriate doses will be readily appreciated by those skilled
in the art.
In one embodiment of the invention according to the fifteenth aspect, there is provided
1a 1d 2 3 4
a compound of formula (Ia) wherein R -R , R , R , R and A----B are as hereinbefore
defined provided that:
3 1b 1d
(i) when R is H, then R and R are independently not OH or
OCH CH=C(CH ) ; and
2 3 2
3 1a-1d 1a-1d
(ii) when R is H, one of R is H and at least one of R is CH CH=C(CH ) , then
2 3 2
A---B is not CH=CH.
According to the fifteenth or sixteenth aspects, in preferred embodiments of the
1a-1d 1a-1d
invention two of R are H. In other preferred embodiments one of R is H, and in
1a-1d
other embodiments none of R are H.
1a-1d
In a preferred embodiment, at least one of R is CH CH=C(CH ) , and in another
2 3 2
1a-1d
preferred embodiment at least one of R is OCH CH=C(CH ) .
2 3 2
1a-1d
In certain embodiments at least one of R is hydroxyl, and in certain other
1a-1d
embodiments at least two of R are hydroxyl. In another embodiment at least one of
1a-1d 4 4 4
R is OR and R is methyl, and in yet another embodiment R is benzyl.
In preferred embodiments of the invention according to the fifteenth or sixteenth
2 3 2
aspects, at least one of R or R is hydroxyl. In another preferred embodiment both R
and R are hydroxyl.
2 3 4 4
In another embodiment at least one of R or R is OR and R is methyl, and in yet
another embodiment R is benzyl.
In preferred embodiments of the invention, the group A----B in formula (Ia) or is
CH=CH or CH=CHX−, where X=(CH )pCH , and p is an integer selected from the
group consisting of 0, 1, 2 or 3.
In other embodiments of the invention the group A----B in formula (Ia) is CH -CH , or
CH -CH X, where X=(CH )pCH , and p is independently an integer selected from the
2 2 2 2
group consisting of 0, 1, 2 or 3.
In a preferred embodiment, the compound of formula (Ia) according to the fifteenth or
sixteenth aspect has the formula (Ib):
4 5 6
Wherein, R , R and R are each independently selected from the group OMe, OEt,
i i t
OPr, O Pr, OBu, O Bu, O Bu, OBn.
In another preferred embodiment the compound of formula (Ia) according to the
fifteenth or sixteenth aspects has the formula (Ic) or (Id):
7 8 9
Wherein, R , R and R are each independently selected from the group OH, OMe, -
i i t
OEt, OPr, O Pr, OBu, O Bu, O Bu.
In yet another preferred embodiment, the compound of formula (Ia) according to the
fifteenth or sixteenth aspects has the formula (Ie) or (If)
(1e) (1f)
OH OH
7 8 9
Wherein, R , R and R are each independently selected from the group OH, OMe, OEt,
i i t
OPr, O Pr, OBu, O Bu, O Bu.
Preferably, the compound according to the fifteenth or sixteenth aspects, or
pharmaceutically acceptable salt or solvate thereof is selected from the group consisting
H CO
OCH OCH
USYDS2
USYDS1
OCH OH
HO O
OH OH
USYDS4
USYDS3
OH OH
USYDS8
USYDS7
H CO
3 HO
USYDS9
USYDS10
USYDS13
More preferably the compound according to the fifteenth or sixteenth aspects, or
pharmaceutically acceptable salt or solvate thereof is selected from the group consisting
In one embodiment the compound according to the fifteenth or sixteenth aspects, or
pharmaceutically acceptable salt or solvate thereof is selected from the group consisting
In another preferred embodiment the compound is USYDS18.
USYDS18
In another preferred embodiment, the compound according to the fifteenth aspect, or
pharmaceutically acceptable salt or solvate thereof is selected from the group consisting
of:
In preliminary in vitro assays to determine the anticancer activity of prenylated
polyhydroxystilbene derivatives, the inventors observed structure dependent inhibition
of cancerous cell growth for all derivatives, USYDS1 to USYDS7 and USYDS13.
Most of these compounds, exhibited potent inhibition of almost all leukemia cell lines
(CCRF-CEM, HL-60(TB), K-562, MOLT-4, RPMI-8226, SR). In some cell lines,
growth was inhibited at nano-molar concentrations. USYDS1 displayed the most potent
activity followed by USYDS10, USYDS9, USYDS2 then USYDS14 in the inhibition
of cancerous cell growth. Structure dependent inhibition of cancerous cell growth for
derivatives USYDS10 and 14 have also been observed. Structure-activity study shows
the C-prenylation at the 2 position with the methoxy group at 3 position exhibits the
highest potency towards inhibition of cancer cells.
Most of the pTHOS in this study have structures built on the piceatannol structure, a
known naturally occurring compound, which displays a wide spectrum of biological
activity. It is now attracting much attention on its anticancer properties because of its
ability to inhibit proliferation of a wide variety of tumor cells, including leukemia,
lymphoma; cancers of the breast, prostate, colon and melanoma. Its anticancer effects
are suggested to mediate through cell-cycle arrest; upregulation of Bid, Bax, Bik, Bok,
Fas; P21WAF1 down-regulation of Bcl-xL; BCL-2, cIAP, activation of caspases, loss
of mitochondrial potential, and release of cytochrome c. Piceatannol has also been
shown to inhibit the activation of some transcription factors, including NF-κB, which
plays a central role in response to cellular stress caused by free radicals, ultraviolet
irradiation, cytokines, or microbial antigens, JAK-1, a key transcription in the STAT
pathway that controlling cellular activities in response to extracellular cytokines.
It has been observed that the pTHOS described in this study display a similar spectrum
of biological activities to that exhibited by piceatannol. Furthermore, the pTHOS (ie.
USYDS1, GI values: 0.02 μM – 5 μM) showed approximately 250 fold more potent
than piceatannol (IC values: 5 μM – 100 μM) in inhibition of proliferation of almost
all types of tumor cells. Therefore, the pTHOS present in this application will be an
attractive lead for pharmaceutical research and development and as biological tools for
further understanding the pathophysiology of cancer.
The potent cytotoxicity of compounds USYDS1 and compound USYDS2 may be
explained in terms of their increased hydrophobicity, as demonstrated by their
calculated Log partition coefficient (Log P) values. USYDS1 and USYDS2 have Log
P values almost twice that of the hydroxystilbene resveratrol. The effects of Log P on
therapeutic compounds relate primarily to tissue penetration and distribution. Higher
Log P values will enable compounds to more easily cross cell membranes and enter
cells.
In other preliminary experiments, particular examples of O- and C- prenylated
hydroxystilbene derivatives were found to exhibit concentration dependent inhibition of
the SIRT1 enzyme, a member of the Sirtuin family of proteins (silent information
regulator two proteins, Sir 2).
Sirtuins have emerged as critical regulators for ageing and longevity in model
organisms. Studies into genetics and physiology of sirtuins have shown that this
enzyme family plays a role in a variety of cellular processes, including gene silencing,
cell death, fatty acid metabolism, neuronal protection and life span extension.
Without being bound to any particular theory, it is proposed that modulation of SIRT1
activity could lead to the development of therapeutic agents for the treatment of
diseases including cancer, metabolic syndrome, obesity, neurodegenerative disorder
and aging-related diseases.
In a preferred embodiment, according to the fifteenth or sixteenth aspects the
compound of formula (Ia) is chemically synthesised. In another preferred embodiment
the compound of formula (Ia) is isolated from propolis, wherein the propolis originates
from plants of the Lepidosperma genus. In yet another preferred embodiment, the
compound of formula (Ia) is isolated from the resin, gum or exudate of the
Lepidosperma genus.
According to the twentieth aspect of the invention, in the preparation of compounds of
the formula (Ib), (Ic), (Id), (Ie) or (If), preferably the condensation reaction in step (ii)
is carried out in the presence of a palladium catalyst. Preferably the palladium catalyst
is palladium (II) acetate.
Preferably, the alkylation reaction in step (iii) is carried out in the presence of a metal
hydride and a halogenated prenyl reagent. Preferably the metal hydride is sodium
hydride; however, it would be appreciated by the person skilled in the art that other
known metal hydrides can be used. Most preferably the halogenated prenyl reagent is
BrCH CH=C(CH ) .
2 3 2
In a preferred embodiment, the hydrogenation reaction in step (iv) or (vi) is carried out
in the presence of a palladium catalyst in a mixture of solvents. Most preferably the
palladium catalyst is palladium on carbon and the mixture of solvents comprises 1,4-
cyclohexadiene and ethanol. However, it would be appreciated by the person skilled in
the art that any other suitable reagents and solvents can be used.
In a preferred embodiment, the rearrangement reaction in step (v) is carried out in the
presence of magnesium silicate particles (Florisil ), silica or alumina particles. In
another preferred embodiment the rearrangement reaction can be carried out in the
presence of microwave radiation or light. In yet another preferred embodiment, the
rearrangement reaction in step (v) is carried out in the presence of magnesium silicate
particles (Florisil ), silica or alumina particles and in the presence of microwave
radiation or light.
Brief Description of the Figures
Figure 1 is a compilation of some of the isolated and synthesised prenylated
polyhydroxystilbene derivatives.
Figure 2 is a scheme summarising the synthesis of the novel O- and C- prenylated
polyhydroxystilbenes derivatives.
Figure 3 exhibits dose response curves for the inhibition of human cancerous cell
growth, for various cell lines, by compound USYDS1.
Figure 4 exhibits dose response curves for the inhibition of human cancerous cell
growth, for various cell lines, by compound USYDS2.
Figure 5 exhibits dose response curves for the inhibition of human cancerous cell
growth, for various cell lines, by compound USYDS13.
Figure 6 exhibits dose response curves for the inhibition of human cancerous cell
growth, for various cell lines, by compound USYDS4.
Figure 7 exhibits dose response curves for the inhibition of human cancerous cell
growth, for various cell lines, by compound USYDS9.
Figure 8 exhibits dose response curves for the inhibition of human cancerous cell
growth, for various cell lines, by compound USYDS6.
Figure 9 exhibits dose response curves for the inhibition of human cancerous cell
growth, for various cell lines, by compound USYDS7.
Figure 10. graphically represents the effect of stilbene compounds on free radical
scavenging.
Figure 11. graphically represents the concentration dependent inhibition of the NAD-
dependent deacetylase sirtuin-2 (SIRT1) enzyme by stilbene compounds.
Modes for Carrying Out the Invention
In order to better understand the nature of the invention a number of examples will now
be described as follows:
Materials
Honey bees observed collecting from the sedges (Lepidosperma viscidum) were
captured in plastic tubes, capped and frozen. Sections of the bee hind legs holding
propolis were cut and pooled. Resin from plants were collected and stored at −20°C
until analysis. Plant samples were obtained and dried at 40°C in a ventilated oven
(Thermoline, NSW Australia) overnight to provide voucher specimens for
identification by botanist, A/Prof Murray Henwood, John Ray Museum, University of
Sydney, Sydney, Australia, and registered as Lepidosperma viscidum chemotype 1a,
voucher number Duke 100222-42 and Lepidosperma viscidum chemotype 2a, voucher
number Duke 100221-21.
76 Beehives made up of 3 10-frame boxes each fitted with a propolis mat under the
hive cover lid were used to collect propolis samples. The individually numbered hives
were used on location in the apiary sites situated in the central southern region of
Kangaroo Island.
Thin layer chromatography sheets precoated with silica gel 60 F and silica gel 60H
for normal-phase short-column chromatography (NPSCC) were purchased from Merck.
TLC plates were visualized with a UVGL-58 mineral-light lamp, Multiband UV-
2544/366.
All the chemicals used in the isolation and synthesis, including deuterated NMR
solvents such as chloroform-d and methanol-d , deuterated dimethyl sulfoxide (d -
dimethyl sulfoxide) were purchased from Sigma-Aldrich Pty Ltd (Castle Hill, NSW,
Australia). Solvents including hexane, dichloromethane, ethyl acetate, isopropanol,
ethanol, methanol , and acetic acid were of analytical grade and purchased from Ajax
Fine Chem, Taren Point, NSW, Australia. or Asia Pacific Specialty Chemical Ltd
(APS).
Rotavapor model R-114 rotary evaporator with a water bath temperature ranging
between 40-60˚C was used to evaporate the solvent fraction. Vacuum pump V-700 or
Vacuubrand MD 4C NT diaphragm pump (Vacuubrand GMBH, Wertheim, Germany)
with vacuum controller V-800 or V-850 is used. Final drying is carried out by a Napco
5831 vacuum oven (NAPCO, Salt Lake City, USA) using a DirectTorr vacuum pump
(Sargent-Welch, Buffalo, USA).
Preparative HPLC was performed on a Shimadzu preparative gradient LC-8A system
on a reversed-phase column (Grace, Alltima C18 5 µM 22 mm ID × 250 mm), injection
volume 500 µL, eluted with methanol (75%) and water at 10 mL/min and detected at
280 nm with a UV-Vis detector (Shimadzu SPD-20A). Analytical HPLC was
performed on Shimadzu UFLC, LC-20AD pump, SIL-20A HT autosampler, with a
Hewlett-Packard Column, NUCLEOSIL 100C18, 5 µm, 4 mm × 125 mm, injection
volume 20 µL, eluted with methanol-water-acetic acid (70:29.8:0.2) at 1 mL/min and
detected at 230 nm with a UV-Vis detector (Shimadzu SPD-20A).
1 13
H and C Nuclear magnetic resonance (NMR) analyses were carried out on Varian
400 MHz System with a SMS autosampler (Palo Alto, California, USA). NMR spectra
were referenced to tetramethylsilane (TMS). Mass spectra were obtained from a
ThermoFinnigan TSQ 7000 (LC-MS/MS system) and a Finnigan Polaris Ion Trap
MS/MS system (Finnigan, San Jose, USA) using an Xcalibur 1.2 data system.
Determination of the H-NMR chemical profiles of the plant and propolis specimens
Resin samples from the base of stem (0.1 g), bee hind leg (0.01 g) and beehive propolis
(1.0 g) were extracted with ethyl acetate at room temperature for 15 min. The extracts
were filtered, dried under reduced pressure and analyzed by H-NMR and HPLC.
Samples from the sedge type-1 were found to contain prenylated hydroxystilbenes and
cinnamates as major constituents, whereas those from sedge type-2 showed only
prenylated stilbenes as major constituents as discussed above. Propolis samples were
subsequently selected for isolation of the components.
Isolation and identification of prenylated polyhydroxystilbenes from propolis of
Kangaroo Island.
General method
Propolis (10 g) was extracted with dichloromethane at room temperature with stirring
for 1 hr. The extract was subjected to purification using normal-phase short column
chromatography (NPSCC). A step-wise gradient of mobile phase (2 x 100 mL)
consisting of dichloromethane (DCM) and ethyl acetate (EtOAc) at 0, 1, 2, 4, 8, 10, 15,
, 50 and 100% was employed to elute the components which were analysed by TLC
and NMR. Further purification of the compounds, if required, was subsequently
carried out on the same NPSCC with different mobile phases consisting of either
hexane and EtOAc or hexane and isopropanol. Normal-phase preparative HPLC was
also employed when required to further purify the compounds (Shimadzu LC-8A). The
compounds were eluted through a silica column (Altima® silica 10 µm, 10 cm x 250
cm) at a flow rate of 10 mL/min with a mobile phase of 2% isopropanol in hexane at
ambient temperature. The elution of compounds was monitored with a UV detector
(UV/Vis SPD-20A) at 280 nm. Structures and identity of these purified compounds
1 13
were characterized by H- and C-NMR and mass spectrometry including high
resolution mass spectrometry. Detailed structural analyses of the isolated compound
were also carried out when needed by 2D-NMR using Gradient Heteronuclear Multiple
Bond Coherence (GHMBC).
Isolated prenylated polyhydroxystilbene derivatives:
(E)(3-methylbutenyl)-4’,5-dihydroxy-3,3’-dimethoxystilbene (USYDS1).
Light yellow liquid. C H O H NMR (methanol-d , 400 MHz): R 14.64 min. δ 7.16 (d, J=16 Hz,
21 24 4 4 t
H), 7.07 (d, J=4 Hz, H), 6.94 (dd, J=8, 4 Hz, H), 6.86 (d, J=16 Hz, H), 6.78 (d, J=8 Hz, H), 6.63 (d,
J=4 Hz, H), 6.34 (d, J=4 Hz, H), 5.06 (m, H), 3.89 (s, 3H), 3.77 (s, 3H), 3.39 (m, 2H), 1.80 (bs, 3H),
1.66 (bs, 3H). C-NMR (CDCl , 100 MHz) δ 158.5, 154.4, 146.7, 145.6, 138.1, 130.6, 130.4,
130.3, 124.3, 123.7 , 120.7, 120.6, 114.5, 108.2, 103.9, 98.2, 55.9, 55.7, 25.8, 24.5, 18.0; CI-
MS: m/z 339 (M−1) , HRESIMS: m/z 341.1749 (M+H) , calcd 341.1747 for C H O .
21 25 4
(E)(3-methylbutenyloxy)-4’,5-dihydroxy-3’-methoxystilbene (USYDS2).
Light yellow liquid. C H O H NMR (methanol-d , 400 MHz): R 15.46 min. δ 7.12 (d, J=4 Hz,
22 4 4 t
1H), 7.01 (d, J=16 Hz, 1H), 6.97 (dd, J=8, 4 Hz, 1H), 6.88 (d, J=16 Hz, 1H), 6.78 (d, J=8 Hz, 2H,
6.56 (m, 2H), 6.24 (m, 1H), 5.46 (m, 1H), 4.52 (d, J=4 Hz, 2H), 3.90 (s, 3H), 1.79 (bs, 3H), 1.76
(bs, 3H). C-NMR (CDCl , 100 MHz) δ 160.2, 156.9, 146.7, 145.5, 139.9, 138.6, 129.9, 129.2,
126.2, 120.6, 119.4, 114.7, 108.4, 105.9, 105.4, 101.5, 65.0, 55.9, 25.8, 18.2; CI-MS m/z 325
(M−1) , HRESIMS m/z 327.15938 (M+H) , calcd 327.1591 for C H O .
23 4
(E)(3-methylbutenyl)-3,4’,5-trihydroxy-3’-methoxystilbene (USYDS13).
