US2004176625A1PendingUtilityA1

Kinesin motor modulators derived from the marine sponge Adocia

Assignee: UNIV CALIFORNIAPriority: Jan 8, 1998Filed: Mar 3, 2004Published: Sep 9, 2004

Est. expiryJan 8, 2018(expired)· nominal 20-yr term from priority

Inventors:Lawrence S. B. Goldstein David John Faulkner Roman Sakowicz Michael S. Berdelis Christine L. Blackburn Cordula Hopmann

A61P 35/00C07C 305/06C07D 313/06C12Q 1/42Y10S977/725Y10S977/71A61P 43/00G01N 2500/00Y10S977/801G01N 33/5011

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References

Claims

Abstract

This invention provides novel compounds derived from a marine sponge, Adocia sp., that specifically modulat kinesin activity by targeting the kinesin motor domain and mimicking the activity a microtubule. The compounds act as potent anti-mitogens are useful in a wide variety of in vitro and in vivo applications.

Claims

exact text as granted — not AI-modified

What is claimed is:

1 . A compound having a formula

wherein R 1 and R 2 are either independent monovalent moieties independently selected from the group of H, hemiterpenes, terpene monomers and terpene oligomers such that at least one of R 1 and R 2 is not H,
or R 1 and R 2 are combined to form a single divalent terpene moiety selected from the group consisting of hemiterpenes, terpene monomers and terpene oligomers;
X 1 and X 2 are the same or different and are anionic derivatives of an organic group, an inorganic group or a group which is a combination of organic and inorganic groups;
Y +n is an organic or inorganic cation;
m is either 1 or 2; and
n is either 1 or 2.

2 . A compound according to claim 1 , wherein said terpene oligomers are members selected from the group consisting of sesquiterpenes, diterpenes, sesterterpenes, triterpenes, tetraterpenes and meroterpenes.

3 . A compound according to claim 1 , wherein
X 1 and X 2 are independently anions derived from members selected from the group consisting of formic acid, acetic acid, glycolic acid, phosphoric acid, phosphonic acid, phosphinic acid, boronic acid, sulfuric acid, and arsonic acid; and Y +n is a member selected from the group consisting of inorganic cations and tetralkylammonium salts.

4 . A compound according to claim 3 , wherein
R 1 is hydrogen; R 2 is a member selected from the group consisting of diterpenes, triterpenes and meroterpenes; and X 1 and X 2 are —OSO 3 − ; n is 1; and m is 2.

5 . A compound according to claim 1 , wherein
Y is a tetraalkylammonium salt according to the formula (R 4 ) 3 N—(CH 2 ) t —R 3 —(CH 2 ) s —N(R 4 ) 3 wherein R 3 is a member selected from the group consisting of C 1 -C 10 aryl, substituted aryl, alkyl and substituted alkyl groups; R 4 is lower alkyl or substituted lower alkyl; m is 1; n is 2; s is an integer between 1 and 5; and t is an integer between 1 and 5.

6 . A compound according to claim 1 having a formula

wherein R 5 and R 6 are either independent monovalent moieties independently selected from the group of H, hemiterpenes, terpene monomers and terpene oligomers such that at least one of R 5 and R 6 is not H,
or R 5 and R 6 are combined to form a single divalent terpene moiety selected from the group consisting of hemiterpenes, terpene monomers and terpene oligomers.

7 . A compound according to claim 6 , wherein said terpene oligomers are members selected from the group consisting of sesquiterpenes, diterpenes, sesterterpenes, triterpenes, tetraterpenes and meroterpenes.

8 . A compound according to claim 1 having the formula

9 . A compound according to claim 1 having the formula:

10 . A compound according to claim 1 having the formula

11 . A composition for in vivo modulation of kinesin motor activity, said composition comprising:
a pharmaceutically acceptable excipient; and a compound having the formula wherein R 1 and R 2 are either independent monovalent moieties independently selected from the group of H, hemiterpenes, terpene monomers and terpene oligomers such that at least one of R 1 and R 2 is not H, or R 1 and R 2 are combined to form a single divalent terpene moiety selected from the group consisting of hemiterpenes, terpene monomers and terpene oligomers; X 1 and X 2 are the same or different and are anionic derivatives of an organic group, an inorganic group or a group which is a combination of organic and inorganic groups; Y +n is an organic or inorganic cation; m is either 1 or 2; and n is either 1 or 2.

