US2004121985A1PendingUtilityA1
Novel prenyl transferase inhibitors
Individually held — no corporate assignee on recordPriority: Jun 16, 1998Filed: Jun 10, 2003Published: Jun 24, 2004
Est. expiryJun 16, 2018(expired)· nominal 20-yr term from priority
Inventors:Richard Gibbs
C07F 9/098C07D 333/16C07D 307/12C07C 33/28C07C 69/738C07C 33/02C07C 69/587
43
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Claims
Abstract
Farnesyl diphosphate analogs, specifically the 3-substituted alcohol precursors of the diphosphate analogs, 3-allylfarnesol and 3-vinylfarnesol, are potent inhibitors of mammalian protein fanesyltransferase (FTase). 3-allylgeranylgeraniol is a highly specific cellular inhibitor of protein geranylgeranylation (GGTase I). Furthermore, these compounds are able to efficiently block the anchorage-dependent growth of ras transformed cells. While 3-allylfarnesol inhibits protein farnesylation in situ, 3-vinylfarnesol instead leads to the abnormal prenylation of proteins with the 3-vinylfarnesyl group. In a similar manner, treatment with 3-allylgeranylgeraniol inhibits protein geranylgeranylation while 3-vinylgeranylgeraniol restores protein geranylgeranylation in cells.
Claims
exact text as granted — not AI-modifiedWhat is claimed is:
1 . A compound of the general formula:
wherein R′ is a substituted or unsubstituted C 10 -C 20 saturated or unsaturated alkyl, aryl, heteroaryl or cycloalkyl; R is a substituted or unsubstituted C 2 -C 10 saturated or unsaturated alkyl, aryl, cycloalkyl, or C 6 -C 10 aromatic or heteroaromatic group; and X is —OH or —P 2 O 7 .
2 . The compound of claim 1 wherein R′ is geranyl.
3 . The compound of claim 1 wherein R′ is farnesyl.
4 . The compound of claim 1 wherein R′ is geranyl or farnesyl and R is selected from the group consisting of vinyl, ethyl, allyl, saturated and unsaturated isomers of propyl, butyl, and pentyl, cyclopropyl, cyclopentyl, phenyl and heterosubstituted moieties, such as fluorophenyl, (trimethylsilyl)methyl, 1-ethoxyvinyl, and 2-furanyl, 2-thiophenyl.
5 . The compound of claim 1 which is 7-allylfarnesol.
6 . The compound of claim 1 which is para-biphenylfarnesol.
7 . A compound of the general formula:
wherein R is a C 2 -C 10 saturated or unsaturated alkyl, aryl, or cycloalkyl group, or a C 6 -C 10 aromatic groups or heteroaromatic group, and X is —OH or —P 2 O 7 .
8 . The compound of claim 7 wherein R is selected from the group consisting allyl, saturated and unsaturated isomers of propyl, butyl, and pentyl, cyclopentyl, phenyl and heterosubstituted moieties, such as fluorophenyl, (trimethylsilyl)methyl, 1-ethoxyvinyl, and 2-furanyl, 2-thiophenyl.
9 . The compound of claim 7 which is 3-allylfarnesol.
10 . The compound of claim 7 which is 3-allyl farnesyl diphosphate.
11 . The compound of claim 7 which is 3-isopropylfarnesol.
12 . The compound of claim 7 which is 3-isopropylfarnesyl diphosphate.
13 . A compound of the general formula:
wherein R is a C 2 -C 10 saturated or unsaturated alkyl, aryl, or cycloalkyl group, or a C 6 -C 10 aromatic groups or heteroaromatic group, and X is —OH or —P 2 O 7 .
14 . The compound of claim 13 wherein R is selected from the group consisting allyl, saturated and unsaturated isomers of propyl, butyl, and pentyl, cyclopentyl, phenyl and heterosubstituted moieties, such as fluorophenyl, (trimethylsilyl)methyl, 1-ethoxyvinyl, and 2-furanyl, 2-thiophenyl.
15 . The compound of claim 13 which is 3-allylgeranylgeraniol.
16 . The compound of claim 13 which is 3-allyl farnesyl diphosphate.