Light yellow liquid. C H O H NMR (methanol-d , 400 MHz): R 11.46 min. δ 7.08 (d, J=4 Hz,
22 4 4 t
1H), 6.93 (dd, J=8, 4 Hz, 1H), 6.91 (d, J=16 Hz, 1H), 6.78 (d, J=16 Hz, 1H), 6.77 (d, J=8 Hz, 1H),
6.46 (s, 2H), 5.23 (m, 1H), 3.89 (s, 3H), 3.28 (m, 2H), 1.76 (bs, 3H), 1.65 (bs, 3H); C NMR-
GHMBC (methanol-d , 100 MHz): δ 157.4 (2C, C-3/5, H-2/6, H-1’’), 149.3 (1C, C-3’, H-2’, H-5’,
OCH ), 147.6 (1C, C-4’, H-2’, H-6’), 137.7 (1C, C-1’, H-beta), 131.4 (1C, C-1, H-alpha), 131.3 (1C,
C-3’’, H-1’’, H-4’’, H-5’’), 128.7 (1C, C-beta, H-2’, H-alpha), 127.6 (1C, C-alpha, H-2/6, H-6’),
124.8 (1C, C-2’’, H-1’’, H-4’’, H-5’’), 121.2 (1C, C-6’, H-2’, H-beta), 116.5 (1C, C-5’), 116.1 (1C, C-
4, H-2/6, H-1’’), 110.4 (1C, C-2’, H-beta), 105.9 (2C, C-2/6, H-2/6, H-alpha), 56.5 (1C, OCH ),
26.1 (1C, C-4’’, H-5’’), 23.5 (1C, C-1”), 18.1 (1C, C-5’’, H-4”); CI-MS: m/z 325 (M−1) ; HRMS:
325.14453 [M − 1] , (calculated 325.14398 for C20H21O4).
(E)(3-methylbutenyloxy)-3’,4’,5-trihydroxystilbene (USYDS4).
Light yellow liquid. C H O H NMR (methanol-d , 400 MHz): R 18.62 min. δ 6.98 (d, J=4 Hz,
19 20 4 4 t
1H), 6.94 (d, J=16 Hz, 1H), 6.85 (dd, J=8, 4 Hz, 1H), 6.80 (d, J=16 Hz, 1H), 6.74 (d, J=8 Hz, 1H),
6.53 (m, 2H), 6.23 (m, 1H), 5.46 (m, 1H), 4.51 (d, J=4 Hz, 2H), 1.79 (bs, 3H), 1.76 (bs, 3H); C
NMR (methanol- d , 100 MHz): δ 160.2, 158.2, 145.2, 145.1, 139.8, 136.9, 129.5, 128.5, 125.5,
119.9, 118.8, 114.9, 112.4, 105.2, 103.8, 100.7, 64.4, 24.4, 16.8; CI-MS: m/z 311 (M−1) ;
HREIMS: m/z 335.1252 (M+Na) , calcd 335. 1259 for C H O Na.
19 20 4
(E)-2,4-di(3-methylbutenyl)-3,4’,5-trihydroxystilbene (USYDS6).
Off-white solid. C H O H NMR (methanol-d , 400 MHz): R 9.35 min. δ 7.30 (d, J=8 Hz, 2H),
24 28 3 4 t
7.11 (d, J=16 Hz, 1H), 6.80 (d, J=16 Hz, 1H), 6.76 (d, J=8 Hz, 2H), 6.63 (s, 1H), 5.21 (m, 1H), 5.10
(m, 1H), 3.41 (m, 2H), 3.35 (m, 2H), 1.81 (bs, 3H), 1.78 (bs, 3H), 1.68 (bs, 6H); CI-MS: m/z 363
(M−1) .
(E)-2,4-di(3-methylbutenyl)-3,3’,4’,5-tetrahydroxystilbene (USYDS7).
Off-white solid. C H O H NMR (methanol-d , 400 MHz): R 10.46 min. δ 7.07 (d, J=16 Hz,
24 28 4 4 t
1H), 6.94 (d, J=4 Hz, 1H), 6.79 (dd, J=8,4 Hz, 1H), 6.73 (d, J=16 Hz, 1H), 6.71 (d, J=8 Hz, 1H),
6.62 (s, 1H), 5.21 (m, 1H), 5.10 (m, 1H), 3.41 (m, 2H), 3.35 (m, 2H), 1.81 (bs, 3H), 1.78 (bs, 3H),
1.68 (bs, 6H); C NMR (methanol-d , 100 MHz): δ 153.23, 152.79, 145.04, 144.84, 134.98,
130.52, 130.26, 129.75, 128.67, 124.08, 123.94, 122.93, 118.56, 118.51, 115.32, 114.93,
112.30, 103.85, 24.54, 24.49, 24.46, 22.32, 16.74, 16.54; CI-MS: m/z 379 (M−1) ; HRMS:
379.19148 [M − 1] , (calculated 379.19092 for C24H27O4).
(E)(3-methylbutenyl)-3,3’,4’,5-tetrahydroxystilbene (USYDS8).
C H O H NMR (acetone-d , 400 MHz): δ 7.07 (d, J=2 Hz, 1H), 7.15 (d, J=16 Hz, 1H), 6.89 (dd,
19 20 4 6
J=8, 2 Hz, 1H), 6.81 (d, J=8 Hz, 1H), 6.80 (d, J=16 Hz, 1H), 6.63 (d, J=2 Hz, 1H), 6.35 (d, J=2 Hz,
1H), 5.15 (t, J=7 Hz, 1H), 3.42 (d, J=7 Hz, 2H), 1.81 (s, 3H), 1.65 (s, 3H). C NMR (acetone-d ,
100 MHz): δ 155.9, 155.8, 145.4, 145.3, 138.4, 130.1, 129.7, 129.4, 124.5, 123.9, 117.4, 119.0,
115.4, 112.9, 103.4, 101.6, 24.0, 25.0, 17.2. HRESIMS: (m/z) 313.1434 (M+H) , calcd 313.1440
for C H O .
19 21 4
(E)(3-methylbutenyl)-3’,4’,5-trihydroxymethoxystilbene (USYDS9).
C H O H NMR (acetone-d , 400 MHz): δ 7.16 (d, J = 16 Hz, 1H), 7.07 (d, J = 2 Hz, 1H), 6.90
22 4 6
(dd, J = 8, 2 Hz, 1H), 6.85 (d, J = 16 Hz, 1H), 6.82 (d, J = 8 Hz, 1H), 6.71 (d, J = 2 Hz, 1H), 6.39 (d,
J = 2.3 Hz, 1H), 5.09 (1H, t, J = 7 Hz, 1H), 3.78 (s, 3H), 3.40 (d, J = 7 Hz, 2H), 1.80 (s, 3H), 1.64 (s,
3H). C NMR (acetone-d , 100 MHz): δ 158.5, 156.3, 145.3 (2C), 138.0, 130.1, 130.0, 129.6,
123.7, 124.2, 119.1, 118.9, 115.3, 112.9, 103.7, 98.1, 55.0, 25.0, 23.9, 17.2. HRESIMS: m/z
327.1592 (M+H) , calcd 327.1596 for C H O .
23 4
(E)(3-methylbutenyl)-3,4’,5-trihydroxy-3’-methoxystilbene (USYDS10).
C H O H NMR: (acetone-d , 400 MHz) δ 7.13 ( d, J = 16 Hz, 1H) 7.02 (dd, J = 8, 2 Hz, 1H),
22 4 6
7.00 (s, 1H), 6.92 (d, J = 8 Hz, 1H), 6.85 (d, J = 16 Hz, 1H), 6.66 (d, J = 2 Hz, 1H), 6.30 (d, J = 2 Hz,
1H), 5.20 (t, J = 7 Hz, 1H), 3.95 (s, 3H), 3.43 (d, J = 7 Hz, 2H), 1.84 (s, 3H), 1.75 (s, 3H). C NMR
(acetone-d , 100 MHz): δ 155.4, 154.4, 146.7, 145.7, 138.8, 133.6, 131.2, 130.1, 124.2, 122.5,
120.5, 117.7, 114.6, 108.4, 105.3, 102.5, 55.9, 25.8, 25.1, 18.0. HRESIMS: m/z 349.1411
(M+Na) , calcd 349.1416 for C H O Na.
22 4
(E)(3-methylbutenyloxy)-4’,5-dihydroxystilbene (USYDS11).
C H O H NMR (CDCl , 400 MHz): δ 7.38 (dd, J = 7, 2 Hz, 2H), 7.00 (d, J = 16 Hz, 1H), 6.84 (d, J
19 22 3 3
= 16 Hz, 1H), 6.82 (dd, J = 7, 2 Hz, 2H), 6.64 (t, J = 2 Hz, 1H), 6.56 (t, J = 2 Hz, 1H), 6.33 (t, J = 2
Hz, 1H), 5.50 (t, J = 7 Hz, 1H), 4.51 (d, J = 7 Hz, 2H), 1.81 (s, 3H), 1.76 (s, 3H). C NMR (CDCl ,
100 MHz): δ 160.4, 156.7, 155.4, 139.9, 138.4, 130.1, 128.8, 128.0 (2C), 126.3, 119.5, 115.6
(2C), 105.6, 105.5, 101.3, 64.9, 25.8, 18.2.
4-(3-methylbutenyl)-3,4’,5-trihydroxydihydrostilbene (USYDS12).
C H O H NMR: (CD OD, 400 MHz) δ 6.97 (d, J = 8 Hz, 2H), 6.66 (d, J = 8 Hz, 2H), 6.13 (s, 2H),
19 22 4 3
.22 (t, J = 7 Hz, 1H), 3.24 (d, J = 7 Hz, 2H), 2.72 (m, 2H), 2.64 (m, 2H), 1.74 (s, 3H), 1.64 (s, 3H).
C NMR (CD OD, 100 MHz): δ 155.5 (2C), 154.9, 140.3, 132.9, 129.4, 128.9 (2C), 123.6, 114.6
(2C), 112.3, 106.5 (2C), 38.0, 36.8, 24.5, 21.7, 16.5.
(E)(3-methylbutenyl)(3-methylbutenyloxy)-3',4’,5-trihydroxystilbene
(USYDS14).
Colourless solid, yield 12 mg. ESI-MS: m/z 379 [M − 1] , H-NMR (methanol-d 400 MHz): δ
7.07 (d, J=16 Hz, 1H), 6.96 (d, J=4 Hz, 1H), 6.80 (dd, J= 8, 4 Hz, 1H), 6.79 (d, J=16 Hz, 1H), 6.74
(d, J=8 Hz, 1 H), 6.61 (d, J=4 Hz, 1H), 6.32 (d, J=4 Hz, 1H), 5.47 (m, 1H), 5.06 (m, 1H), 4.48 (m,
2H), 3.37 (m, 2H), 1.78 (m, 6H), 1.75 (m, 3H), 1.66 (m, 3H). C-NMR (100 MHz, CD OD): δ
16.75, 16.80, 23.84, 24.45, 24.54, 64.86, 99.04, 103.41, 112.39, 114.96, 118.71, 119.14,
120.14, 123.54, 123.97, 129.51, 129.70, 130.01, 136.78, 137.95, 145.08, 145.09, 155.59,
157.47. HRMS: 379.19148 [M − 1] , (calculated 379.19092 for C24H27O4).
(E)-2,6-di(3-methylbutenyl)-3,3’,5,5'-tetrahydroxystilbene USYDS15
USYDS15
Colourless solid, yield 9 mg. ESI-MS: m/z 379 [M − 1] , H NMR (methanol-d 400 MHz): δ 6.91
(br t, 1H), 6.82 (d, J=16 Hz, 1H), 6.73 (d, J=1 Hz, 2H),, 6.28 (s, 1H), 6.27 (d, J=16 Hz, 1H), 5.12
(m,2H), 3.26 (d, J=6 Hz 4H), 1.65 (m, 6H), 1.59 (m, 6H). C-NMR (100 MHz, CD OD): δ 16.75,
24.53, 25.60, 112.27, 114.86, 117.66, 118.24, 124.06, 124.63, 130.20, 133.33, 139.41, 144.73,
144.97, 153.04. HRMS: 379.19149 [M − 1] , (calculated 379.19092 for C24H27O4).
(E)-2,6-di(3-methylbutenyl)-3,4’,5-trihydroxy-3'-methoxystilbene USYDS18
USYDS18
Yield 5 mg. ESI-MS: m/z 393 [M − 1] . H NMR: (CD OD, 400 MHz) δ 7.03 (d, J = 2 Hz, 1H), 6.87
(d, J = 17 Hz, 1H), 6.85 (dd, J = 8, 2 Hz, 1H), 6.77 (d, J = 8 Hz, 1H), 6.33 (d, J = 17 Hz, 1H), 6.30 (s,
1H), 5.14 (br t, J = 6 Hz, 2H), 3.88 (s, 3H), 3.26 (br d, J = 6 Hz, 4H), 1.66 (br s, 6H), 1.60 (br s,
6H). C NMR (CD OD, 100 MHz): δ 18.37 (2C), 26.12 (2C), 27.20 (2C), 56.53, 102.58, 110.27,
116.42, 119.23 (2C), 121.03, 126.02 (2C), 126.31, 130.41 (2C), 131.7, 134.87, 140.95, 147.51,
149.26, 154.65 (2C) . HRMS: 417.20363 [M + 23] , (calculated 417.20418 for C25H30O4Na).
Chemical modification and synthesis of prenylated polyhydroxystilbenes
A. Rearrangement of O-prenyl to C-prenyl polyhydroxystilbene
A mixture of USYDS2 (5 mg) and Florisil (5 mg) in xylene (2 ml) was heated at 120°C
for 30 min in a microwave reactor (CEM Discover Microwave). The product was dried
under reduced pressure and purified using NPSCC. Two rearrangement products were
observed in a combined yield of approximately 30%.
The major product observed was (E)(3-methylbutenyl)-3,4’,5-trihydroxy-3’-
methoxystilbene (USDYS13):
The minor product observed was (E)(3-methylbutenyl)-3,4’,5-trihydroxy-3’-
methoxystilbene (USYDS10).
B. Synthesis of prenylated polyhydroxystilbenes
1. Preparation of 3,5-dihydroxybenzoic acid methyl ester (1)
To a solution of 3,5-dihydroxybenzoic acid (10 g, 64.9 mmol) in anhydrous methanol
(150 mL) acetyl chloride (2 mL, 28.1 mmol) was added dropwise. The mixture was
heated at reflux under N for 17 hours. The solvent was evaporated and the residue was
dissolved in ethyl acetate (100 mL), then washed with saturated sodium hydrogen
carbonate (3 x 100 mL). The combined organic layers were washed with water (2 x
100 mL), dried over sodium sulfate, filtered and concentrated in vacuo to afford 2 as a
colourless solid (9.80 g, 90%): mp 167-168ºC (lit. mp 168-169ºC); H NMR (400
MHz, Acetone-d ) δ 8.66 (s, 2H), 7.00 (d, J = 2.4 Hz, 2H), 6.59 (t, J = 2.4 Hz, 2H),
3.83 (s, 3H).
2. Preparation of 3-hydroxybenzyloxybenzoic acid methyl ester (2)
To a suspension of NaH (60% dispersion in mineral oil, 3.3 g, 137.3 mmol) in
anhydrous N,N-dimethylformamide (DMF) (100 mL) was added a solution of 2 (10 g,
59.5 mmol) in anhydrous DMF (30 mL) at 0 C under N , followed by the dropwise
addition of benzyl bromide (6.4 mL, 53.8 mmol). The reaction mixture was stirred at
room temperature for 2 hours, quenched with cold water (50 mL), acidified with cold 1
M HCl (20 mL) and extracted with diethyl ether (3 x 50 mL). The combined organic
extracts were washed with water (2 x 50 mL), dried over sodium sulfate, filtered and
evaporated in vacuo. The product was purified using NPSCC using a step-wise gradient
consisting of chloroform/ethanol to afford 2 as an off-white solid (4.5 g, 60%) : mp 97-
98ºC (lit. mp 98ºC); C H O H NMR (400 MHz, CDCl ) δ 8.01 (s, 1H), 7.43-7.33
14 4 3
(m, 5H), 7.24 (dd, J = 2.0, 1.2 Hz, 1H), 7.20 (dd, J = 2.0, 1.2 Hz, 1H), 6.70 (t, J = 2.0
Hz, 1H), 5.07 (s, 2H), 3.90 (s, 3H).
3. Preparation of 3-hydroxybenzyloxybenzoic acid (3)
To a solution of 2 (4.5 g, 16.7 mmol) in methanol (30 mL) was added 1 M NaOH (60
mL, 60 mmol). The resulting reaction mixture was stirred at 45ºC for 4 hours under
N , followed by the addition of 1 M HCl (50 mL) to acidify the solution before
extraction with ethyl acetate (3 x 40 mL). The combined organic extracts were washed
with water (2 x 30 mL) and dried over sodium sulfate. The solvent was evaporated in
vacuo to afford 3 as an off-white solid (4.02 g, 94%): mp 196-198ºC; C H O H
14 12 4
NMR (400 MHz, Acetone-d ) δ 7.42-7.33 (m, 5H), 7.21 (dd, J = 2.4, 1.2 Hz, 1H), 7.11
(dd, J = 2.4, 1.2 Hz, 1H), 6.68 (t, J = 2.4 Hz, 1H), 5.07 (s, 2H).
4. Preparation of 3-hydroxymethoxybenzoic acid (4).
The title compound was prepared as described above by using methyl iodide instead of
benzyl bromide to afford 4 as an off-white solid, mp 199-200ºC (lit. mp 199-200ºC);
C H O H NMR (400 MHz, Acetone-d ) δ 8.01 (s, 2H), 7.16 (t, J = 1.2 Hz, 1H), 7.13
8 8 4 6
(t, J = 1.2 Hz, 1H), 6.15 (t, J = 2.4 Hz, 1H), 3.82 (s, 3H).
