Claims
- 1. A method comprising:
(a) contacting tubulin with a compound having the structure of formula I: 36 wherein:
at least one of X1, X2, and X3 is O and the others are C; R1 and R2 are the same or different and are each independently H, provided both R1 and R2 are not H, or (C1-C8)alkyl, (C1-C8)cycloalkyl, (C1-C8)alkoxy, (C1-C8)aryloxy, (C1-C8)arylthio, (C1-C8)aryl, C(═)NRaRb or NRaRb; wherein Ra and Rb are each independently hydrogen, acyl, (C1-C8)alkyl, (C3-C7)cycloalkyl, (C6-C10)aryl; n and m are the same or different, and are each independently 0 to 7; S1 and S2 can be the same or different, and are each independently OH, SH, CO2H, halogen, CN, acyl, thioacyl, ester, thioester, (C1-C6)alkoxy, (C1-C6)aryloxy, (C1-C6)alkylthio, (C1-C6)arylthio, (C1-C6)alkyl, (C1-C6)alkenyl, (C1-C6)alkynyl, (C3-C7)cycloalkyl, (C6-C10)aryl, C(═O)NRaRb or NRaRb; wherein Ra and Rb are each independently hydrogen, acyl, (C1-C6)alkyl, (C3-C7)cycloalkyl, (C6-C10)aryl; taken together, any two S1 and S2 can form a ring, and any two adjacent substituents can form a double bond between the two carbons to which they are attached; and wherein said contacting inhibits polymerization of tubulin or induces depolymerization of tubulin.
- 2. The method of claim 1, wherein one or more of R1, R2, Ra, and Rb are substituted with at least one functional group selected from OH, SH, CO2H, halogen, CN, acyl, thioacyl, ester, thioester.
- 3. The method of claim 1, wherein at least one of R1, R2, Ra, and Rb comprise an aromatic ring.
- 4. The method of claim 1, wherein at least one of R1, R2, R1, and Rb is a group capable of hydrogen bonding wherein the group is —(CH2)nOH, n being 0-7, or (C1-C6)aryloxy.
- 5. The method of claim 1, wherein one or more of R1, R2, Ra, and Rb is capable of hydrophobic interaction with one or more hydrophobic residues of the spongistatin binding pocket selected from Y185, Y408, F399, F404, and W407 of tubulin.
- 6. A method of claim 1, wherein compound I comprises a compound having the structure of formula II:
- 7. The method of claim 6, wherein compound II comprises a compound having the structure of formula VI:
- 8. The method of claim 1, wherein the compound comprises a compound of formula VI:
- 9. The method of claim 1 wherein the step of contacting comprises contacting tubulin with the compound of formula I and a carrier.
- 10. A method comprising:
(a) contacting cells with an inhibitory amount of a compound having the structure of formula I: 41 wherein:
at least one of X1, X2, and X3 is O and the others are C; R1 and R2 are the same or different and are each independently H, provided both R1 and R2 are not H, or (C1-C8)alkyl, (C1-C8)cycloalkyl, (C1-C8)alkoxy, (C1-C8)aryloxy, (C1-C8)arylthio, (C1-C8)aryl, C(═)NRaRb or NRaRb; wherein Ra and Rb are each independently hydrogen, acyl, (C1-C8)alkyl, (C3-C7)cycloalkyl, (C6-C10)aryl; n and m are the same or different, and are each independently 0 to 7; S1 and S2 can be the same or different, and are each independently OH, SH, CO2H, halogen, CN, acyl, thioacyl, ester, thioester, (C1-C6)alkoxy, (C1-C6)aryloxy, (C1-C6)alkylthio, (C1-C6)arylthio, (C1-C6)alkyl, (C1-C6)alkenyl, (C1-C6)alkynyl, (C3-C7)cycloalkyl, (C6-C10)aryl, C(═O)NRaRb or NRaRb; wherein Ra and Rb are each independently hydrogen, acyl, (C1-C6)alkyl, (C3-C7)cycloalkyl, (C6-C10)aryl; taken together, any two S1 and S2 can form a ring, and any two adjacent substituents can form a double bond between the two carbons to which they are attached; and wherein said contacting inhibits proliferation of cells.