12 . The composition according to claim 11 , wherein said terpene oligomers are members selected from the group consisting of sesquiterpenes, diterpenes, sesterterpenes, triterpenes, tetraterpenes and meroterpenes

13 . The composition according to claim 11 , wherein
X 1 and X 2 are independently anions derived from members selected from the group consisting of formic acid, acetic acid, glycolic acid, phosphoric acid, phosphonic acid, phosphinic acid, boronic acid, sulfuric acid, and arsonic acid; and Y +n is a member selected from the group consisting of inorganic cations and tetralkylammonium salts.

14 . The composition according to claim 13 , wherein X 1 and X 2 are the same.

15 . The composition according to claim 13 , wherein
R 1 is hydrogen; R 2 is a member selected from the group consisting of diterpenes, triterpenes and meroterpenes; and X 1 and X 2 are —OSO 3 − ; n is 1; and m is 2

16 . The composition according to claim 11 , wherein Y is a tetraalkylammonium salt according to the formula
(R 4 ) 3 N—(CH 2 ) t —R 3 —(CH 2 ) s —N(R 4 ) 3 wherein R 3 is a member selected from the group consisting of C 1 -C 10 aryl, substituted aryl, alkyl and substituted alkyl groups; R 4 is lower alkyl or substituted lower alkyl; m is 1; n is 2; s is an integer between 1 and 5; and t is an integer between 1 and 5.

17 . The composition according to claim 11 , having a formula:

18 . The composition according to claim 17 , wherein said terpene oligomers are members selected from the group consisting of sesquiterpenes, diterpenes, sesterterpenes, triterpenes, tetraterpenes and meroterpenes.

19 . The composition according to claim 11 , having the formula

20 . The composition according to claim 11 , having the formula

21 . The composition according to claim 11 having the formula

22 . A method for modulating kinesin motor activity in a cell, said method comprising the step of:
(i) contacting s aid cell with a compound having the formula wherein R 1 and R 2 are either independent monovalent moieties independently selected from the group of H, hemiterpenes, terpene monomers and terpene oligomers such that at least one of R 1 and R 2 is not H, or R 1 and R 2 are combined to form a single divalent terpene moiety selected from the group consisting of hemiterpenes, terpene monomers and terpene oligomers; X 1 and X 2 are the same or different and are anionic derivatives of an organic group, an inorganic group or a group which is a combination of organic and inorganic groups; Y +n is an organic or inorganic cation; m is either 1 or 2; and n is either 1 or 2.

23 . The method of claim 22 , wherein said terpene oligomers are members selected from the group consisting of sesquiterpenes, diterpenes, sesterterpenes, triterpenes, tetraterpenes and meroterpenes.

24 . The method of claim 22 , wherein
X 1 and X 2 are independently anions derived from members selected from the group consisting of formic acid, acetic acid, glycolic acid, phosphoric acid, phosphonic acid, phosphinic acid, boronic acid, sulfuric acid, and arsonic acid; and Y +n is a member selected from the group consisting of inorganic cations and tetralkylammonium salts.

25 . The method of claim 24 , wherein X 1 and X 2 are the same.

26 . The method of claim 24 , wherein
R 1 is hydrogen; R 2 is a member selected from the group consisting of diterpenes, triterpenes and meroterpenes; and X 1 and X 2 are —OSO 3 ′; n is 1; and m is 2.

27 . The method of claim 22 , wherein Y is a tetraalkylammonium salt according to the formula
(R 4 ) 3 N—(CH 2 ) t —R 3 —(CH 2 ) s —N(R 4 ) 3 wherein R 3 is a member selected from the group consisting of C 1 -C 10 aryl, substituted aryl, alkyl and substituted alkyl groups; R 4 is lower alkyl or substituted lower alkyl; m is 1; n is 2; s is an integer between 1 and 5; and t is an integer between 1 and 5.