5. Preparation of 3-acetoxybenzyloxybenzoic acid (5)
To the solution of 3 (4.02 g, 17.6 mmol) in acetic anhydride (20 mL, 21.6 mmol) was
added pyridine (10%, 0.15 mL, 1.76mmol). The mixture was stirred at room
temperature for 4 hours, quenched with water (30 mL), acidified by 0.1 M HCl (10 mL)
and extracted with ethyl acetate (3 × 40 mL). The combined organic extracts were
washed with water (2 x 30 mL), dried over sodium sulfate and filtered. The solvent was
evaporated in vacuo and recrystallised from a mixture (1:1) of hexane/ethyl acetate to
afford 5 as pinkish crystals (3.86 g, 96%) : mp 133-134ºC; C H O H NMR (400
16 14 5
MHz, CDCl ) δ 7.59 (dd, J = 2.4, 1.2 Hz, 1H), 7.45 (dd, J = 2.4, 1.2 Hz, 1H), 7.43-7.34
(m, 5H), 6.99 (t, J = 2.4 Hz, 1H), 5.1 (s, 2H), 2.32 (s, 3H).
6. Preparation of 3-acetoxymethoxybenzoic acid (6)
The title compound was prepared as described in 5 was used to give 6 as an off white
solid: mp 151-153ºC; C H O H NMR (400 MHz, CDCl ) δ 7.50 (dd, J = 2.0, 1.4
10 5 3
Hz, 1H), 7.43 (dd, J = 2.0, 1.4 Hz, 1H), 6.90 (t, J = 2.0 Hz, 1H), 3.86 (s, 3H), 2.32 (s,
3H).
7. Preparation of 3-methoxybenzyloxybenzaldehyde (7)
To a suspension of NaH (60% dispersion in mineral oil, 1.6g, 66.6 mmol) in anhydrous
DMF (50 mL) at 0 C under N was added vanillin (4-hydroxymethoxy
benzaldehyde, 4 g, 26.3 mmol) in anhydrous DMF (20 mL) slowly via syringe,
followed by the dropwise addition of benzyl bromide (3 mL, 25.2 mmol). The mixture
was stirred at room temperature for 4 hours, quenched with cold water (30 mL),
acidified with cold 1 M HCl (15 mL) and extracted with diethyl ether (3 x 40 mL). The
combined organic extracts were washed with water (2 x 30 mL), dried over sodium
sulfate and dried under reduced pressure to afford 7 as a colourless solid (6 g, 92%):
mp 60-62ºC (lit. mp 61-62ºC); C H O H NMR (400 MHz, CDCl ) δ 9.84 (s, 1H)),
14 3 3
7.43-7.31 (m, 7H)), 7.00 (d, J = 8.4 Hz, 1H)), 5.25 (s, 2H)), 3.95 (s, 3H)).
8. Preparation of 4-methoxybenzyloxybenzaldehyde (8)
The title compound was prepared as described in 7 to give 8 as a colourless solid: mp
61-63ºC (lit. mp 61-63ºC); C H O H NMR (400 MHz, CDCl ) δ 9.80 (s, 1H)),
14 3 3
7.49-7.31 (m, 7H)), 7.00 (d, J = 8.1 Hz, 1H)), 5.20 (s, 2H)), 3.97 (s, 3H)).
9. Preparation of 4-ethenylmethoxybenzyloxybenzene (9).
To a suspension of methyltriphenylphosphonium bromide (6.5 g, 18.2 mmol) in
anhydrous tetrahydrofuran (THF) (15 mL) under N at 0ºC was added potassium tert-
butoxide (2.3 g, 20.5 mmol) and the reaction mixture was warmed to room temperature.
A solution of benzyl vanillin (7) (4 g, 16.5 mmol) in anhydrous THF (15 mL) was
added dropwise and stirred for 2 hours, then quenched with cold water (20 mL),
acidified with 0.1 M HCl (20 mL), and extracted with ethyl acetate (3 x 40 mL). The
combined organic extracts were washed with 20% aq. sodium chloride (20 mL) then
dried under reduced pressure. The product was purified using NPSCC using a step-wise
mobile phase consisting of hexane/ethyl acetate to afford 9 as a colourless solid (3.37 g,
85%); mp 53-54ºC (lit. mp 50-51ºC); C H O H NMR (400 MHz, CDCl ) δ 7.45-
16 16 2 3
7.28 (m, 5H), 6.99 (d, J = 2 Hz, 1H), 6.90 (dd, J = 4, 1 Hz, 1H), 6.83 (d, J = 4 Hz, 1H),
6.68 (dd, J = 17, 1 Hz, 1H), 5.64 (dd, J = 17, 1 Hz, 1H), 5.17 (s, 2H), 5.14 (d, J = 1 Hz,
1H), 3.92 (s, 3H).
. Preparation of 5-ethenylmethoxybenzyloxybenzene (10).
The title compound was prepared as described in 9 to give 10 as an off-white solid; mp
68-69ºC (lit. mp 68-69ºC); C H O H NMR (400 MHz, CDCl ): δ 7.48-7.31 (m,
16 16 2 3
5H), 7.01 (d, J = 2 Hz, 1H), 6.97 (dd, J = 8, 2 Hz, 1H), 6.85 (d, J = 8 Hz, 1H), 6.64 (dd,
J = 17, 1 Hz, 1H), 5.56 (dd, J = 17, 1 Hz, 1H), 5.17 (s, 2H), 5.12 (d, J = 1 Hz, 1H), 3.92
(s, 3H).
11. Preparation of E[3-acetoxybenzyloxyphenyl][3-methoxy
benzyloxyphenyl]ethene (11):
To a solution of N,N-bis(2,6-diisopropyl) dihydro imidazolium chloride (0.093 g, 10%,
0.217 mmol) and Pd(OAc) (0.048 g, 10%, 0.217 mmol ) in xylene (3 mL) under N at
room temperature was added the acid chloride of 5 (0.7 g, 2.17 mmol) in xylene 2 mL,
followed by the addition of 4-ethylmorpholine (0.04 mL, 0.316 mmol) and reagent 9
(0.627 g, 2.61 mmol) in xylene (3 mL). The mixture was heated at 130ºC for 18-22
hours. The solvent was evaporated in vacuo and the product was purified using NPSCC
(hexane/ethyl acetate 3:1 as mobile phase) to give 11 as an yellow oil (0.33 g, 31.6%);
C H O H NMR (400 MHz, CDCl ) δ 7.45-7.28 (m, 13H), 7.06 (d, J = 2.0 Hz, 1H),
31 28 5 3
7.02 (d, J = 17 Hz, 1H), 6.97 (dd, J = 6, 2 Hz, 1H), 6.89 (m, 1H), 6.62 (t, J = 2 Hz, 1H),
.18 (s, 2H), 5.07 (s, 2H), 3.94 (s, 3H), 2.30 (s, 3H); C NMR (100MHz, CDCl ) δ
169.39, 159.78, 151.81, 149.79, 148.32, 139.82, 137.00, 136.57, 130.48, 129.78,
128.63 (2C), 128.58 (2C), 128.10, 127.88, 127.55 (2C), 127.24 (2C), 126.02, 119.98,
113.95, 112.02, 110.50, 109.48, 107.28, 71.0, 70.27, 56.02, 21.19; CI-MS m/z (%): 481
+ + +
(M+1) , 503 (M+Na) ; HRMS: m/z 503.1828 (M+Na) , calcd 503.1834 for
C H O Na.
31 28 5
12. Preparation of E[3-acetoxybenzyloxyphenyl][3-benzyloxy
methoxyphenyl]ethene (12).
The title compound was prepared as described in 11 to condense the acid chloride of 5
with reagent 10. The product was recrystallised from a mixture (2:1) of hexane /
toluene to afford yellowish needle crystals; C H O mp 133-134ºC; H NMR (400
31 28 5
MHz, CDCl ) δ 7.49-7.29 (m, 10H), 7.07 (d, J = 2 Hz, 1H), 7.05 (dd, J = 8, 2 Hz, 1H),
6.97 (d, J = 16 Hz, 1H), 6.95 (t, J = 2 Hz, 1H), 6.89 (d, J = 8 Hz, 1H), 6.84 (t, J = 2 Hz,
1H), 6.82 (d, J = 16 Hz, 1H), 6.62 (t, J = 2 Hz, 1H), 5.18 (s, 2H), 5.07 (s, 2H), 3.94 (s,
3H), 2.30 (s, 3H); C NMR (100MHz, CDCl ) δ 169.39, 159.76, 151.80, 149.90,
148.34, 139.83, 137.05, 136.58, 129.94, 129.78, 128.64 (2C), 128.60 (2C), 128.11,
127.94, 127.58 (2C), 127.38 (2C), 125.88, 120.59, 112.00, 111.91, 111.81, 110.52,
107.22, 71.16, 70.27, 56.06, 21.18 (CH CO); CI-MS m/z 481 (M+1) , 503 (M+Na) ;
HRMS m/z 503.1832 (M+Na) , calcd 503.1834 for C H O Na.
31 28 5
13. Preparation of E[3-acetoxymethoxyphenyl][3-methoxy
benzyloxyphenyl]ethene (13).
The title compound was prepared as described in 11 to condense the acid chloride of 6
with reagent 9 to give the title compound as an off white solid; mp 104-106ºC;
C H O H NMR (400 MHz, CDCl ) δ 7.45-7.30 (m, 8H), 7.07 (d, J = 2 Hz, 1H), 7.03
24 5 3
(d, J = 16 Hz, 1H), 6.98 (dd, J = 8, 2 Hz, 1H), 6.90 (d, J = 16 Hz, 1H), 6.88 (m, 1H),
.18 (s, 2H), 3.95 (s, 3H), 3.83 (s, 3H), 2.31 (s, 3H); C NMR (100MHz, CDCl ) δ
169.41, 160.58, 151.83, 149.78, 148.31, 139.76, 137.00, 130.49, 129.72, 128.58 (2C),
127.88, 127.24 (2C), 126.07, 119.97, 113.94, 111.73, 109.67, 109.46, 106.54, 71.01,
56.02, 55.50, 21.18; CI-MS m/z 405 [M+1] ; HRMS m/z 405.1695 (M+H) , calcd
405.1702 for C H O .
25 5
14. Preparation of E[3-hydroxybenzyloxyphenyl][3-methoxy
benzyloxyphenyl]ethene (14)
To a solution of stilbene 11 (0.04 g, 0.083 mmol) in mixed solvent (MeOH / THF /
H O, 3/ 3/ 3 mL) was added NaOH (0.02 g, 0.35 mmol) at 0ºC under N . The reaction
mixture was warmed up to room temperature and stirred for 3 hours. The solution was
acidified with 0.1 M HCl (5 mL) and extracted with ethyl acetate (3 x 20 mL). The
combined organic extracts were washed with 20% aq. sodium chloride (10 mL), dried
over sodium sulphate and evaporated in vacuo. The product was purified using NPSCC
(mobile phase of hexane/ethyl acetate) followed by recrystallisation to afford 14 as a
colourless solid (0.016 g, 44.5%); mp 114-115ºC; C H O H NMR (400 MHz,
29 26 4
Methanol-d ) δ 7.45-7.28 (m, 10H), 7.06 (d, J = 2 Hz, 1H), 7.00 (d, J = 16 Hz, 1H),
6.98 (dd, J = 8, 2 Hz, 1H), 6.87 (d, J = 8 Hz, 1H), 6.86 (d, J = 16 Hz, 1H), 6.71 (t, J =
2.0 Hz, 1H), 6.59 (t, J = 2 Hz, 1H), 6.38 (t, J = 2 Hz, 1H), 5.18 (s, 2H), 5.07 (s, 2H),
3.95 (s, 3H); C NMR (100 MHz, Methanol-d ) δ 160.29, 156.78, 149.76, 148.19,
139.92, 136.98, 136.84, 130.65, 129.20, 128.61 (2C), 128.57 (2C), 128.02, 127.88,
127.49 (2C), 127.26 (2C), 126.54, 119.94, 113.96, 109.45, 105.97, 105.69, 101.54,
+ + +
71.02, 70.01, 56.03; CI-MS: 461 (M+Na) , 439 (M+1) ; HRMS m/z 439.1908 (M+H) ,
calcd 439.1909 for C H O .
29 27 4
. Preparation of E[3-hydroxybenzyloxyphenyl][3-benzyloxy
methoxyphenyl]ethene (15).
Basic hydrolysis of 12 was carried out as described for compound 14 to give the title
compound as a colourless solid; mp 117-119ºC; C H O H NMR (400 MHz,
29 26 4
Methanol-d ) δ 7.49-7.30 (m, 10H), 7.07 (d, J = 2.0 Hz, 1H), 7.06 (dd, J=8.4, 2.0 Hz,
1H), 6.96 (d, J = 16.0 Hz, 1H), 6.87 (d, J = 8.0 Hz, 1H), 6.79 (d, J = 16.4 Hz, 1H),
6.99 (t, J = 1.6 Hz, 1H), 6.57 (t, J = 2.0 Hz, 1H), 6.38 (t, J = 2.4 Hz, 1H), 5.19 (s, 2H),
5.07 (s, 2H), 3.90 (s, 3H). C NMR (100MHz, Methanol-d ) δ 160.20, 158.30, 149.68,
148.25, 139.70, 137.41, 137.31, 130.62, 128.16, 128.07 (2C), 128.05 (2C), 127.52,
127.41 (3C), 127.15 (2C), 126.62, 120.35, 111.95 (2C), 105.67, 104.09, 101.11, 70.88,
+ + +
69.56, 55.10; CI-MS: m/z 461 (M+Na) , 439 (M+1) ; HRMS m/z 439.1907 (M+H) ,
calcd 439.1909 for C H O .
29 27 4
16. Preparation of E[3-hydroxymethoxyphenyl][3-methoxy
benzyloxyphenyl]ethene (16).
Basic hydrolysis of 13 was carried out as described for compound 14 to give the title
compound as a yellowish solid; mp 110-112ºC; C H O H NMR (400 MHz, CDCl )
23 22 4 3
δ 7.45-7.28 (m, 5H), 7.07 (d, J = 2 Hz, 1H), 7.00 (d, J=16 Hz, 1H), 6.98 (dd, J = 8, 2
Hz, 1H), 6.87 (d, J = 17 Hz, 1H), 6.85 (d, J = 8 Hz, 1H), 6.62 (t, J = 2 Hz, 1H), 6.57 (t,
J = 2 Hz, 1H), 6.31 (t, J = 2 Hz, 1H), 5.17 (s, 2H), 3.94 (s, 3H), 3.81 (s, 3H); C NMR
(100MHz, CDCl ) δ 161.08, 156.86, 149.73, 148.16, 139.85, 136.96, 130.69, 129.11,
128.57 (2C), 127.90, 127.29 (2C), 126.61, 119.95, 113.97, 109.47, 105.72, 104.73,
100.72, 71.03, 56.03, 55.36; CI-MS, m/z 384 (M+Na) , 363 (M+1) ; HRMS m/z
363.1592 (M+H) , calcd 363.1596 for C H O .
23 23 4
17. Preparation of E[3-(3-methylbutenyloxy)benzyloxyphenyl][3-
methoxybenzyloxyphenyl]ethene (17)
To the suspension of NaH (60% dispersion in mineral oil, 0.0051 g, 0.213 mmol) in
anhydrous DMF (5 mL) under N at 0ºC, stilbene 14 (0.04 g, 0.091 mmol) was added
dropwise in DMF (3 mL), followed by the dropwise addition of 3,3-dimetylallyl
bromide (0.011 mL, 0.091 mmol). The mixture was stirred at room temperature for 2-
3 hours, then quenched with cold water (5 mL), acidified with cooled 0.1 M HCl (5
mL) and extracted with diethyl ether (3 x 10 mL). The combined organic extracts were
washed with water (2 x 10 mL) and dried under reduced pressure. The product was
purified using NPSCC (hexane/ethyl acetate as mobile phase) to give 17 as a yellowish
oil (0.02 g, 43.3 %); C H O H NMR (400 MHz, CDCl ) δ 7.46-7.28 (m, 10H), 7.07
34 34 4 3
(d, J = 2 Hz, 1H), 7.01 (d, J = 16 Hz, 1H), 6.96 (d, J = 2 Hz, 1H), 6.90 (d, J = 16 Hz,
1H), 6.87 (d, J = 8 Hz, 1H), 6.73 (t, J = 2 Hz, 1H), 6.68 (t, J = 2 Hz, 1H), 6.48 (t, J = 2
Hz, 1H), 5.52 (m, 1H), 5.17 (s, 2H), 5.07 (s, 2H), 4.52 (d, J = 7 Hz, 2H), 3.95 (s, 3H),
1.80 (d, J = 1 Hz, 3H), 1.76 (d, J = 1 Hz, 3H); C NMR (100MHz, CDCl ) δ 160.21,
160.12, 149.78, 148.14, 139.49, 138.35, 137.03, 136.94, 130.76, 128.94, 128.59 (2C),
128.56 (2C), 127.94, 127.86, 127.54 (2C), 127.24 (2C), 126.97, 119.87, 119.53,
113.98, 109.43, 105.38, 105.32, 101.14, 71.01, 70.09, 64.84, 56.03, 25.85, 18.22; CI-
+ + +
MS: m/z 529 (M+Na) , 507 (M+1) ; HRMS m/z 507.2528 (M+H) , calcd 507.2535 for
C H O .
34 35 4
18. Preparation of E[3-(3-methylbutenyloxy)benzyloxyphenyl][3-
benzyloxymethoxyphenyl]ethene (18).
Prenylation of 15 was carried out as described for compound 17 to give the title
compound as an off white solid; mp 88-90ºC; C H O H NMR (400 MHz, CDCl ) δ
34 34 4 3
7.49-7.32 (m, 10H), 7.08 (d, J = 2 Hz, 1H), 7.06 (dd, J = 8, 2 Hz, 1H), 6.97 (d, J = 16
Hz, 1H), 6.89 (d, J = 8 Hz, 1H), 6.82 (d, J =16 Hz, 1H), 6.71 (t, J = 2 Hz, 1H), 6.66 (t,
J = 2 Hz, 1H), 6.47 (t, J = 2 Hz, 1H), 5.53 (m, 1H), 5.20 (s, 2H), 5.07 (s, 2H), 4.52 (d, J
= 6 Hz, 2H), 3.91 (s, 3H), 1.80 (d, J = 1 Hz, 3H), 1.75 (d, J = 1 Hz, 3H); C NMR (100
MHz, CDCl ) δ 161.04, 160.95, 150.51, 149.11, 140.24, 139.03, 137.81, 137.67,
130.91, 129.57, 129.27 (4C), 128.66, 128.58, 128.22 (2C), 128.05 (2C), 127.50,
121.10, 120.20, 112.48, 112.40, 105.95, 105.86, 101.60, 71.55, 70.47, 65.18, 56.36,
+ + +
26.00, 18.33; CI-MS: m/z 529 (M+Na) , 507 (M+1) ; HRMS m/z 507.2530 (M+H) ,
calcd 507.2535 for C H O .
