Tubulysin D analogues
The present invention provides novel tubulysin analogues, methods of making and methods of using such analogues and conjugates thereof. The compounds of the invention are highly potent cell-growth inhibitors have been developed that are smaller and considerably more stable than tubulysin D.
1. A compound of the formula which is selected from:
wherein
R 1 is a nitrogen containing moiety selected from an azide, a hydrazide and a hydrazone;
R 2 is selected from H, substituted alkyl and substituted or unsubstituted heteroalkyl;
R 3 is selected from H, acyl, substituted or unsubstituted alkyl, and substituted or unsubstituted heteroalkyl;
R 6 is a member selected from H, substituted or unsubstituted alkyl and substituted or unsubstituted heteroalkyl;
R 6a , R 7a and R 8 are independently selected from H, substituted or unsubstituted alkyl and substituted or unsubstituted heteroalkyl; and
Y is a member selected from (CH 2 ) n COOR 4a , (CH 2 ) n OR 4 ; and (CH 2 ) n NR 4 R 5
wherein
n is an integer from 0 to 10;
R 4a is selected from H, substituted or unsubstituted alkyl and substituted or unsubstituted heteroalkyl; and
R 4 and R 5 are independently selected from H, substituted or unsubstituted alkyl and substituted or unsubstituted heteroalkyl;
or a pharmaceutically acceptable salt or prodrug thereof.
2. A compound of the formula:
wherein
R 2 is selected from H, substituted alkyl and substituted or unsubstituted heteroalkyl;
R 3 is selected from H, acyl, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl;
R 6a is selected from H, substituted or unsubstituted alkyl and substituted or unsubstituted heteroalkyl; and
Y is a member selected from (CH 2 ) n COOR 4a , (CH 2 ) n OR 4 ; and (CH 2 ) n NR 4 R 5
wherein
n is an integer from 0 to 10;
R 4a is selected from H, substituted or unsubstituted alkyl and substituted or unsubstituted heteroalkyl; and
R 4 and R 5 are independently selected from H, substituted or unsubstituted alkyl and substituted or unsubstituted heteroalkyl;
or a pharmaceutically acceptable salt or prodrug thereof.
3. The compound according to claim 2 wherein Y is (CH 2 ) n COOR 4a ; and n is an integer from 0 to 10.
4. The compound according to claim 2 wherein R 6a comprises an amino acid residue.
5. A pharmaceutical formulation comprising a compound according to claim 1 and a pharmaceutically acceptable diluent.
6. A method of treating colon cancer and cervix cancer in a subject, said method comprising administering to said subject a therapeutically effective amount of a compound according to claim 1 .
7. A compound according to claim 1 of the formula:
wherein
R 1a and R 2a are independently selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl and substituted or unsubstituted heteroarylalkyl.
8. A compound according to claim 7 of the formula:
wherein R 1b and R 2b are independently selected from H and unsubstituted alkyl.
9. A compound according to claim 7 of the formula:
10. A compound according to claim 1 of the formula:
wherein R 1b and R 2b are independently selected from H and unsubstituted alkyl.
11. A compound according to claim 1 of the formula:
12. The compound according to claim 1 , which is selected from
13. A compound of the formula which is selected from:
wherein
R 1 is a nitrogen containing moiety selected from an azide, a hydrazide and a hydrazone;
R 2 is selected from H, substituted alkyl and substituted or unsubstituted heteroalkyl;
R 3 is selected from H, acyl, substituted or unsubstituted alkyl, and substituted or unsubstituted heteroalkyl;
R 6 is a member selected from H, substituted or unsubstituted alkyl and substituted or unsubstituted heteroalkyl;
R 6a , R 7a and R 8 are independently selected from H, substituted or unsubstituted alkyl and substituted or unsubstituted heteroalkyl; and
Y is (CH 2 ) n C(O)NR 4 R 5
wherein
n is an integer from 0 to 10; and
R 4 and R 5 are independently selected from H, unsubstituted alkyl and substituted or unsubstituted heteroalkyl;
or a pharmaceutically acceptable salt or prodrug thereof.
14. A compound according to claim 13 of the formula:
wherein
R 1a and R 2a are independently selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl and substituted or unsubstituted heteroarylalkyl.
15. A compound according to claim 13 of the formula:
wherein R 1b and R 2b are independently selected from H and unsubstituted alkyl.
16. A compound according to claim 13 of the formula:
17. A compound according to claim 13 of the formula:
wherein R 1b and R 2b are independently selected from H and unsubstituted alkyl.
18. A compound according to claim 13 of the formula:
19. The compound according to claim 13 , which is selected from
20. A pharmaceutical formulation comprising a compound according to claim 13 and a pharmaceutically acceptable diluent.
21. A method of treating colon cancer and cervix cancer in a subject, said method comprising administering to said subject a therapeutically effective amount of a compound according to claim 13 .
22. A compound which is selected from
23. A pharmaceutical formulation comprising a compound according to claim 22 and a pharmaceutically acceptable diluent.
24. A method of treating colon cancer and cervix cancer in a subject, said method comprising administering to said subject a therapeutically effective amount of a compound according to claim 22 .