28 . The method of claim 22 , wherein said compound has the formula

29 . The method of claim 28 , wherein said terpene oligomers are members selected from the group consisting of sesquiterpenes, diterpenes, sesterterpenes, triterpenes, tetraterpenes and meroterpenes

30 . The method of claim 22 , wherein said compound has the formula

31 . The method of claim 22 , wherein said compound has the formula

32 . The method of claim 22 , wherein said compound has the formula

33 . The method of claim 22 , wherein said cell is an animal cell.

34 . The method of claim 22 , wherein said cell is a neuron.

35 . The method of claim 22 , wherein said cell is a plant cell.

36 . The method of claim 22 , wherein said cell is a fungal cell.

37 . The method of claim 22 , wherein said cell is a tumor cell.

38 . A method of assaying a test compound for kinesin modulatory activity, said method comprising the steps of:
(i) contacting a microtubule and a kinesin motor with said test compound having the formula wherein R 1 and R 2 are either independent monovalent moieties independently selected from the group of H, hemiterpenes, terpene monomers and terpene oligomers such that at least one of R 1 and R 2 is not H, or R 1 and R 2 are combined to form a single divalent terpene moiety selected from the group consisting of hemiterpenes, terpene monomers and terpene oligomers; X 1 and X 2 are the same or different and are anionic derivatives of an organic group, an inorganic group or a group which is a combination of organic and inorganic groups; Y +n is an organic or inorganic cation; m is either 1 or 2; and n is either 1 or 2; and (ii) detecting a change in kinesin motor activity resulting from said contacting.

39 . The method of claim 22 , wherein said terpene oligomers are members selected from the group consisting of sesquiterpenes, diterpenes, sesterterpenes, triterpenes, tetraterpenes and meroterpenes.

40 . The method of claim 38 , wherein
X 1 and X 2 are independently anions derived from members selected from the group consisting of formic acid, acetic acid, glycolic acid, phosphoric acid, phosphonic acid, phosphinic acid, boronic acid, sulfuric acid, and arsonic acid; and Y +n is a member selected from the group consisting of inorganic cations and tetralkylammonium salts.

41 . The method of claim 40 , wherein X 1 and X 2 are the same.

42 . The method of claim 40 , wherein
R 1 is hydrogen; R 2 is a member selected from the group consisting of diterpenes, triterpenes and meroterpenes; and X 1 and X 2 are —OSO 3 —; n is 1; and m is 2.

43 . The method of claim 38 , wherein
Y is a tetraalkylammonium salt according to the formula (R 4 ) 3 N—(CH 2 ) t —(CH 2 ) s —N(R 4 ) 3 wherein R 3 is a member selected from the group consisting of C 1 -C 10 aryl, substituted aryl, alkyl and substituted alkyl groups; R 4 is lower alkyl or substituted lower alkyl; m is 1; n is 2; s is an integer between 1 and 5; and t is an integer between 1 and 5.

44 . The method of claim 38 , wherein said compound has the formula

wherein R 5 and R 6 are either independent monovalent moieties independently selected from the group of H, hemiterpenes, terpene monomers and terpene oligomers such that at least one of R 5 and R 6 is not H,
or R 5 and R are combined to form a single divalent terpene moiety selected from the group consisting of hemiterpenes, terpene monomers and terpene oligomers.

45 . The method of claim 44 , wherein said terpene oligomers are members selected from the group consisting of sesquiterpenes, diterpenes, sesterterpenes, triterpenes, tetraterpenes and meroterpenes.

46 . The method of claim 38 , wherein said detecting comprises a motility assay.

47 . The method of claim 38 , wherein said detecting comprises a microtubule kinesin binding assay.

48 . The method of claim 38 , wherein said detecting comprises an ATPase assay.

49 . The method of claim 38 , wherein said detecting comprises an anti-mitotic assay in situ, in vitro, or in vivo.

50 . The method of claim 38 , wherein said change is with reference to a control assay lacking said test compound.

51 . A kit for modulating kinesin motor activity, said kit comprising a container containing compound having a formula

52 . The kit according to claim 51 , wherein said terpene oligomers are members selected from the group consisting of sesquiterpenes, diterpenes, sesterterpenes, triterpenes, tetraterpenes and meroterpenes.