34 35 4
19. Preparation of E[3-(3-methylbutenyloxy)methoxyphenyl][3-
methoxybenzyloxyphenyl]ethene (19).
Prenylation of 16 was carried out as described for compound 17 to give the title
compound as off white crystal; mp 66-69ºC; C H O H NMR (400 MHz, CDCl ) δ
28 30 4 3
7.45-7.28 (m, 5H), 7.08 (d, J = 2 Hz, 1H), 7.02 (d, J = 16 Hz, 1H), 6.98 (d, J = 2 Hz,
1H), 6.90 (d, J = 16 Hz, 1H), 6.87 (d, J = 8 Hz, 1H), 6.67 (t, J = 2 Hz, 1H), 6.64 (t, J =
2 Hz, 1H), 6.40 (t, J = 2 Hz, 1H), 5.53 (m, 1H), 5.17 (s, 2H), 4.53 (d, J = 7 Hz, 2H),
3.96 (s, 3H), 3.81 (s, 3H), 1.81 (d, J = 1 Hz, 3H), 1.76 (d, J = 1 Hz, 3H); C NMR (100
MHz, CDCl ) δ 160.91, 160.23, 149.76, 148.14, 139.46, 138.35, 137.04, 130.78,
128.90, 128.56 (2C), 127.87, 127.25 (2C), 127.02, 119.86, 119.56, 113.98, 109.44,
104.96, 104.49, 100.37, 71.02, 64.82, 56.04, 55.36, 25.86, 18.22; CI-MS: m/z 453
(M+Na) ; HRMS m/z 453.2036 (M+Na) , calcd 453.2042 for C H O Na.
28 30 4
. Preparation of (E)(3-methylbutenyloxy)-4’,5-dihydroxy-3’-
methoxystilbene (20, equivalent to USYDS2)
To a solution of 17 (0.02 g, 0.035 mmol) in absolute ethanol (8 mL), was added 1,4-
cyclohexadiene (3 mL, 0.030 mmol) and Pd-C (10%, 0.002 g). The mixture was stirred
under N and refluxed at 80ºC for 4 hours. The solution was filtered and dried under
reduced pressure to give an oil residue which was purified by high performance liquid
chromatography (HPLC) to afford 20 as a yellowish oil; C H O H NMR (400 MHz,
22 4
CDCl ) δ 7.02 (d, J = 2 Hz, 1H), 7.00 (d, J = 16 Hz, 1H), 6.99 (d, J = 2 Hz, 1H), 6.91
(dd, J = 8, 1 Hz, 1H), 6.85 (d, J = 16 Hz, 1H), 6.64 (t, J = 2 Hz, 1H), 6.56 (t, J = 2 Hz,
1H), 6.33 (t, J = 2 Hz, 1H), 5.53 (m, 1H), 4.52 (d, J = 7 Hz, 2H), 3.95 (s, 3H), 1.82 (d, J
= 1 Hz, 3H), 1.76 (d, J = 1 Hz, 3H); C NMR (100 MHz, CDCl ) δ 160.38, 156.70,
146.67, 145.69, 139.87, 138.37, 129.73, 129.29, 126.15, 120.63, 119.49, 114.54,
108.24, 105.58, 105.38, 101.29, 64.85, 55.92, 25.85, 18.22; CI-MS: m/z 325 (M−1) ;
HRMS m/z 327.1588 (M+H) , calcd 327.1596 for C H O .
23 4
21. Preparation of 3-(3-methylbutenyloxy)-4’,5-dihydroxy-3’-methoxydihydro-
stilbene (21).
The title compound was obtained by hydrogenation of the double bond on the bridging
C=C during removal of the benzyl group of compound 20. The title compound was
obtained as a light yellow oil; C H O H NMR (400 MHz, CDCl ) δ 6.84 (d, J = 8
24 4 3
Hz, 1H), 6.69 (dd, J = 8, 2 Hz, 1H), 6.62 (d, J = 2 Hz, 1H), 6.34 (t, J = 2 Hz, 1H), 6.26
(t, J = 2.0 Hz, 1H), 6.24 (t, J = 2 Hz, 1H), ), 5.46 (m, 1H), 5.46 (s, 1H), 4.68 (s, 1H),
4.53 (d, J = 7 Hz, 2H), 3.84 (s, 3H), 2.85 (m, 4H), 1.80 (d, J = 0.4 Hz, 3H), 1.73 (d, J =
0.5 Hz, 3H); C NMR (100 MHz, CDCl ) δ 160.11, 156.44, 146.22, 144.46, 143.73,
138.23, 133.61, 120.95, 119.55, 114.15, 111.10, 107.89, 107.58, 99.62, 64.72, 55.84,
38.29, 37.23, 25.84, 18.18; CI-MS: m/z 351 (M+Na) ; HRMS m/z 351.1566 (M+Na) ,
calcd 351.1572 for C H O Na.
24 4
22. Preparation of (E)(3-methylbutenyloxy)-3’,5-dihydroxy-4’-
methoxystilbene (22).
Removal of benzyl group of 18 was carried out as described for compound 20 to give
the title compound as a light yellow oil; C H O H NMR (400 MHz, CDCl ) δ 7.13
22 4 3
(d, J = 2 Hz, 1H), 6.98 (d, J = 16 Hz, 1H), 6.97 (dd, J = 8, 2 Hz, 1H), 6.86 (d, J = 8 Hz,
1H), 6.86 (d, J = 16 Hz, 1H), 6.64 (t, J = 2 Hz, 1H), 6.57 (t, J = 2 Hz, 1H), 6.33 (t, J = 2
Hz, 1H), 5.60 (s, 1H), 5.52 (m, 1H), 4.77 (s, 1H), 4.52 (d, J = 9 Hz, 2H), 3.91 (s, 3H),
1.82 (d, J = 1 Hz, 3H), 1.76 (d, J = 1 Hz, 3H); C NMR (100 MHz, CDCl ) δ 160.37,
156.69, 146.51, 145.75, 139.83, 138.36, 130.87, 128.92, 126.78, 119.51, 119.40,
111.84, 110.62, 105.66, 105.48, 101.33, 65.18, 56.36, 26.00, 18.33; CI-MS: m/z
349.1408 (M+Na) , calcd 349.1416 for C H O Na.
22 4
23. Preparation of 3-(3-methylbutenyloxy)-3’,5-dihydroxy-4’-methoxydihydro-
stilbene (23).
The title compound was obtained by hydrogenation of double bond on the side chain
during removal of the benzyl groups of compound 18. The title compound was
obtained as a light yellow oil; C H O H NMR (400 MHz, CDCl ) δ 6.79 (d, J = 2
24 4 3
Hz, 1H), 6.77 (d, J = 4 Hz, 1H), 6.66 (dd, J = 8, 2 Hz, 1H), 6.35 (t, J = 2 Hz, 1H), 6.27
(m, 1H), 5.56 (s, 1H), 5.50 (m, 1H), 4.74 (s, 1H), 4.46 (d, J = 7 Hz, 2H), 3.88 (s, 3H),
2.80 (m, 4H), 1.80 (d, J = 1 Hz, 3H), 1.74 (d, J = 1 Hz, 3H); C NMR (100 MHz,
CDCl ) δ 160.11, 156.42, 145.41, 144.80, 144.51, 138.18, 135.07, 119.73, 119.59,
114.59, 110.55, 107.81, 107.49, 99.64, 64.73, 55.00, 38.05, 36.89, 25.83, 18.18; CI-
MS: m/z 351 (M+Na) ; HRMS m/z 351.1566 (M+Na) , calcd 351.1572 for
C H O Na.
24 4
24. Preparation of E[2-(3-methylbutenyl)hydroxybenzyloxyphenyl]
[3-methoxybenzyloxyphenyl]ethene (24)
To a solution of 17 (0.024 g, 0.061 mmol) in toluene (30 mL) was added 100-200 mesh
Florisil (0.24 g, 10x) and heated at 110ºC under N for 4 hours. The reaction mixture
was filtered, evaporated in vacuo and the red-brown residue was purified using NPSCC
(hexane / ethyl acetate as mobile phase) to afford a brownish solid (0.014 g, 58.3 %).
The product was recrystallised from hexane/ethyl acetate (3:1) mixture to give 24 as an
off white solid; mp 145-150ºC; C H O H NMR (400 MHz, CDCl ) δ 7.46-7.28 (m,
34 34 4 3
10H), 7.20 (d, J = 16 Hz, 1H), 7.06 (d, J = 2 Hz, 1H), 6.97 (dd, J = 8, 2 Hz, 1H), 6.88
(d, J = 16 Hz, 1H), 6.87 (d, J = 8 Hz, 1H), 6.68 (d, J = 2 Hz, 1H), 6.40 (d, J = 2 Hz,
1H), 5.18 (s, 2H), 5.17 (m, 1H), 5.05 (s, 2H), 4.69 (s, 1H), 3.94 (s, 3H), 3.48 (d, J = 7
Hz, 2H), 1.73 (d, J = 1 Hz, 3H), 1.67 (d, J = 1 Hz, 3H); C NMR (100 MHz, CDCl ) δ
157.60, 154.27, 149.76, 148.08, 138.31, 137.14, 137.04, 131.18, 130.59, 130.35,
128.56 (2C), 128.49 (2C), 127.86, 127.78, 127.23 (2C), 127.21 (2C), 124.74, 123.63,
121.13, 119.85,113.99, 109.47, 104.31, 99.53, 71.03, 70.29, 55.98, 25.77, 24.69, 18.01.
25. Preparation of E[2-(3-methylbutenyl)hydroxymethoxyphenyl][3-methoxy-
4-benzyloxyphenyl]ethene (25).
Rearrangment of 19 was carried out as described for compound 24 to give a pinkish
solid: mp 161-162ºC; C H O H NMR (400 MHz, CDCl ) δ 7.46-7.28 (m, 5H), 7.19
28 30 4 3
(d, J = 16 Hz, 1H), 7.06 (d, J = 2 Hz, 1H), 6.97 (dd, J = 8, 2 Hz, 1H), 6.88 (d, J = 16
Hz, 1H), 6.87 (d, J = 8 Hz, 1H), 6.66 (t, J = 2 Hz, 1H), 6.40 (t, J = 2 Hz, 1H), 5.18 (s,
2H), 5.13 (m, 1H), 4.64 (s, 1H), 3.94 (s, 3H), 3.80 (s, 3H), 3.42 (d, J = 6 Hz, 2H), 1.80
(d, J = 1 Hz, 3H), 1.68 (d, J = 1 Hz, 3H); C NMR (100 MHz, CDCl ) δ 158.56,
154.35, 149.76, 148.07, 138.11, 137.04, 131.21, 130.63, 130.24, 128.56 (2C), 127.86,
127.22 (2C), 124.73, 123.61, 120.78, 119.84, 113.99, 109.42, 103.88, 98.21, 71.03,
55.97, 55.68, 25.77, 24.46, 17.98; CI-MS: m/z 453 (M+Na) , 431 (M+1) ; HRMS m/z
431.2217 (M+1) , calcd 431.2222 for C H O .
28 31 4
26. Preparation of (E)(3-methylbutenyl)-3,4’,5-trihydroxy-3’-methoxy-
stilbene (26, equivalent to USYDS10).
To a solution of 24 (0.02 g, 0.035 mmol) in absolute ethanol (6 mL) was added 1,4-
cyclohexadiene (3 mL) and Pd-C (10%, 0.0035 mmol). The mixture was stirred under
N and heated at 80 C for 4 hours. The solution was filtered and evaporated in vacuo to
give an oil residue which was purified using NPSCC (hexane/ethyl acetate as mobile
phase) followed by normal phase HPLC (2:1 hexane/ isopropanol as mobile phase) to
afford the title compound as a light yellow oil: Data analogous to that of USYDS10..
27. Preparation of (E)(3-methylbutenyl)-5,4’-dihydroxy-3’,3-dimethoxy-
stilbene (27, equivalent to USYDS1).
The title compound was prepared using the procedure as described for compound 25 to
give 27 as light yellow oil; C H O H NMR (400 MHz, CDCl ) δ 7.17 (d, J = 16 Hz,
21 24 4 3
1H), 7.01 (dd, J = 12, 2 Hz, 1H), 7.0 (d, J = 2 Hz, 1H), 6.91 (d, J = 8 Hz, 1H), 6.87 (d,
J = 16 Hz, 1H), 6.66 (t, J = 2 Hz, 1H), 6.36 (t, J = 2 Hz, 1H), 5.15 (m, 1H), 4.64 (s,
1H), 3.94 (s, 3H), 3.80 (s, 3H), 3.42 (d, J = 7 Hz, 2H), 1.81 (d, J = 1 Hz, 3H), 1.68 (d, J
= 1 Hz, 3H); C NMR (100 MHz, CDCl ) δ 158.57, 154.37, 146.68, 145.60, 138.18,
130.61, 130.44, 130.27, 124.28, 123.67, 120.73, 120.58, 114.55, 108.26, 103.88, 98.18,
55.88, 55.71, 25.79, 24.48, 17.98; CI-MS: m/z 339 (M−1) ; HRMS m/z 363.1566
(M+Na) , calcd 363.1572 for C H O Na.
21 24 4
28. Preparation of 2-(3-methylbutenyl)-5,4’-dihydroxy-3’,3-
dimethoxydihydro-stilbene (28).
CH O
The title compound was obtained by hydrogenation of double bond on the side chain
during removal of the benzyl group of compound 27. The title compound was obtained
as a light yellow oil; C H O H NMR (400 MHz, CDCl ) δ 6.86 (d, J = 8 Hz, 1H),
21 26 4 3
6.70 (dd, J = 8, 2 Hz, 1H), 6.64 (d, J = 2 Hz, 1H), 6.30 (d, J = 2 Hz, 1H), 6.24 (d, J = 2
Hz, 1H), 5.48 (s, 1H), 5.07 (m, 1H), 4.67 (s, 1H), 3.85 (s, 3H), 3.78 (s, 3H), 3.28 (d, J =
6 Hz, 2H), 2.82 (m, 4H), 1.74 (d, J = 1 Hz, 3H), 1.66 (d, J = 1 Hz, 3H); C NMR (100
MHz, CDCl ) δ 158.63, 154.23, 146.23, 143.73, 142.01, 133.93, 130.59, 123.87,
120.92, 120.67, 114.21, 111.02, 107.96, 96.90, 55.84, 55.60, 37.19, 35.49, 25.76,
24.38, 17.95; CI-MS: m/z 365 (M+Na) ; HRMS m/z 365.1723 (M+Na) , calcd
365.1729 for C H O Na.
21 26 4
Biological evaluations of prenylated polyhydroxystilbene derivatives
1. Anticancer activities of the prenylated polyhydroxystilbene derivatives.
A) Seven prenylated polyhydroxystilbene derivatives, namely USYDS1, USYDS2,
USYDS4, USYDS6, USYDS7, USYDS9 and USYDS13 were evaluated for inhibition
of cell growth, as shown in table 1 below, against the 60 cell lines at a range of
-8 -4
concentrations (1 x 10 – 1 x 10 M) at the National Cancer Institute (NCI), USA.
Methodology of the in vitro cancer screen: General method adopted from NCI
The human tumor cell lines were grown in RPMI 1640 medium containing 5% fetal
bovine serum and 2 mM L-glutamine. For a typical experiment, cells were inoculated
into 96 well microtiter plates in 100 µL at plating densities ranging from 5,000 to
40,000 cells/well depending on the doubling time of individual cell lines. After cell
inoculation, the microtiter plates were incubated at 37°C, 5% CO , 95% air and 100%
relative humidity for 24 h prior to addition of the drugs.
After 24 h, two plates of each cell line were fixed in situ with trichloroacetic acid
(TCA), to represent a measurement of the cell population for each cell line at the time
of drug addition. Experimental drugs are solubilized in dimethyl sulfoxide (DMSO) at
400-fold the desired final maximum test concentration and stored frozen prior to use.
At the time of drug addition, an aliquot of frozen concentrate was thawed and diluted to
twice the desired final maximum test concentration with complete medium containing
50µg/mL gentamicin. Aliquots of 100 µL of the drug were added to the appropriate
microtiter wells already containing 100 µL of medium, resulting in the required final
drug concentrations.
Following drug addition, the plates were incubated for an additional 48 h at 37°C, 5%
CO , 95% air, and 100% relative humidity. For adherent cells, the assay was terminated
by the addition of cold TCA. Cells were fixed in situ by the gentle addition of 50 µL of
cold 50 % (w/v) TCA (final concentration, 10 % TCA) and incubated for 60 minutes at
4°C. The supernatant was discarded, and the plates were washed five times with tap
water and air dried. Sulforhodamine B (SRB) solution (100 µL) at 0.4% (w/v) in 1%
acetic acid was added to each well, and plates were incubated for 10 minutes at room
temperature. After staining, unbound dye was removed by washing five times with 1%
acetic acid and the plates were air dried. Bound stain was subsequently solubilized with
mM trizma base, and the absorbance was read on an automated plate reader at a
wavelength of 515 nm. For suspension cells, the methodology was the same except that
the assay was terminated by fixing settled cells at the bottom of the wells by gently
adding 50 µL of 80% TCA (final concentration, 16% TCA), and the absorbance was
read on an automated plate reader at a wavelength of 515 nm. The GI value
(concentration required for 50% inhibition of cell growth), TGI value (concentration
required for total inhibition of cell growth) and LC value (concentration required for
50% cell lethality or death) were calculated for each of USYDS1, USYDS2, USYDS4,
USYDS6, USYDS7, USYDS9 and USYDS13, and the results are presented in tables 1
to 3 below.
Table 1: Effect of pPHOS USYDS1, USYDS2 and USYDS13 on human cancerous cells growth.