17 . A therapeutic composition comprising:
a 3-substituted isoprenol analog of the general formula: wherein R′ is a substituted or unsubstituted C 10 -C 20 saturated or unsaturated alkyl, aryl, heteroaryl or cycloalkyl; R is a substituted or unsubstituted C 2 -C 10 saturated or unsaturated alkyl, aryl, cycloalkyl, or C 6 -C 10 aromatic or heteroaromatic group; and X is —OH or —P 2 O 7 ; and a pharmaceutically acceptable carrier.
18 . The therapeutic composition of claim 17 wherein R is selected from the group consisting of vinyl, ethyl, allyl, saturated and unsaturated isomers of propyl, butyl, and pentyl, cyclopropyl, cyclopentyl, phenyl and heterosubstituted moieties, such as fluorophenyl, (trimethylsilyl)methyl, 1-ethoxyvinyl, and 2-furanyl, 2-thiophenyl.
19 . A method of treating cancer comprising administering an effective amount of at least one 3-substituted isoprenol derivative to a patient having a cancer of the type that is susceptible to treatment with a 3-substituted isoprenol derivative having the general formula:
wherein R is a C 2 -C 10 saturated or unsaturated alkyl, aryl, cycloalkyl, or C 6 -C 10 aromatic or heteroaromatic group.
20 . The method of claim 19 wherein the 3-substituted isoprenol derivative is selected from the group consisting of 3-vinyl farnesol, 3-allylfarnesol, 3-isopropylfarnesol, 3-vinyl geranylgeraniol, and 3-allylgeranylgeraniol.
21 . The method of claim 19 wherein the cancer is human pancreatic cancer.
22 . The method of claim 19 wherein the cancer is human colon cancer.
23 . A method for reducing the level of protein farnesylation in mammalian cells in a mammalian host, wherein said cells are sensitive to treatment with a compound with the formula:
wherein R is a C 2 -C 10 saturated or unsaturated alkyl, aryl, cycloalkyl, or C 6 -C 10 aromatic or heteroaromatic group, and X is —OH or —P 2 O 7 ; the said method comprising administering to said mammalian host an amount of the compound effective to inhibit the activity of farnesyl protein transferase; wherein the activity of farnesyl protein transferase is reduced.
24 . The method of claim 23 wherein the compound is selected from the group consisting of 3-vinyl farnesol, 3-allylfarnesol, 3-isopropylfarnesol, 3-vinyl geranylgeraniol, and 3-allylgeranylgeraniol.
25 . A method for reducing the level of protein geranylgeranylation in mammalian cells in a mammalian host, wherein said cells are sensitive to treatment with a compound with the formula:
wherein R is a C 2 -C 10 saturated or unsaturated alkyl, aryl, cycloalkyl, or C 6 -C 10 aromatic or heteroaromatic group, and X is —OH or —P 2 O 7 ; the said method comprising administering to said mammalian host an amount of the compound effective to inhibit the activity of geranylgeranyl protein transferase; wherein the activity of geranylgeranyl protein transferase is reduced.
26 . The method of claim 25 wherein the compound is selected from the group consisting of 3-vinyl geranylgeraniol and 3-allylgeranylgeraniol.
27 . A method of reducing the proliferation of tumor cells of the type that are sensitive to treatment with a 3-substituted isoprenol analogs of the formula:
wherein R is a C 2 -C 10 saturated or unsaturated alkyl, aryl, cycloalkyl, or C 6 -C 10 aromatic or heteroaromatic group, and X is —OH or —P 2 O 7 , the method comprising subjecting the tumor cells to an amount of the 3-substituted isoprenol derivatives sufficient to act as a competitive inhibitor of prenyl protein transferase thereby reducing the proliferation of the tumor cells.
28 . The method of claim 27 wherein the mammalian cells are tumor cells that are associated with abnormal activity of oncogenes in the ras family or its pathway.
29 . The method of using of 3-allyl farnesyl or 3-vinyl farnesyl diphosphate-based farnesyl transferase inhibitors as probes for analyzing the FPP-binding site of FTase.
30 . The method of using of 3-allyl geranylgeranyl or 3-vinyl geranylgeranyl diphosphate-based geranylgeranyl transferase inhibitors as probes for analyzing the GPP-binding site of GGTase.
31 . A method of preventing restenosis by administering an effective amount of 3-allyl or 3-vinyl geranylgeraniol to a patient in need of treatment for restenosis following cardiac catheterization or angioplasty.Join the waitlist — get patent alerts
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