- 11. The method of claim 10, wherein one or more of R1, R2, Ra, and Rb are substituted with at least one functional group selected from OH, SH, CO2H, halogen, CN, acyl, thioacyl, ester, thioester.
- 12. The method of claim 10, wherein at least one of R1, R2, Ra, and Rb comprise an aromatic ring.
- 13. The method of claim 10, wherein at least one of R1, R2, Ra, and Rb is a group capable of hydrogen bonding wherein the group is —(CH2)nOH, n being 0-7, or (C1-C6)aryloxy.
- 14. The method of claim 10, wherein one or more of R1, R2, Ra, and Rb is capable of hydrophobic interaction with one or more hydrophobic residues of the spongistatin binding pocket selected from Y185, Y408, F399, F404, and W407 of tubulin.
- 15. The method of claim 10, wherein the compound comprises a compound of formula VI:
- 16. The method of claim 10 wherein the step of contacting comprises contacting cells with an inhibitory amount of the compound of formula I and a carrier.
- 17. The method of claim 10 wherein said cells are tumor cells.
- 18. A method comprising:
(a) administering to a patient a compound having the structure of formula I: 43 wherein:
at least one of X1, X2, and X3 is O and the others are C; R1 and R2 are the same or different and are each independently H, provided both R1 and R2 are not H, or (C1-C8)alkyl, (C1-C8)cycloalkyl, (C1-C8)alkoxy, (C1-C8)aryloxy, (C1-C8)arylthio, (C1-C8)aryl, C(═)NRaRb or NRaRb; wherein Ra and Rb are each independently hydrogen, acyl, (C1-C8)alkyl, (C3-C7)cycloalkyl, (C6-C10)aryl; n and m are the same or different, and are each independently 0 to 7; S1 and S2 can be the same or different, and are each independently OH, SH, CO2H, halogen, CN, acyl, thioacyl, ester, thioester, (C1-C6)alkoxy, (C1-C6)aryloxy, (C1-C6)alkylthio, (C1-C6)arylthio, (C1-C6)alkyl, (C1-C6)alkenyl, (C1-C6)alkynyl, (C3-C7)cycloalkyl, (C6-C10)aryl, C(═O)NRaRb or NRaRb; wherein Ra and Rb are each independently hydrogen, acyl, (C1-C6)alkyl, (C3-C7)cycloalkyl, (C6-C10)aryl; taken together, any two S1 and S2 can form a ring, and any two adjacent substituents can form a double bond between the two carbons to which they are attached; and wherein said administering is performed to treat a cellular proliferation disorder.
- 19. The method of claim 18, wherein one or more of R1, R2, Ra, and Rb are substituted with at least one functional group selected from OH, SH, CO2H, halogen, CN, acyl, thioacyl, ester, thioester.
- 20. The method of claim 18, wherein at least one of R1, R2, Ra, and Rb comprise an aromatic ring.
- 21. The method of claim 18, wherein at least one of R1, R2, Ra, and Rb is a group capable of hydrogen bonding wherein the group is —(CH2)nOH, n being 0-7, or (C1-C6)aryloxy.
- 22. The method of claim 18, wherein one or more of R1, R2, Ra, and Rb is capable of hydrophobic interaction with one or more hydrophobic residues of the spongistatin binding pocket selected from Y185, Y408, F399, F404, and W407 of tubulin.
- 23. The method of claim 18, wherein the compound comprises a compound of formula VI:
- 24. The method of claim 18 wherein the step of administering comprises administering to a patient the compound of formula I and a carrier.
- 25. The method of claim 18 wherein the cellular proliferation disorder is cancer.
- 26. The method of claim 25 wherein the step of administering comprises administering to a patient the compound of formula I in a dose effective to inhibit the growth of cancerous cells.
RELATED APPLICATIONS
[0001] This application is a Continuation of application Ser. No. 09/352,648, filed on Jun. 29, 1999, which claims the benefit of priority to provisional application Serial No. 60/091,002, filed on Jun. 29, 1998, which applications are incorporated herein by reference.
Provisional Applications (1)
|
Number |
Date |
Country |
|
60091002 |
Jun 1998 |
US |
Continuations (1)
|
Number |
Date |
Country |
Parent |
09352648 |
Jun 1999 |
US |
Child |
09974070 |
Oct 2001 |
US |