Compounds USYDS1 (μ μ μ μM) USYDS2 (μ μ μ μM) USYDS13 (μ μ μ μM)
Leukemia GI TGI LC GI TGI LC GI TGI LC
50 50 50 50 50 50
CCRF-CEM 0.35 24.6 >100 5.06 >100 >100 6.56 >100 >100
HL-60 (TB) 0.02 0.06 68.9 1.34 9.77 >100 2.55 17.1 >100
K-562 0.04 11.7 >100 0.48 >100 >100 4.08 57.5 >100
MOLT-4 0.43 12.3 80.2 4.16 28.3 >100 2.95 13.7 >100
RPMI-8226 0.11 14.8 >100 4.32 52.8 >100 9.05 51.6 >100
SR 0.04 24.4 >100 0.54 >100 >100 2.80 >100 >100
Non-Small Cell Lung Cancer
A549/ATCC 0.50 11.3 40.3 3.28 13.0 42.1 4.01 20.4 >100
EKVX 10.8 24.3 54.4 9.04 25.2 66.4 12.8 54.6 >100
HOP-62 0.44 16.0 42.2 4.44 18.5 43.4 5.66 20.4 53.7
HOP-92 0.06 12.3 39.6 3.98 21.1 60.1 5.96 30.5 >100
NCI-H226 3.13 13.3 45.6 5.43 19.1 46.4 10.9 50.1 >100
NCI-H23 0.28 15.1 62.5 2.89 23.6 >100 5.66 28.0 >100
NCI-H322M 11.8 25.7 55.9 9.64 22.7 52.3 5.90 28.5 >100
NCI-H460 0.23 1.38 42.0 2.47 10.9 58.7 3.09 15.6 >100
NCI-H522 0.02 - 44.8 1.14 3.57 14.7 2.13 59.8 25.6
Colon Cancer
COLO 205 3.86 16.1 42.6 17.3 31.7 57.9 15.6 28.9 53.8
HCC-2998 1.07 11.5 35.8 4.61 17.3 46.4 11.0 30.6 85.3
HCT-116 0.30 11.1 40.4 2.09 11.9 40.0 4.33 15.6 45.6
HCT-15 0.05 16.1 >100 0.76 17.8 97.3 4.25 20.5 84.5
HT29 4.73 15.3 44.4 17.4 32.2 59.6 17.8 36.9 76.8
KM12 0.32 13.9 46.7 2.09 11.7 45.0 3.15 16.1 49.0
SW-620 0.04 15.1 44.3 0.53 14.0 40.7 3.98 15.9 42.8
CNS Cancer
SF-268 0.25 14.1 50.2 4.50 19.2 51.6 6.17 32.9 >100
SF-295 0.65 16.2 55.7 3.94 14.7 49.2 5.22 23.5 77.5
SF-539 0.04 14.4 48.6 1.92 13.8 50.2 7.32 29.9 >100
SNB-19 0.17 19.3 51.5 5.02 20.4 53.6 8.02 24.2 64.5
SNB-75 0.03 20.2 72.0 2.14 10.3 55.8 5.47 36.6 >100
U251 0.37 10.9 36.0 2.96 14.7 41.0 5.47 20.7 57.6
Melanoma
LOX IMVI 0.05 16.2 58.8 1.56 19.4 >100 4.48 20.2 80.0
MALME-3M 3.47 25.8 78.3 1.88 26.2 94.9 5.53 32.1 >100
M14 0.04 13.9 44.0 0.53 15.4 49.4 4.92 18.5 51.6
MDA-MB-435 0.03 13.8 43.0 0.34 11.0 41.3 3.08 15.9 >100
SK-MEL-2 0.32 10.6 38.0 1.25 9.59 41.6 3.09 9.37 40.2
SK-MEL-28 10.9 23.8 51.7 5.04 19.4 46.7 5.64 22.5 70.5
SK-MEL-5 0.05 0.75 5.99 1.58 11.5 34.3 2.50 8.54 29.2
UACC-257 2.53 17.7 45.4 7.89 20.6 46.0 5.35 18.1 44.0
UACC-62 1.62 18.3 46.6 3.73 15.9 44.6 5.30 19.7 58.8
Ovarian Cancer
IGROV1 2.65 27.9 >100 5.84 46.7 >100 6.70 86.2 >100
OVCAR-3 0.26 - 37.3 3.02 10.7 36.1 7.98 39.8 >100
OVCAR-4 0.58 18.4 52.0 5.34 28.0 >100 9.68 74.8 >100
OVCAR-5 6.0 21.4 55.3 10.1 24.8 60.9 13.9 79.3 >100
OVCAR-8 0.08 11.7 50.0 2.80 14.8 44.6 5.48 59.8 >100
ADR-RES 0.03 - 70.7 0.40 4.95 >100 4.41 >100 >100
SK-OV-3 0.19 11.6 34.7 3.69 14.9 38.9 7.96 36.2 >100
Renal Cancer
786-0 0.48 14.0 >100 3.55 15.9 98.8 5.24 24.5 >100
A498 1.84 8.45 32.2 10.3 23.8 55.2 3.88 21.0 63.5
ACHN 0.07 14.0 44.6 3.76 17.5 52.1 5.11 >100 >100
CAKI-1 4.77 39.3 >100 6.13 >100 >100 5.90 >100 >100
RXF-393 0.03 - 39.1 1.35 5.46 23.6 5.48 18.9 46.5
SN12C 0.99 16.9 54.2 4.02 18.8 60.2 7.16 >100 >100
TK-10 4.10 15.7 40.5 4.69 14.3 40.1 6.98 31.4 >100
UO-31 0.25 16.0 51.3 2.60 16.9 48.9 4.16 38.1 >100
Prostate Cancer
PC-3 0.42 16.1 47.9 3.84 18.7 65.8 6.36 >100 >100
DU-145 0.06 12.7 38.6 3.05 12.5 37.8 6.82 31.6 >100
Breast Cancer
MCF7 0.23 13.0 52.9 1.24 15.0 41.0 0.68 19.9 82.7
MDA-MB-231 0.15 2.43 61.2 0.25 2.10 15.7 1.63 7.82 >100
BT-549
HS 578T 0.02 - >100 1.28 10.3 >100 2.40 15.0 >100
T-47D 0.72 19.8 67.4 5.66 33.6 >100 2.92 14.7 70.5
MDA-MB-468 0.36 8.37 33.2 2.72 9.41 36.8 1.68 7.63 >100
Table 2: Effect of pPHOS USYDS4, USYDS9 and USYDS6 on human cancerous cells growth
Compounds USYDS4 (μ μM) USYDS9 (μ μ μ μM) USYDS6 (μ μM)
μ μ μ μ
Leukemia GI TGI LC GI TGI LC GI TGI LC
50 50 50 50 50 50
CCRF-CEM 3.50 >100 >100 2.14 >100 >100 2.96 9.17 82.1
HL-60 (TB) 2.59 6.04 >100 0.20 0.43 0.95 2.07 4.83 15.4
K-562 2.35 >100 >100 0.33 13.9 >100 1.46 4.13 22.6
MOLT-4 4.31 21.6 >100 1.27 6.77 >100 1.59 4.27 16.8
RPMI-8226 2.35 25.4 >100 0.45 >100 >100 2.34 5.61 62.0
SR 0.95 >100 >100 - - - - - -
Non-Small Cell Lung Cancer
A549/ATCC 4.74 25.6 >100 2.62 41.5 >100 2.69 8.42 33.7
EKVX 9.55 59.6 >100 26.4 >100 >100 7.19 21.4 54.4
HOP-62 6.49 26.3 83.4 2.87 >100 >100 5.11 17.5 44.0
HOP-92 1.92 13.6 62.3 0.62 >100 >100 1.86 4.67 14.5
NCI-H226 5.14 23.1 78.0 18.6 57.9 >100 1.47 30.1 61.5
NCI-H23 3.42 20.8 81.9 1.43 >100 >100 3.38 15.7 47.6
NCI-H322M 12.8 54.7 >100 0.76 >100 >100 1.16 25.5 56.2
NCI-H460 3.65 20.3 >100 0.47 10.3 75.7 1.89 3.90 8.06
NCI-H522 1.07 2.54 6.04 0.15 0.45 44.8 2.18 5.15 17.8
Colon Cancer
COLO 205 9.72 23.0 53.5 21.7 83.6 >100 16.0 30.2 57.2
HCC-2998 5.16 19.0 53.4 4.18 21.2 >100 2.81 8.78 32.2
HCT-116 4.55 16.0 40.6 1.40 12.8 75.0 1.89 3.78 7.54
HCT-15 1.77 34.9 >100 0.43 >100 >100 2.13 6.26 48.2
HT29 16.3 32.5 64.7 18.6 46.6 >100 5.44 17.6 48.3
KM12 3.27 14.2 46.5 0.52 12.2 63.9 2.21 4.37 8.64
SW-620 2.97 16.6 46.5 0.31 15.3 75.0 1.84 3.54 6.82
CNS Cancer
SF-268 3.89 23.2 >100 0.63 37.6 >100 2.78 8.97 44.3
SF-295 7.29 24.3 70.9 2.60 20.5 >100 6.78 20.8 53.2
SF-539 3.45 22.3 97.5 0.28 1.02 >100 4.48 17.6 57.1
SNB-19 10.5 25.8 63.8 0.55 >100 >100 6.38 20.6 52.7
SNB-75 1.77 9.11 48.3 0.24 - >100 6.67 21.4 54.0
U251 3.67 15.6 45.5 0.59 19.6 >100 2.33 5.31 16.7
Melanoma
LOX IMVI 3.82 19.3 58.5 0.64 58.6 >100 1.76 3.42 6.68
MALME-3M 7.25 30.6 >100 0.62 >100 >100 2.80 8.56 37.1
M14 0.91 15.4 46.3 0.30 5.69 >100 2.82 8.46 33.4
MDA-MB-435 0.36 21.6 >100 0.13 0.42 >100 3.37 10.8 42.1
SK-MEL-2 2.18 6.57 31.0 2.17 12.1 >100 13.1 33.6 86.1
SK-MEL-28 9.18 27.6 77.9 8.14 >100 >100 11.2 24.0 51.3
SK-MEL-5 1.42 8.35 30.0 0.39 2.52 >100 2.29 6.17 22.1
UACC-257 5.44 19.4 48.6 6.15 59.2 >100 3.49 14.4 39.8
UACC-62 4.53 16.8 44.4 3.22 34.8 >100 10.3 23.5 53.8
Ovarian Cancer
IGROV1 3.74 44.8 >100 4.57 >100 >100 5.23 17.7 54.1
OVCAR-3 3.98 15.0 44.9 0.90 3.84 24.8 2.10 4.31 8.85
OVCAR-4 3.98 50.4 >100 5.48 >100 >100 4.40 16.1 43.5
OVCAR-5 15.9 51.4 >100 30.7 >100 >100 5.86 20.0 53.3
OVCAR-8 4.94 31.1 >100 0.50 38.3 >100 2.95 9.51 42.9
ADR-RES 1.11 48.3 >100 0.29 3.69 >100 3.46 15.2 51.2
SK-OV-3 8.91 57.0 >100 0.50 5.12 >100 13.9 27.1 53.2
Renal Cancer
786-0 4.41 20.5 >100 2.99 18.7 >100 2.46 6.96 28.8
A498 9.07 23.5 55.2 10.3 53.5 >100 11.7 25.0 53.1
ACHN 4.57 >100 >100 0.66 >100 >100 3.94 14.6 50.4
CAKI-1 5.25 >100 >100 19.1 >100 >100 8.37 22.6 55.7
RXF-393 2.17 15.3 46.0 0.23 0.63 >100 2.15 5.39 18.7
SN12C 3.94 20.0 74.1 1.76 83.5 >100 2.85 7.98 30.8
TK-10 3.87 9.66 >100 5.34 41.2 >100 3.36 9.33 31.2
UO-31 3.31 20.7 66.4 0.46 >100 >100 2.51 7.50 33.5
Prostate Cancer
PC-3 4.47 22.0 87.9 2.92 >100 >100 1.80 3.89 8.44
DU-145 6.37 44.6 >100 0.35 2.62 >100 3.47 12.9 40.1
Breast Cancer
MCF7 2.57 18.2 51.1 2.81 >100 >100 4.02 18.0 60.5
MDA-MB-231 1.04 18.4 >100 0.38 2.61 >100 1.72 4.54 17.2
HS 578T 1.00 7.11 >100 0.20 0.73 >100 1.67 5.29 35.8
T-47D 2.13 6.93 >100 4.78 36.9 >100 5.03 20.3 57.9
MDA-MB-468 2.53 9.51 55.1 2.42 8.48 >100 2.30 6.39 26.0
Table 3: Effect of pPHOS USYDS7 on human cancerous cells growth
Compound
USYDS7 (μ μ μ μM)
Leukemia GI TGI LC Melanoma GI TGI LC
50 50 50 50
CCRF-CEM 2.73 8.48 71.2 LOX IMVI 1.71 3.41 6.81
HL-60 (TB) 2.39 5.06 13.8 MALME-3M 1.97 4.46 10.4
K-562 2.14 4.78 17.4 M14 1.79 3.71 7.73
MOLT-4 2.01 5.19 26.5 MDA-MB-435 2.29 6.47 31.7
RPMI-8226 2.31 6.01 61.1 SK-MEL-2 3.20 7.82 42.9
SK-MEL-28 3.65 11.8 36.7
Non-Small Cell Lung Cancer
A549/ATCC 1.88 4.06 8.78 SK-MEL-5 1.80 3.68 7.54
EKVX 4.25 14.7 44.9 UACC-257 2.18 5.93 23.0
HOP-62 3.67 15.0 51.6 UACC-62 2.80 7.84 31.5
HOP-92 1.52 4.21 14.2
Ovarian Cancer
NCI-H226 2.28 6.24 28.1 IGROV1 3.12 8.39 36.7
NCI-H23 1.81 5.22 29.5 OVCAR-3 1.82 3.36 6.19
NCI-H322M 5.29 18.1 44.7 OVCAR-4 2.85 11.1 66.8
NCI-H460 1.64 3.22 6.33 OVCAR-5 3.04 11.6 39.0
NCI-H522 1.61 3.57 7.92 OVCAR-8 1.68 3.65 7.95
Colon Cancer ADR-RES 2.23 7.90 42.4
COLO 205 1.79 4.34 12.2 SK-OV-3 5.98 19.4 46.5
HCC-2998 1.95 4.26 9.34
Renal Cancer
HCT-116 1.57 3.02 5.82 786-0 1.99 4.47 10.2
HCT-15 1.29 3.78 22.0 A498 11.1 23.8 50.8
HT29 3.64 10.8 45.8 ACHN 2.58 9.12 37.6
KM12 1.93 3.88 7.79 CAKI-1 4.24 16.2 49.0
SW-620 1.58 3.19 6.42 RXF-393 1.53 3.23 6.80
CNS Cancer SN12C 1.65 3.16 6.03
SF-268 2.26 5.47 22.7 TK-10 3.62 11.2 34.3
SF-295 3.37 11.4 44.6 UO-31 1.60 3.46 7.46
SF-539 2.21 6.14 35.2 Breast Cancer
SNB-19 2.80 8.64 39.9 MCF7 2.10 12.0 57.9
SNB-75 2.98 12.8 49.1 MDA-MB-231 1.49 3.89 10.7
U251 1.49 2.93 5.74 HS 578T 1.84 8.09 50.9
Prostate Cancer T-47D 1.88 6.09 43.5
PC-3 2.02 4.57 11.3 MDA-MB-468 2.12 4.84 13.9
DU-145 2.65 7.62 28.3
In summary, all the prenylated polyhydroxystilbene derivatives USYDS1 to USYDS9
and USYDS13 exhibited structure dependent inhibition of cancerous cell growth. In
some cell lines, growth was inhibited at nano-molar concentrations. USYDS1 displayed
the most potent activity followed by USYDS9 then USYDS2 in the inhibition of
cancerous cell growth. The other pPHOS compounds tested were shown to be moderate
inhibitors. Figures 3 to 9 show dose response curves for the inhibition of human
cancerous cell growth, for the various cell lines exhibited in the table above, by
compounds USYDS1 to USYDS9 and USYDS13.
Worthy of note is that these pPHOS required at least a 10 fold excess in concentration
to cause cell death (LC values) or cause necrosis, over that required to inhibit cell
growth (GI values). This indicates that the pPHOS were likely to cause the cancer
cells to undergo programmed cell death (apoptosis) or cell cycle arrest.
B) Two prenylated polyhydroxystilbene derivatives, namely USYDS10 and USYDS14
were evaluated for inhibition of cell growth, as shown in Table 4A and 4B below,
-8 -4
against the cell lines indicated at a range of concentrations (1 x 10 – 1 x 10 M) at the
National Cancer Institute (NCI), USA.