53 . The kit according to claim 51 , wherein
X 1 and X 2 are independently anions derived from a members selected from the group consisting of formic acid, acetic acid, glycolic acid, phosphoric acid, phosphonic acid, phosphinic acid, boronic acid, sulfuric acid, and arsonic acid; and Y +n is a member selected from the group consisting of inorganic cations and tetralkylammonium salts.

54 . The kit according to claim 53 , wherein X 1 and X 2 are the same.

55 . The kit according to claim 53 , wherein
R 1 is hydrogen; R 2 is a member selected from the group consisting of diterpenes, triterpenes and meroterpenes; and X is —OSO 3 − ; n is 1; and m is 2.

56 . The kit according to claim 51 , wherein
Y is a tetraalkylammonium salt according to the formula (R 4 ) 3 N—(CH 2 ) t —R 3 —(CH 2 ) s —N(R 4 ) 3 wherein R 3 is a member selected from the group consisting of C 1 -C 10 aryl, substituted aryl, alkyl and substituted alkyl groups; R 4 is lower alkyl or substituted lower alkyl; m is 1; n is 2; s is an integer between 1 and 5; and t is an integer between 1 and 5.

57 . The kit according to claim 51 having a formula

58 . The kit according to claim 57 , wherein said terpene oligomers are members selected from the group consisting of sesquiterpenes, diterpenes, sesterterpenes, triterpenes, tetraterpenes and meroterpenes.

59 . The kit according to claim 51 having the formula

60 . The kit according to claim 51 having the formula

61 . The kit according to claim 51 having the formula

62 . A method of identifying a compound that specifically modulates a kinesin motor at a microtubule binding site, said method comprising the steps of:
(i) assaying for competitive inhibition of said motor by said molecule at a kinesin ATPase site; (ii) assaying for competitive inhibition of said motor by said molecule at a microtubule binding site; (iii) identifying said small molecule as a kinesin modulator specific to a microtubule binding site when said small molecule is a competitive modulator at said microtubule binding site, but not at said ATPase site.

63 . The method of claim 62 , wherein said assaying comprises detecting ATPase activity of said kinesin motor.

64 . The method of claim 62 , wherein compound is a polypeptide.

65 . The method of claim 62 , wherein compound is a nucleic acid.

66 . The method of claim 62 , wherein compound is an antibody.

67 . The method of claim 62 , wherein compound is a small organic molecule.

68 . The method of claim 62 , wherein compound is an inorganic molecule.

69 . A method of modulating kinesin motor activity, said method comprising contacting said kinesin motor with a small organic molecule that competitively inhibits said kinesin motor at a microtubule binding site.

70 . The method of claim 69 , wherein said small organic molecule is identified according to the method of claim 62 .

71 . A method of modulating kinesin motor activity, said method comprising contacting said kinesin motor with a small organic molecule that competitively inhibits said kinesin motor at a microtubule binding site.

72 . The method of claim 71 , wherein said small organic molecule is identified according to the method of claim 62 .

73 . A method of identifying an agent that modulates the kinesin inhibitory activity of an Adocia kinesin inhibitor, said method comprising:
(i) contacting a microtubule, a kinesin motor, and an Adocia kinesin inhibitor with a candidate agent; and (ii) detecting a change in the kinesin inhibitory activity of the Adocia kinesin inhibitor resulting from said contacting, wherein a change indicates the identification of an agent that modulates the kinesin inhibitory activity of the Adocia kinesin inhibitor.

74 . A method of identifying an agent that interferes with the binding of an Adocia kinesin inhibitor with a kinesin, said method comprising:
(i) contacting a kinesin and an Adocia kinesin inhibitor with a candidate agent; and (ii) detecting a decrease in the binding of the Adocia kinesin inhibitor with the kinesin resulting from said contacting, wherein a decrease indicates the identification of an agent that interferes with the binding of the Adocia kinesin inhibitor and the kinesin.

75 . A complex comprising an Adocia kinesin inhibitor and a kinesin.

76 . A method of modulating cellular growth in an organism, said method comprising administering to said organism a composition comprising a pharmaceutically acceptable carrier the compound of claim 1 in a quantity sufficient to alter said cellular growth in an organism.

77 . The method of claim 76 , wherein said organism is an animal.

78 . The method of claim 76 , wherein said organism is an plant.

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