Table 4A: Inhibitory effect on cancer cells growth of USYDS10
GI50 TGI LC50
Leukemia
HL-60(TB) 3.27E-7 1.88E-6 > 1.00E-4
K-562 3.86E-7 3.17E-5 > 1.00E-4
MOLT 5.96E-7 1.99E-5 > 1.00E-4
RPMI 3.24E-7 1.63E-5 > 1.00E-4
SR 1.88E-7 > 1.00E-4 > 1.00E-4
Non-Small Cell Lung Cancer
A549/ATCC 6.60E-7 2.25E-5 > 1.00E-4
EKVX 1.22E-5 7.34E-5 > 1.00E-4
HOP 5.81E-7 1.77E-5 4.23E-5
HOP 3.98E-7 2.63E-5 9.32E-5
NCI-H226 5.35E-6 3.50E-5 > 1.00E-4
NCI-H23 3.80E-7 1.52E-5 7.83E-5
NCI-H322M 1.18E-5 3.14E-5 8.37E-5
NCI-H460 3.81E-7 1.29E-5 6.61E-5
NCI-H522 3.49E-7 1.46E-5 4.22E-5
Colon Cancer
COLO 1.53E-5 2.97E-5 5.77E-5
HCC-2998 1.81E-6 1.19E-5 3.98E-5
HCT-116 4.80E-7 1.30E-5 4.27E-5
HCT-15 4.98E-7 2.09E-5 > 1.00E-4
HT29 5.72E-6 2.13E-5 6.90E-5
KM12 4.97E-7 1.53E-5 8.58E-5
SW-620 3.62E-7 2.15E-5 8.55E-5
CNS Cancer
SF-268 1.40E-6 4.96E-5 > 1.00E-4
SF-295 2.01E-6 1.91E-5 > 1.00E-4
SF-539 3.76E-7 1.29E-5 4.17E-5
SNB-19 6.13E-7 2.28E-5 > 1.00E-4
SNB-75 2.36E-7 1.22E-5 3.61E-5
U251 4.19E-7 1.62E-5 7.88E-5
Melanoma
LOX IMVI 5.72E-7 1.93E-5 8.00E-5
MALME-3M 1.87E-5 4.17E-5 9.29E-5
M14 2.84E-7 1.42E-5 4.16E-5
MDA-MB-435 3.85E-8 2.56E-7 > 1.00E-4
SK-MEL-2 5.76E-7 3.26E-5 > 1.00E-4
SK-MEL-28 5.72E-7 1.69E-5 4.30E-5
SK-MEL-5 2.91E-7 1.27E-5 3.60E-5
UACC-257 1.17E-5 2.94E-5 7.37E-5
UACC-62 5.21E-7 1.55E-5 4.28E-5
Ovarian Cancer
IGROV1 2.03E-6 > 1.00E-4 > 1.00E-4
OVCAR-3 3.72E-7 2.03E-5 > 1.00E-4
OVCAR-4 1.03E-6 1.82E-5 5.77E-5
OVCAR-5 8.92E-6 2.80E-5 8.31E-5
OVCAR-8 4.67E-7 6.50E-5 > 1.00E-4
NCI/ADR-RES 1.83E-7 8.04E-7 > 1.00E-4
SK-OV-3 4.22E-7 1.14E-5 3.42E-5
40 Renal Cancer
786-0 6.81E-7 2.01E-5 7.45E-5
A498 2.17E-6 7.85E-6 3.48E-5
ACHN 9.03E-7 3.79E-5 > 1.00E-4
CAKI-1 5.39E-7 6.68E-5 > 1.00E-4
45 RXF 393 2.21E-7 3.76E-5
SN12C 6.71E-7 2.98E-5 > 1.00E-4
TK-10 9.55E-6 5.15E-5 > 1.00E-4
UO-31 8.78E-7 2.17E-5 9.52E-5
Prostate Cancer
PC-3 2.27E-6 3.12E-5 > 1.00E-4
DU-145 4.42E-7 2.05E-5 > 1.00E-4
Breast Cancer
MCF7 3.32E-7 1.30E-5 5.06E-5
MDA-MB-231/ATCC 6.42E-7 3.20E-5 > 1.00E-4
HS 578T 2.92E-7 2.60E-5 > 1.00E-4
BT-549 7.98E-7 1.90E-5 4.93E-5
T-47D 1.47E-6 2.47E-5 > 1.00E-4
MDA-MB-468 3.73E-7 1.44E-5 4.49E-5
Table 4B - Inhibitory effect on cancer cells growth of USYDS14
GI50 TGI LC50
Leukemia
HL-60(TB) 4.06E-6 1.63E-5 > 1.00E-4
K-562 8.33E-7 1.42E-5 > 1.00E-4
MOLT-4 4.03E-6 2.10E-5 > 1.00E-4
RPMI-8226 4.07E-6 2.45E-5 > 1.00E-4
SR 6.70E-7 2.46E-5 > 1.00E-4
Non-Small Cell Lung Cancer
A549/ATCC 4.33E-6 1.65E-5 4.55E-5
EKVX 6.45E-6 2.12E-5 5.17E-5
HOP-62 1.43E-6 3.77E-6 9.98E-6
HOP-92 1.49E-6 7.58E-6 3.29E-5
NCI-H226 1.72E-6 3.60E-6 7.52E-6
NCI-H23 2.92E-6 1.73E-5 5.76E-5
NCI-H322M 1.25E-5 2.57E-5 5.28E-5
NCI-H460 3.87E-6 1.49E-5 5.12E-5
NCI-H522 7.50E-7 2.26E-6 5.85E-6
Colon Cancer
COLO 205 1.46E-5 2.85E-5 5.57E-5
HCC-2998 2.90E-6 1.06E-5 4.07E-5
HCT-116 4.20E-6 1.60E-5 4.66E-5
HCT-15 2.06E-6 1.04E-5 4.33E-5
HT29 1.40E-5 2.91E-5 6.09E-5
KM12 3.74E-6 1.44E-5 5.74E-5
SW-620 2.88E-6 1.67E-5 6.38E-5
40 CNS Cancer
SF-268 4.65E-6 1.78E-5 4.85E-5
SF-295 3.91E-6 1.53E-5 4.31E-5
SF-539 2.96E-6 1.05E-5 3.78E-5
SNB-19 5.01E-6 2.01E-5 5.22E-5
45 SNB-75 1.79E-6 7.80E-6 2.93E-5
U251 3.09E-6 1.27E-5 3.94E-5
Melanoma
LOX IMVI 1.36E-6 3.37E-6 8.35E-6
MALME-3M 3.14E-6 2.18E-5 5.48E-5
M14 2.95E-6 1.36E-5 5.00E-5
MDA-MB-435 3.73E-7 8.45E-6 4.00E-5
SK-MEL-2 3.72E-6 1.25E-5 4.12E-5
SK-MEL-28 3.05E-6 1.64E-5 4.16E-5
SK-MEL-5 5.54E-7 1.87E-6 4.46E-6
UACC-257 1.02E-5 2.35E-5 5.40E-5
UACC-62 2.61E-6 1.32E-5 3.91E-5
Ovarian Cancer
IGROV1 3.65E-6 1.37E-5 6.54E-5
OVCAR-3 3.52E-6 1.35E-5 4.11E-5
OVCAR-4 2.98E-6 1.36E-5 3.86E-5
OVCAR-5 1.24E-5 2.58E-5 5.36E-5
OVCAR-8 3.59E-6 1.56E-5 6.49E-5
NCI/ADR-RES 7.80E-7 1.14E-5 4.93E-5
SK-OV-3 2.85E-6 1.37E-5 3.72E-5
Renal Cancer
786-0 3.44E-6 1.18E-5 4.00E-5
A498 1.30E-5 2.66E-5 5.46E-5
ACHN 2.98E-6 1.25E-5 3.65E-5
CAKI-1 3.59E-6 1.75E-5 4.54E-5
RXF 393 1.07E-6 3.58E-6 1.48E-5
SN12C 3.61E-6 1.51E-5 4.20E-5
TK-10 3.79E-6 1.21E-5 3.54E-5
UO-31 3.71E-6 1.79E-5 4.63E-5
Prostate Cancer
PC-3 6.65E-6 2.16E-5 5.50E-5
DU-145 8.20E-6 2.11E-5 4.75E-5
Breast Cancer
MCF7 2.74E-6 1.18E-5 4.19E-5
MDA-MB-231/ATCC 3.15E-6 1.43E-5 4.53E-5
HS 578T 2.71E-6 2.05E-5 > 1.00E-4
BT-549 4.27E-6 1.63E-5 4.69E-5
T-47D 2.71E-6 7.84E-6 6.18E-5
MDA-MB-468 1.42E-6 4.12E-6 1.64E-5
In summary, all the prenylated polyhydroxystilbene derivatives USYDS10 and
USYDS14 exhibited structure dependent inhibition of cancerous cell growth.
40 2. Calculated Log partition coefficients (Log P) values of various hydroxystilbenes.
The calculated Log P values for USYDS1 and USYDS2 and known hydroxystilbenes
are presented in the table 5 below.
45 Table 5. Calculated Log P values of various hydroxystilbenes
Compound USYDS2 5.37 Rhapontigenin 2.82
Compound USYDS1 5.58 Compound USYDS1 without a 3.49
prenyl group.
Resveratrol 3.14 Pinosylvin 3.68
Piceatannol 1.90
The potent inhibition of pPHOS compounds, for example USYDS1 and USYDS2, may
be explained in terms of their increased hydrophobicity, as demonstrated by their
calculated Log partition coefficient (Log P) values. USYDS1 and USYDS2 have Log
P values almost twice that of the hydroxystilbene resveratrol. The effects of Log P on
therapeutic compounds relate primarily to tissue penetration and distribution. Higher
Log P values will enable compounds to more easily cross cell membranes and enter
cells.
3. Effect of prenylated polyhydroxystilbene derivatives on UV-irradiated human
skin cells.
Normal adult human keratinocytes (NHK) cells (Invitrogen, Vic, Australia) were
cultured in keratinocyte growth medium Epilife supplemented with calcium and human
keratinocyte growth supplement (HKGS, containing 0.2 ng EGF per mL, 5 mg insulin
per mL, 5 mg transferrin per mL, 0.18 mg hydrocortisone per mL, and 0.2% bovine
pituitary extract) (Invitrogen, Vic, Australia) in 12-well culture plates until the
subconfluent state is reached. Cells were cultured to a density of 5 x 10 cells per
mL/well in a 24-well plate for 24 h at 37°C in a humidified incubator with 5% carbon
dioxide and tested according to the protocols described below:
Determination of optimal doses of UV irradiation.
Cells, seeded at a density as described above, were washed twice with PBS (phosphate
buffered saline) then irradiated with a range of UVA and UVB doses known as MED
(minimal erythema dose, 1 MED = 25.43/light intensity). Cells were replaced with
growth medium and incubated for about 24 h at 37°C in a humidified incubator with
% carbon dioxide. Cell viability was measured using the MTS assay (CellTiter 96
AQ One Solution Cell Proliferation Assay) (Promega, Vic Australia).
ueous
Rescue assay.
Cells were washed twice with PBS, replaced with a thin layer of PBS, then irradiated
with the optimal doses of UVA and UVB as determined above. Immediately after
irradiation, cells were replaced with fresh culture medium containing the test samples at
a range of concentrations, and further incubated in a humidified CO incubator at 37°C
for 24 hr. Supernatants were collected and kept at –80°C until determination of PGE2
and cytokines (IL1, 6, 8, 10 & 12) concentration using ELISA kits.
Protective assay.
Cells were washed twice with PBS, replaced with a thin layer of PBS containing
different concentrations of the test compounds then irradiated with optimal doses of
UVA and UVB as determined above. Immediately after irradiation, cells were replaced
with fresh culture medium and further incubated in a humidified CO incubator at 37°C
for 24 h. Supernatants were be collected and kept at –80°C until determination of PGE2
and cytokines (IL1, 6, 8, 10 & 12) concentration using ELISA kits.
Sham-treated control cultures were handled identically but not exposed to UV
irradiation. Stilbenes compounds including USYDS1, 2, 13, 5, and 7 and propolis
extract were tested at 0.1, 1 and 10 μM or μg/mL.
Results for the determination of optimal doses of UV irradiation revealed that at 1
MED of UVA and UVB irradiation, there is no significant effect on cell viability. Thus,
this condition was chosen for investigation of the effects of stilbenes and propolis
extract on levels of cytokines in the rescue assay.
In preliminary investigation on modulation of cytokine productions in UV irradiated
human epidermal keratinocytes (HEK) it was observed that a mixture of USYDS1 and
USYDS2 moderately inhibit the production of IL-6, TGFα, G-CSF and GM-CSF (2-3
fold). However, it was found that the prenylated polyhydroxystilbene derivatives
significantly increased IL-8 and IL-1rα production (4-5 fold) from UV irradiated cells.
IL-8 is known to play a role in the onset of immunity response. IL-1rα (naturally
occurring cytokine receptor antagonist) on the other hand plays an important role in
inhibition of deleterious effect of IL-1 during inflammatory processes. Therefore, these
preliminary results demonstrate that the prenylated polyhydroxystilbene derivates of
the present invention may be good candidates for the treatment of conditions associated
with immunity suppression and inflammation.
4. Antioxidant activities of the stilbenes and propolis extracts
1,1-Diphenylpicrylhydrazyl (DPPH ) scavenging activity assay
The (1,1-diphenylpicrylhydrazyl) DPPH assay is commonly used to test free radical
scavenging ability of a compound or extracts of natural products by measurement of the
reduction of DPPH radicals at 517 nm. In its radical form, DPPH shows a strong
absorption at 517 nm due to its odd electron. Upon reduction by an antioxidant or
radical scavenger, the absorption disappears and the resulting decolorization by
scavenging the radical is stoichiometric with respect to the number of electrons taken
up (DPPH + AH → DPPH:H + A ). The DPPH assay was carried out in a stepwise
procedure as described below.
A methanolic solution of DPPH (0.1 mM) was stirred in a dark container at room
temperature for 20 min. The solution was scanned between 400 – 750 nm to obtain a
maximum wavelength (λmax, ~ 510 nm). The concentration of the DPPH solution was
adjusted with methanol to result in a maximum absorbance of approximately 1.0. Test
samples at different concentrations and standard antioxidant solution (0.05 mL) were
added to 0.95 mL of methanolic DPPH solution in a cuvette. Final concentrations of
the test samples were 0.1, 1, 10, 50, 100 and 200 μM. The mixtures were shaken
vigorously and allowed to stand in the dark for 30 min at room temperature.
Absorbance of the resulting solution was measured at the maximum wavelength (~510
nm). A decrease in absorbance indicated a free radical scavenging effect of the test
samples. Dose response curves of the test samples were established to determine their
IC values (concentrations that show 50% reduction in UV absorbance).
Results
pPHOS compounds in this study exhibited a moderate to weak effect on free radical
scavenging except for USYDS7 which exhibited a strong effect. These results are
displayed in Figure 10.
. Effect of stilbene derivatives on nicotinamide adenine dinucleotide (NAD)-
dependent deacetylase sirtuin-2 (SIRT1).
SIRT1 is a member of Sir2 family (class ΙΙΙ) which is a NAD-dependent histone
deacetylase. Deacetylation by SIRT1 enzyme can target many substrates including
histone, tumor suppressor p53, forkhead transcription factor (FOXO), peroxisome
proliferator-activated receptor-γ (PPARγ) and co-activator-1α (PGC-1α). SIRT1 has
been shown to be involved in the regulation of many physiopathological processes like
inflammation, cellular aging, apoptosis/proliferation, metabolism and cell cycle
regulation (Chung, Yao et al. 2010). Accordingly, modulating SIRT1 activity could be
a potential therapeutic target to control many diseases such as cancer, metabolic
syndrome, obesity, neurodegenerative disorder, skeletal muscle dysfunction and aging-
related diseases.
SIRT1 assay kit (Cayman Chemical, Ann Arbor, Michigan, USA) provides a
fluorescence-based method for screening of SIRT1 inhibitors or activators. The assay
was carried out according to the instructions from the manufacturer. In brief, the assay
consists of two steps, both performed in the same plate. In the first step, the substrate,
which comprises the p53 sequence Arg-His-Lys-Lys(ε-acetyl)-AMC (7-amino
methylcoumarin), is incubated with human recombinant SIRT1 along with its
cosubstrate NAD . Deacetylation sensitizes the substrate such that treatment with the
developer in the second step releases a fluorescent product which was analysed using
fluorometric plate reader at an excitation wavelength of 350-360 nm and an emission
wavelength of 450-465 nm. Stilbenes were assayed at three concentrations (1, 10 and
100 μM). Data represents two independent experiments each performed in triplicate.
Results
All the stilbenes, except resveratrol, exhibited a concentration dependent inhibition of
SIRT1 as shown in Figure 11 A and B. Modulation of SIRT1 activity could lead to the
development of therapeutic agents for the treatment of diseases including cancer,
metabolic syndrome, obesity, neurodegenerative disorder, and aging-related diseases.
6. Antibacterial activities of USYDS1, USYDS2 and ethanolic extract of sedge
type-1 propolis
Summary.
The minimum inhibition concentration (MIC) screening was performed with 14
bacterial strains and 4 compounds. The MICs were determined by the broth
microdilution method according to the Clinical and Laboratory Standards Institute
(CLSI) guidelines. The MIC screening was performed on 96-well plates containing the
compounds in serial 2-fold dilutions from 64 to 0.06 μg/ml. The bacterial inoculations
were prepared in cation-adjusted Mueller Hinton medium broth from cultures grown on
appropriate agar plates which are prepared freshly every week. The growth controls and
sterile controls were included in each assay plates. The assay plates were incubated in
an ambient-air incubator at 35 ± 2°C for 16-20 hr (24 hr for MRSA), and bacterial
growth was observed and recorded. All MICs of reference compound levofloxacin in
the MIC screening are within the standard range described in CLSI S100-A20. The
potency of 3 test samples is the order of USYDS1 > USYDS2 > ethanolic propolis
extract.
1. Materials
1.1. Strains
Bacteria panel for MIC screening
Microorganism Gram Strain Resistance Plasmid Cultivation MIC screening
condition condition
Escherichia coli G ATCC TSA, ambient CAMHB, ambient
(25922)
air, 35 ± 2°C air, 35±2°C, 20 hr
Pseudomonas ATCC TSA, ambient CAMHB, ambient
aeruginosa (27853)
air, 35 ± 2°C air, 35±2°C, 20 hr
Klebsiella G ATCC AMP, AZT, Yes TSA, ambient
pneumoniae (700603) CFX, CPD, air, 35 ± 2°C
CAMHB, ambient
CAZ, CHL,
PIP, TET air, 35±2°C, 20 hr
Haemophilus G ATCC Chocolate agar,
influenzae (49247) 5% CO , HTM, ambient air,
±2°C 35±2°C, 20 hr
Acinetobacter G ATCC IMI TSA, ambient CAMHB, ambient
calcoaceticus (51432) air, 35 ± 2°C air, 35±2°C, 20 hr
Enterococcus G ATCC VAN TSA + 5% sheep
faecium (700221) blood, ambient CAMHB, ambient
air, 35 ± 2°C air, 35±2°C, 20 hr
Enterococcus G ATCC TSA + 5% sheep
faecalis (29212) blood, ambient CAMHB, ambient
air, 35 ± 2°C air, 35±2°C, 20 hr
Streptococcus G ATCC TSA + 5% sheep
CAMHB + 3% horse
pyogenes (700492) blood, 5% CO , blood, ambient air,
± 2°C 35±2°C, 20 hr
Streptococcus G ATCC PEN TSA + 5% sheep CAMHB + 3% horse
pneumoniae (49619) blood, 5% CO , blood, ambient air,
± 2°C 35±2°C, 20 hr
Streptococcus G Clinical ERY TSA + 5% sheep CAMHB + 3% horse
pneumoniae isolate blood, 5% CO , blood, ambient air,
± 2°C 35±2°C, 20 hr
Staphylococcus G ATCC TSA, ambient CAMHB, ambient
aureus (29213) air, 35 ± 2°C air, 35±2°C, 20 hr
Staphylococcus G ATCC MET, OXA TSA, ambient CAMHB, ambient
aureus (43300)
air, 35 ± 2°C air, 35±2°C, 20 hr
Staphylococcus G Clinical LEV TSA, ambient CAMHB, ambient
aureus isolate
air, 35 ± 2°C air, 35±2°C, 20 hr
Staphylococcus G Clinical MET, ERY, TSA, ambient CAMHB, ambient
aureus isolate CLI air, 35 ± 2°C air, 35±2°C, 20 hr
Known resistance; Known plasmid presence
Abbreviation: TSA, trypticase soy agar; CAMHB, cation-adjusted Mueller Hinton
broth; HTM, Haemophilus test medium; AMP, ampicillin; AZT, aztreonam; CFX,
cefoxitin; CPD, cefpodoxime; CAZ, ceftazidime; CHL, chloramphenicol; PIP,
piperacillin; TET, tetracycline; IMI, imipenem; VAN, vancomycin; PEN, penicillin;
ERY, erythromycin; MET, methicillin; OXA, oxacillin; LEV, levofloxacin; CLI,
clindamycin.
1.2. Media and reagents
Trypticase soy agar (BD 211043), Cation-adjusted Mueller Hinton broth (BD 212322),
Haemophilus test medium base (Fluka 51295), Hemin (Fluka 51280), β-NAD (Fluka
43410), Levofloxacin (Sigma 28266), Sheep blood (Quad Five 630-500), Lysed horse
blood (Quad Five 205-500), 0.5 McFarland barium sulfate standard, Sterile 0.85%
NaCl (w/v).
2. Methods
2.1. Prepare bacterial strains
A. Revive bacterial strains from storage frozen (-80°C) two days before the MIC
screening. Streak onto surface of appropriate agar plates, and incubate the plates for 20-
24 hr at 35 ± 2°C in an appropriate atmosphere.
Streptococci: TSA II, 5% CO
Enterococci: TSA II, ambient air
Haemophilus influenzae: chocolate agar, 5% CO
Other strains in the panel: TSA, ambient air
B. Select 5-10 well-isolated colonies of similar morphology and restreak onto fresh
agar plates using sterile loops. Incubate the plates for 20-24 hr at 35 ± 2°C in an
appropriate atmosphere as above.
2.2. Prepare compound plates
Compound stock solutions were prepared in 100% DMSO on the day of MIC screening
and use immediately. Compound stock concentration = [(highest testing concentration)
x 103 μl / 3 μl] (e.g. if the required highest testing concentration is 64 μg/ml in assay
plates, stock concentration = 64 x 103/3=2.2 mg/ml). The potency of testing compound
is assumed as 100% unless otherwise stated whereas the potency of reference
compound is calculated according to manufacturer’s analysis data.
Eleven two-fold dilutions per compound were made then transferred 3 μl to each well
of test plate. Final concentration of DMSO in the MIC screening is ~3%.
2.3. Prepare bacterial inoculation
A. Take out medium broth from 4°C fridge and allow it to warm to room temperature.
B. Transfer colonies from fresh culture plates into 5 ml of saline with sterile loops and
mix well. Measure and adjust turbidity to 0.5 McFarland barium sulphate standard
using a turbidity meter. Alternatively, transfer 1-2 colonies into 500 μl of saline and
adjust OD625 to ~0.1 using a plate reader.
C. Dilute bacterial inoculum 1:280 for Gram-positive and fastidious strains and 1:400
for Gram-negative strains into corresponding medium broth (CAMHB, CAMHB+3%
lysed horse blood, HTM) (e.g. 35.6 μl of inoculum into 10 ml of CAMHB or 25 μl of
inoculum into 10 ml of CAMHB).
H. influenzae: HTM
Streptococci: CAMHB + 3% lysed horse blood
Other strains in the panel: CAMHB
2.4. Prepare assay plates
A. Add 100 μl of the bacterial inoculum to each well of the compound plates except
wells B12, D12, F12 and H12.
B. Add 100 μl of medium broth to wells B12, D12, F12 and H12 of the compound
plates.
C. Stack four plates together and cover with a sterile plate lid. Incubate in an ambient-
air incubator at 35 ± 2°C for 16-20 hours (24 hours for MRSA).
2.5. Perform colony counts
A. Dilute the bacterial inoculum (0.5 McFarland) to a serial of 10-1 to 10-7 in saline
solution (e.g. 100 μl bacterial inoculum + 900 μl of saline).
B. Spread 100 μl of each dilution (10-4, 10-5, 10-6, and 10-7) onto CAMHA plates in
triplication, let the liquid soak into the agar for 10 minutes, invert the agar plates and
incubate for 24 hr at 35 ± 2°C.
2.6. Record MICs and calculate CFUs
A. Open the compound plate layout in the compound management system, and check
the assay plate barcode.
B. Place the assay plate on the top of MIC reader, and adjust the magnification mirror
to read each wells, record growth status as raw data. (Optional) Record photo image of
each assay plates using high-speed high-resolution scanner.
C. Determine MIC break points according to CLSI guideline.
D. Count colonies and calculate CFU of bacterial inoculum.
3. Results
3.1. MIC summary table
The MIC screening was performed with 14 bacterial strains (11 ATCC strains and 3
clinical isolates) and 4 compounds (USYDS1, USYDS2 and ethanolic extract of
propolis and reference compound levofloxacin). The MICs are summarized in the
below Table 6. The MIC values of reference compound Levofloxacin obtained in this
study are within the standard range as described in S100-A20 [2]. The final
concentration of DMSO in the MIC screening was ~3%, and did not inhibit the growth
of most microorganisms.
Table 6. MICs (μg/ml) of USYDS1, USYDS2 and ethanolic extract of propolis against
fourteen bacterial strains. Levofloxacin is reference compound.
Ethanolic propolis
Compounds Levofloxacin USYDS1 USYDS2 extract
Exp 1 Exp 2 Exp 1 Exp 2 Exp 1 Exp 2 Exp 1 Exp 2
Acinetobacter
4 4 >64 >64 >64 >64 >64 >64
calcoaceticus
<0.0625 <0.0625 16 16 64 32 >64 >64
Escherichia coli
Enterococcus faecalis
1 1 16 16 32 32 64 64
(ATCC 29212)
Enterococcus faecium
>64 >64 8 16 32 32 64 32
(ATCC 700221)
<0.0625 <0.0625 32 32 32 32 64 64
Haemophilus influenzae
1 1 >64 >64 >64 >64 >64 >64
Klebsiella pneumoniae
Pseudomonas
1 1 >64 >64 >64 >64 >64 >64
aeruginosa
Staphylococcus aureus
0.5 0.25 16 8 32 16 32 32
(ATCC 29213)
Staphylococcus aureus
0.25 0.25 8 8 16 16 32 32
(ATCC 43300)
Staphylococcus aureus
64 64 8 8 16 16 16 16
(Levofloxacin-resistant)
Staphylococcus aureus
(MRSA, Erythromycin &
8 8 8 8 16 16 32 32
clindamycin-resistant)
Streptococcus
pneumoniae (ATCC
0.5 0.5 32 32 32 32 32 32
49619)
Streptococcus pyogenes
0.5 0.5 64 64 64 64 >64 >64
(ATCC 700942)
Streptococcus
pneumoniae
1 1 32 32 32 64 64 >64
(Erythromycin-resistant)
4. Discussion
The prenylated tetrahydroxystilbenes USYDS1 and USYDS2 showed a moderate anti-
bacterial activities with the rank of potency of USYDS1 > USYDS2 > ethanolic extract
of propolis.
7. The effect of USYDS1, USYDS2 and USYDS10 compounds on kinases activities
The following is a list of kinases in the studied.
No. Kinase No. Kinase No. Kinase No. Kinase
1 ABL2 20 CDK4/CyclinD3 39 FGFR3 58 PKAcγ
2 AKT1 21 CDK5/CyclinP25 40 FGR 59 PKCα
3 AKT2 22 CDK6/CyclinD1 41 FLT1 60 PKCβI
(VEGFR1)
4 AKT3 23 CDK6/CyclinD3 42 FLT3 61 PKCγ
ALK1 24 CDK7/CyclinH1/MNAT1 43 GSK3α 62 PKCε
6 AMPK 25 CHK1 44 HER2 63 PKCθ
(A1/B1/G1)
7 AMPK 26 c-KIT 45 IGF1R 64 PKCδ
(A2/B1/G1)
8 Aurora A 27 c-KIT(V654A) 46 InsR 65 PKCδ
9 Aurora B 28 EGFR(T790M,L858R) 47 KDR 66 PKCι
Aurora C 29 EphA1 48 LCK 67 PLK2
11 AXL 30 EphA2 49 NEK2 68 PLK3
12 BLK 31 EphA3 50 p38β 69 RAF1
13 BTK 32 EphA4 51 PDGFRβ 70 BRAF
14 CAMK1 33 EphB1 52 PI3Kα 71 BRAF(v599E)
CDK1/CyclinA2 34 EphB2 53 PI3Kβ 72 RET
16 CDK1/CyclinB 35 EphB3 54 PI3Kγ 73 RON
17 CDK2/CyclinA2 36 ERK1 55 PI3Kδ 74 SRC
18 CDK3/CyclinE1 37 FGFR1(V561M) 56 PKAcα 75 TrkA
19 CDK4/CyclinD1 38 FGFR2 57 PKAcβ 76 TrkB
Experiments
Materials:
•Kinase-Glo(Plus) / ADP-Gloassay buffer
mMHEPES, 10 mMMgCl2, 0.01% Triton X-100, 100 μg/mLBSA, 2.5 mMDTT,
pH7.4.
•Caliper assay buffer
100 mMHEPES, 10 mMMgCl2, 100 μl/L Brij35 (30%), 1 mMDTT, pH7.4.
Assay substrates
•MBP protein, UnactiveMEK1, Rbprotein were purchased from SignalChem.
Poly(glu:tyr)(4:1) was purchased from Sigma. PIP2 was purchased from Cayman.
Peptide substrates were synthesized in HD Biosciences, China.
ATP was purchased from Sigma. KinaseGloPlus reagent, KinaseGloreagent and ADP
Gloreagent were purchased from Promega
Assay Procedure -Caliper Format
Mix Kinases, substrate, ATP and compound in 96-well assay plate, total volume is 50
μL. Incubate assay plate at 30°C for 1 hour. Stop reaction by adding 20 μL of 35 mM
EDTA and transfer 26 μL stopped reaction to 384-well assay plate. Read the assay
plate on the plate reader.
Assay Procedure –ADP-GloFormat
Mix Kinases, substrate, ATP and compound in 384-well assay plate, total volume is 10
μl. Incubate assay plate at 30°C for 1 hour. Add 10μl/well of ADP GloReagent to the
assay plate, incubate at 27°C for 40 min.
Add 20 μl/well Detection Reagent to the assay plate, incubate at 27°C for 30 min. Read
the assay plate on the plate reader
Assay Procedure –Kinase-Glo(Plus)Format
Mix Kinase, substrate, ATP and compound in 384-well assay plate, total volume is 10
μl. Incubate assay plate at 30°C for 1 hour. Add 10 μl/well KinaseGlo(Plus ) reagent to
the reaction mixture, and then incubate at 27°C for 20 min. Read the assay plate on
plate reader.
•Hundred percent effect was performed without compound and enzyme, but containing
ATP and substrate.
•Zero percent effect was carried out without compound, but containing ATP, substrate
and enzyme.
•SB202190 is reference compounds for kinase p38β; Staurosporine(STSP) is reference
compound for the remaining kinases.
Results
Kinases that inhibited more than 60% are summarised in the table below. It is
interesting to note that all three compounds inhibited kinases TrKA and PI3Kδ and
PI3Kγ. Both USYDS1 and USYDS10 appear to display similar inhibitory activities
towards the kinases.
Compound Kinases
USYDS1 FLT3,TrkA, CDK2/CyclinA2, CDK4/CyclinD3, PI3Kα,PI3Kδ, PI3Kγ
USYDS2 TrkA, PI3Kβ, PI3Kδ, PI3Kγ
USYDS10 FLT3, TrkA, KDR, FLT1,CDK2/CyclinA2, PI3Kα, PI3Kβ, PI3Kδ,
PI3Kγ,CDK1/CyclinB
8. Acute Toxicity Study of USYDS1
Method
A single mouse is given a single IP injection of 400 mg/kg; a second mouse receives a
dose of 200 mg/kg IP and a third mouse receives a single dose of 100 mg/kg IP. The
mice are observed for a period of 2 weeks. They are sacrificed if they lose more than
% of their body weight or if there are other signs of significant toxicity. If all 3 mice
must be sacrificed, then the next 3 dose levels (50, 25,12.5 mg/kg) are tested in a
similar way. This process is repeated until a tolerated dose is found. This dose is then
designated the maximum tolerated dose (MTD) and is used to calculate the amount of
material given to experimental mice during anti-tumor testing. The mice are allowed ad
libitum feed and water. Drug was dissolved in 100% DMSO at concentration of 200
mg/mL.
Result
Group Dose Route Death Survivor/Total day Injection
(mg/kg/dose) days 15 volume
1 100 IP None 1/1 0.5 µL/gm body
2 200 IP 1 0/1 1 µL/gm body
3 400 IP 1 0/1 2 µL/gm body
The MTD of USYDS1 was determined as 100 mg/kg. This concentration indicates low
mammalian toxicity and is being used for further anti-tumor testing. Hollow fiber
assay (BEC/C) for USYDS1 is under progression. The hollow fibre assay is a
preliminary rapid screen for assessing novel putative chemotherapeutic compounds
against a range of cancer cell lines prior to their evaluation in the mouse xenograft
model. The hollow fiber model has a shorter evaluation time and a reduced compound
requirement compared to traditional xenograft models. The model allows for the
effective selection of cancer cell types in the xenograft.
Chemotypes of plants that produce resins as sources of prenylated
polyhydroxystilbene derivatives
Resins, gums or exudates obtained from plants of the Lepidosperma genus from
different locations were analysed by quantitative H-NMR (q-NMR) for prenylated
polyhydroxystilbene content, which include C- and O-prenylated, O-methylated and
non-O-methylated derivatives. Different proportions of these prenylated
polyhydroxystilbene derivatives from the resins form a basis to classify the plants
accordingly.
There are at least 3 different chemotypes of Lepidosperma plants identified thus far and
each of these plants display several sub-chemotypes. Type 1 is the most common plant
which contains approximately equal proportion of both C- and O-prenylated
derivatives. Type 2 plant contains only C-prenylated derivatives. Where as, type 3 plant
contains no O-methylated prenylated polyhydroxystilbene derivatives.
It will be appreciated by persons skilled in the art that numerous variations and/or
modifications may be made to the invention as shown in the specific embodiments
without departing from the scope of the invention as broadly described. The present
embodiments are, therefore, to be considered in all respects as illustrative and not
restrictive.
References
(1) Denmark, E.; Regens, C. S.; Tetsuya, K. J. of Am. Chem. Soc. 2007, 129, 2774-
2276.
(2) Ali, I. A. I.; Fathalla, W. Heteroatom Chemistry 2006, 17, 280-288.
(3) Krohn, K.; Thiem, J. J. Chem. Soc., Perkin Trans. 1 1977, 1186-1190.
(4) Soerme, P.; Arnoux, P.; Kahl-Knutsson, B.; Leffler, H.; Rini, J. M.; Nilsson, U.
J. J. Am. Chem. Soc. 2005, 127, 1737-1743.
(5) Andrus, M. B.; Liu, J.; Meredith, E. L.; Nartey, E. Tetrahedron Lett. 2003, 44,
4819-4822.
(6) Rao, M. L. N.; Awasthi, D. K.; Banerjee, D. Tetrahedron Lett. 2010, 51, 1979-
1981.
(7) Yang, P.-Y.; Zhou, Y.-G. Tetrahedron Asymmetry 2004, 15, 1145-1149.
(8) Rooney, J. M. Journal of Macromolecular Science, Part A 1986, 23, 823 - 829.
(9) Batsomboon, P.; Phakhodee, W.; Ruchirawat, S.; Ploypradith, P. J. Org. Chem.
2009, 74, 4009-4012.
(10) Michan, S.; Sinclair D. Biochem. J. 2007, 404, 1-13.
(11) Yamamoto H.; Schoonjans K.; Auwerx J. Mol. Endocrinol. 2007, 21, 1745-
1755.
Claims (57)
1. Use of a compound of formula (Ia), or a pharmaceutically acceptable salt, solvate, or pharmaceutical composition including said compounds, wherein: 1a 4 R is selected from the group consisting of, OH, OR , CH CH=C(CH ) , 2 3 2 10 OCH CH=C(CH ) , CH=CHCH(CH ) , CH=CHC(CH )=CH , 2 3 2 3 2 3 2 OCH=CHCH(CH ) , or OCH=CHC(CH )=CH , 3 2 3 2 1b 4 R is selected from the group consisting of H, OH, OR , CH CH=C(CH ) , OCH CH=C(CH ) , CH=CHCH(CH ) , 2 3 2 2 3 2 3 2 CH=CHC(CH )=CH , OCH=CHCH(CH ) , or OCH=CHC(CH )=CH , 3 2 3 2 3 2 1c 4 15 R is selected from the group consisting of H, OH, OR , CH CH=C(CH ) , OCH CH=C(CH ) , CH=CHCH(CH ) , 2 3 2 2 3 2 3 2 CH=CHC(CH )=CH , OCH=CHCH(CH ) , or OCH=CHC(CH )=CH , 3 2 3 2 3 2 1d 4 R is selected from the group consisting of H, OH, OR , CH CH=C(CH ) , OCH CH=C(CH ) , CH=CHCH(CH ) , 2 3 2 2 3 2 3 2 20 CH=CHC(CH )=CH , OCH=CHCH(CH ) , or OCH=CHC(CH )=CH , 3 2 3 2 3 2 1a-1d 1a-1d wherein at least one of R is OH and at least one of R is CH CH=C(CH ) , OCH CH=C(CH ) , CH=CHCH(CH ) , 2 3 2 2 3 2 3 2 CH=CHC(CH )=CH , OCH=CHCH(CH ) or OCH=CHC(CH )=CH ; 3 2 3 2 3 2 R is selected from OH, OR , CH CH=C(CH ) , OCH CH=C(CH ) , 2 3 2 2 3 2 25 CH=CHC(CH )=CH , OCH=CHCH(CH ) , or OCH=CHC(CH )=CH ; 3 2 3 2 3 2 R is selected from OH, OR , CH CH=C(CH ) , OCH CH=C(CH ) , 2 3 2 2 3 2 CH=CHC(CH )=CH , OCH=CHCH(CH ) , or OCH=CHC(CH )=CH ; 3 2 3 2 3 2 R is selected from, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl or benzyl; and A----B is selected from CH=CH, CH -CH , CH=CHX, or CH -CH X, 2 2 2 2 where X=(CH )pCH , and p is an integer selected from the group consisting of 5 0, 1, 2 or 3 in the preparation of a medicament for treating cancer, immunosuppression, bacterial or fungal infection, or skin aging.
2. Use of a compound of formula (Ia), or a pharmaceutically acceptable salt, solvate, or pharmaceutical composition including said compounds, 15 wherein: 1a 4 R is selected from the group consisting of, OH, OR , CH CH=C(CH ) , 2 3 2 OCH CH=C(CH ) , CH=CHCH(CH ) , CH=CHC(CH )=CH , 2 3 2 3 2 3 2 OCH=CHCH(CH ) , or OCH=CHC(CH )=CH , 3 2 3 2 1b 4 R is selected from the group consisting of H, OH, OR , 20 CH CH=C(CH ) , OCH CH=C(CH ) , CH=CHCH(CH ) , 2 3 2 2 3 2 3 2 CH=CHC(CH )=CH , OCH=CHCH(CH ) , or OCH=CHC(CH )=CH , 3 2 3 2 3 2 1c 4 R is selected from the group consisting of H, OH, OR , CH CH=C(CH ) , OCH CH=C(CH ) , CH=CHCH(CH ) , 2 3 2 2 3 2 3 2 CH=CHC(CH )=CH , OCH=CHCH(CH ) , or OCH=CHC(CH )=CH , 3 2 3 2 3 2 1d 4 25 R is selected from the group consisting of H, OH, OR , CH CH=C(CH ) , OCH CH=C(CH ) , CH=CHCH(CH ) , 2 3 2 2 3 2 3 2 CH=CHC(CH )=CH , OCH=CHCH(CH ) , or OCH=CHC(CH )=CH , 3 2 3 2 3 2 1a-1d 1a-1d wherein at least one of R is OH and at least one of R is CH CH=C(CH ) , OCH CH=C(CH ) , CH=CHCH(CH ) , 2 3 2 2 3 2 3 2 CH=CHC(CH )=CH , OCH=CHCH(CH ) or OCH=CHC(CH )=CH ; 3 2 3 2 3 2 R is selected from OH, OR , CH CH=C(CH ) , OCH CH=C(CH ) , 2 3 2 2 3 2 5 CH=CHC(CH )=CH , OCH=CHCH(CH ) , or OCH=CHC(CH )=CH ; 3 2 3 2 3 2 R is selected from OH, OR , CH CH=C(CH ) , OCH CH=C(CH ) , 2 3 2 2 3 2 CH=CHC(CH )=CH , OCH=CHCH(CH ) , or OCH=CHC(CH )=CH ; 3 2 3 2 3 2 R is selected from, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl or benzyl; 10 and A----B is selected from CH=CH, CH=CHX, or CH -CH X, where X=(CH )pCH , and p is an integer selected from the group consisting of 0, 1, 2 or 3 in the preparation of a medicament for treating inflammation. 15 3. Use according to claim 1 or 2 wherein R is selected from OH, OR , CH CH=C(CH ) , OCH CH=C(CH ) , 2 3 2 2 3 2 CH=CHC(CH )=CH , OCH=CHCH(CH ) , or OCH=CHC(CH )=CH .
3 2 3 2 3 2
4. Use according to claim 1 wherein A----B is selected from CH=CH or 20 CH -CH .
5. Use of a compound of formula (Ia), wherein: 1a 1c 1b R is CH CH=C(CH ) and R is H or CH CH=C(CH ) ; R is selected from 2 3 2 2 3 2 1d 1a 1c OH, OCH or OCH CH=C(CH ) ; R is OH; wherein at least one of R or R 3 2 3 2 1b 2 is CH CH=C(CH ) and/or R is OCH CH=C(CH ) ; R is selected from OH or 2 3 2 2 3 2 OCH ; R is selected from OH or OCH ; and A----B is CH=CH; or a pharmaceutically acceptable salt, solvate, or pharmaceutical composition 5 including said compounds, in the preparation of a medicament for treating cancer, immunosuppression, inflammation, bacterial or fungal infection, or skin aging.
6. Use according to any one of claims 1 to 5, wherein the compound is selected 10 from the group consisting of:
7. Use of a compound or a pharmaceutically acceptable salt or pharmaceutical composition including said compounds, in the preparation of a medicament for treating cancer, immunosuppression, inflammation, bacterial or fungal infection, or skin aging, 5 wherein the compound is: USYDS18 10
8. Use of a compound according to any one of claims 1, 3, 5, or 7 or a pharmaceutical composition thereof in the preparation of a medicament for the treatment of cancer.
9. Use of a compound according to claim 8 wherein the cancer is leukemia, non- 15 small cell lung cancer, colon cancer, CNS cancer, melanoma, ovarian cancer, renal cancer, prostate cancer or breast cancer.
10. Use of a compound according to claim 9 wherein the cancer is leukemia. 20
11. Use of a compound according to claim 9 wherein the cancer is melanoma.
12 Use of a compound according to any one of claims 1, 3, 5, or 7 or a pharmaceutical composition thereof in the preparation of a medicament for the treatment of immunosuppression.
13. Use of a compound according to any one of claims 2, 5, , or 7, or a pharmaceutical composition thereof in the preparation of a medicament for the treatment of inflammation.
14. Use of a compound according to any one of claims 1, 3, 5, or 7, or a pharmaceutical composition thereof in the preparation of a medicament for the treatment of a bacterial or fungal infection. 5
15. Use of a compound according to any one of claims 1, 3, 5, or 7, or a pharmaceutical composition thereof in the preparation of a medicament for the treatment of skin aging.
16. A compound of formula (Ia) or a pharmaceutically acceptable salt or solvate thereof, wherein: R is selected from, CH CH=C(CH ) , OCH CH=C(CH ) , CH=CHCH(CH ) , 2 3 2 2 3 2 3 2 15 CH=CHC(CH )=CH , OCH=CHCH(CH ) , or OCH=CHC(CH )=CH ; 3 2 3 2 3 2 1b 4 R is selected from, H, OH, OR , CH CH=C(CH ) , OCH CH=C(CH ) , 2 3 2 2 3 2 CH=CHCH(CH ) , CH=CHC(CH )=CH , OCH=CHCH(CH ) , or 3 2 3 2 3 2 OCH=CHC(CH )=CH ; 1c 4a R is selected from H, OH, OR , CH CH=C(CH ) , OCH CH=C(CH ) , 2 3 2 2 3 2 20 CH=CHCH(CH ) , CH=CHC(CH )=CH , OCH=CHCH(CH ) , or 3 2 3 2 3 2 OCH=CHC(CH )=CH ; R is selected from H, OH, CH CH=C(CH ) , OCH CH=C(CH ) , 2 3 2 2 3 2 CH=CHCH(CH ) , CH=CHC(CH )=CH , OCH=CHCH(CH ) , or 3 2 3 2 3 2 OCH=CHC(CH )=CH ; 1b-1d 1a-1d 25 wherein at least one of R is OH and at least one of R is \ CH CH=C(CH ) , OCH CH=C(CH ) , CH=CHCH(CH ) , 2 3 2 2 3 2 3 2 CH=CHC(CH )=CH , OCH=CHCH(CH ) , or OCH=CHC(CH )=CH ; 3 2 3 2 3 2 R is selected from OH, OCH CH=C(CH ) , CH=CHC(CH )=CH , 2 3 2 3 2 OCH=CHCH(CH ) , or OCH=CHC(CH )=CH ; 3 2 3 2 R is selected from OH, OR , OCH CH=C(CH ) , CH=CHC(CH )=CH , 2 3 2 3 2 OCH=CHCH(CH ) , or OCH=CHC(CH )=CH ; 3 2 3 2 5 R is selected from, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl or benzyl; R is selected from, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl or benzyl; and A----B is selected from CH=CH, CH=CHX, or −CH -CH X, where X=(CH )pCH and p is an integer selected from the group consisting of 0, 1, 2 10 or 3.
17. A compound of formula (Ia) or a pharmaceutically acceptable salt or solvate thereof, wherein: R is selected from, CH CH=C(CH ) , OCH CH=C(CH ) , 2 3 2 2 3 2 20 CH=CHC(CH )=CH , OCH=CHCH(CH ) , or OCH=CHC(CH )=CH ; 3 2 3 2 3 2 1b 4 R is selected from, H, OH, OR , CH CH=C(CH ) , OCH CH=C(CH ) , 2 3 2 2 3 2 CH=CHC(CH )=CH , OCH=CHCH(CH ) , or OCH=CHC(CH )=CH ; 3 2 3 2 3 2 1c 4a R is selected from H, OH, OR , CH CH=C(CH ) , OCH CH=C(CH ) , 2 3 2 2 3 2 CH=CHC(CH )=CH , OCH=CHCH(CH ) , or OCH=CHC(CH )=CH ; 3 2 3 2 3 2 1d 4a 25 R is selected from H, OH, OR ,CH CH=C(CH ) , OCH CH=C(CH ) , 2 3 2 2 3 2 CH=CHC(CH )=CH , OCH=CHCH(CH ) , or OCH=CHC(CH )=CH ; 3 2 3 2 3 2 1b-1d 1a-1d wherein at least one of R is OH and at least one of R is CH CH=C(CH ) , OCH CH=C(CH ) , CH=CHC(CH )=CH , 2 3 2 2 3 2 3 2 OCH=CHCH(CH ) , or OCH=CHC(CH )=CH ; 3 2 3 2 2 3 4a R and R are each independently selected from OH, OR , OCH CH=C(CH ) , 2 3 2 5 CH=CHC(CH )=CH , OCH=CHCH(CH ) , or OCH=CHC(CH )=CH ; 3 2 3 2 3 2 R is selected from, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl or benzyl; R is selected from, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl or benzyl; and A----B is selected from CH=CH, CH=CHX, or −CH -CH X, where 10 X=(CH )pCH and p is an integer selected from the group consisting of 0, 1, 2 or 3.
18. A compound of formula (Ia) or a pharmaceutically acceptable salt or solvate thereof, wherein: 1a 1c 20 R is CH CH=C(CH ) or CH=CHCH(CH ) , R is selected from H or 2 3 2 3 2 CH CH=C(CH ) or CH=CHCH(CH ) ; R is selected from OH, OCH or 2 3 2 3 2 3 1d 1a 1c OCH CH=C(CH ) ; R is OH; wherein at least one of R or R is 2 3 2 1b 2 CH CH=C(CH ) and/or R is OCH CH=C(CH ) ; R is selected from OH or 2 3 2 2 3 2 OCH ; R is OCH ; 25 and A----B is CH=CH.
19. A compound of formula (Ia) or a pharmaceutically acceptable salt or solvate thereof, wherein: 1a 1b 5 R is CH CH=C(CH ) or CH=CHCH(CH ) ; R is selected from OH, OCH 2 3 2 3 2 3 or OCH CH=C(CH ) ; R is selected from H or CH CH=C(CH ) or 2 3 2 2 3 2 1d 1a 1c CH=CHCH(CH ) ,; R is OH; wherein at least one of R or R is 1b 2 CH CH=C(CH ) and/or R is OCH CH=C(CH ) ; R is selected from OH or 2 3 2 2 3 2 OCH ; R is selected from OH or OCH ; 10 and A----B is CH=CH. 1b-1d
20. A compound according to claim 16 or 17 wherein two of R are H. 1b-1d
21. A compound according to claim 16 or 17 wherein one of R is H. 1b-1d
22. A compound according to claim 16 or 17 wherein none of R are H. 1a-1d
23. A compound according to claim 16 or 17 wherein at least one of R is CH CH=C(CH ) . 2 3 2 1a-1d
24. A compound according to claim 16 or 17 wherein at least one of R is OCH CH=C(CH ) . 2 3 2 1b-1d
25. A compound according to claim 16 or 17 wherein at least two of R are OH. 1b-1d 4
26. A compound according to claim 16 or 17 wherein at least one of R is OR and R is methyl. 1b-1d 4
27. A compound according to claim 16 or 17 wherein at least one of R is OR or 4a 4 4a OR and R or R is benzyl.
28. A compound according to claim 16 or 17 wherein at least one of R or R is OH. 3 4 4
29. A compound according to claim 16 or 17 wherein R is OR and R is methyl.
30. A compound according to claim 16 or 17 wherein both R and R are OH. 3 4 4 10
31. A compound according to claim 16 or 17 wherein R is OR and R is benzyl.
32. A compound according to claim 16 or 17 wherein A----B is CH=CH or CH=CHX, where X=(CH )pCH , and p is an integer selected from the group consisting of 0, 1, 2 or 3.
33. A compound according to claim 16 or 17 wherein A----B is CH -CH X, where X=(CH ) pCH , and p is an integer selected from the group 2 2 2 2 consisting of 0, 1, 2 or 3. 20
34. A compound with the formula of (Ib): wherein, 5 i i t 6 25 R is selected from the group OEt, OPr, O Pr, OBu, O Bu, O Bu, OBn; and R and R are each independently selected from the group OMe, OEt, OPr, O Pr, OBu, O Bu, O Bu, OBn.
35. A compound with the formula of (Ic) or (Id): wherein, 8 i i t 9 R is selected from the group OH, OEt, OPr, O Pr, OBu, O Bu, O Bu; and R and 10 i 5 R are each independently selected from the group OH, OMe, OEt, OPr, O Pr, OBu, O Bu, O Bu.
36. A compound with the formula of (Ie) or (If): 15 wherein, 8 9 10 R , R and R are each independently selected from the group OH, OMe, OEt, i i t OPr, O Pr, OBu, O Bu, O Bu.
37. A compound according to claim 16 or 17, selected from the group consisting of: 5 or pharmaceutically acceptable salt or solvate thereof.
38. A compound according to structure USYDS18: USYDS18
39. A compound according to any one of claims 16 to 37 wherein the compound is chemically synthesised.
40. A compound according to any one of claims 16 to 37 isolated from propolis, wherein the propolis originates from plants of the Lepidosperma genus.
41. A compound according to anyone of claims 16 to 37 isolated from the resin, 5 gum or exudate of the Lepidosperma genus.
42. A pharmaceutical composition comprising a compound according to any one of claims 16 to 37, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient.
43. A method of preparing the compound according to claim 34 which comprises: (i) treating the carboxylic acid with a suitable agent to provide the acid chloride as follows: (ii) condensation of the corresponding acid chloride with an aryl alkene as follows: (iii) deprotection of the acetate group and alkylation as follows: 5 i i t wherein, R is selected from the group OEt, OPr, O Pr, OBu, O Bu, O Bu, OBn; R and R are each independently selected from the group OMe, OEt, OPr, i i t O Pr, OBu, O Bu, O Bu, OBn.
44. A method according to claim 43 for preparing compounds of formula (Ic) and (Id) according to claim 34, comprising the additional step: (iv) a hydrogenation reaction as follows: (Ic) (Id) 5 6 7 wherein, R , R and R are as defined in claim 43, provided that at least one of 5 6 7 R , R or R is OBn; 8 i i t 15 wherein, R is selected from the group OH, OEt, OPr, O Pr, OBu, O Bu, O Bu; 9 10 R and R are each independently selected from the group OH, OMe, OEt, OPr, i i t O Pr, OBu, O Bu, O Bu. 20
45. A method according to claim 43 for preparing compounds of formula (Ie) and (If) according to claim 36, comprising the additional steps: (v) rearrangement of the prenyl group as follows: (vi) and a hydrogenation reaction as follows: 5 6 7 wherein, R , R and R are as defined in claim 43, provided that at least one of 5 6 7 R , R or R is OBn; 8 9 10 10 R , R and R are each independently selected from the group OH, OMe, OEt, i i t OPr, O Pr, OBu, O Bu, O Bu.
46. A method according to any one of claims 43 to 45 wherein the condensation reaction in step (ii) is carried out in the presence of a palladium catalyst.
47. A method according to claim 46 in which the palladium catalyst is palladium (II) acetate.
48. A method according to any one of claims 43 to 45 wherein the alkylation 20 reaction in step (iii) is carried out in the presence of a metal hydride and a halogenated prenyl reagent.
49. A method according to claim 48 wherein the metal hydride is sodium hydride.
50. A method according to claim 48 or 49 wherein the halogenated prenyl reagent is 5 BrCH CH=C(CH ) . 2 3 2
51. A method according to claim 43 or 45 wherein the hydrogenation in step (iv) or (vi) is carried out in the presence of a palladium catalyst in a mixture of solvents.
52. A method according to claim 51 wherein the palladium catalyst is palladium on carbon.
53. A method according to claim 51 or 52 wherein the mixture of solvents 15 comprises 1,4-cyclohexadiene and ethanol.
54. A method according to claim 45 wherein the rearrangement in step (v) is carried out in the presence of magnesium silicate particles, silica or alumina particles. 20
55. A method according to claim 45 or 54 wherein the rearrangement in step (v) is carried out in the presence of microwave radiation or light.
56. A compound according to structure USYDS15: USYDS15
57. Use of the compound according to claim 56 in the preparation of a medicament for the treatment of cancer, immunosuppresion, inflammation, fungal or 30 bacterial infection or of skin aging.
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
AU2011901663 | 2011-05-04 | ||
AU2011901663A AU2011901663A0 (en) | 2011-05-04 | Prenylated Hydroxystilbenes | |
PCT/AU2012/000482 WO2012149608A1 (en) | 2011-05-04 | 2012-05-04 | Prenylated hydroxystilbenes |
Publications (2)
Publication Number | Publication Date |
---|---|
NZ616960A NZ616960A (en) | 2016-01-29 |
NZ616960B2 true NZ616960B2 (en) | 2016-05-03 |
Family
ID=
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