Alcohol-, diol-, and carbohydrate-substituted indenoisoquinolines as topoisomerase I inhibitors
The invention described herein pertains to substituted indenoisoquinoline compounds as described herein, wherein R A , R D , W, X and Y are defined herein, pharmaceutical compositions and formulations comprising the indenoisoquinoline compounds, their synthesis, and methods for their use in the treatment and/or prevention of cancer.
1. A compound of the formula
or a pharmaceutically acceptable salt thereof, wherein
R A represents four substituents each independently selected from the group consisting of hydrogen, halo, azido, and nitro, and hydroxy, amino, and thio, and acyl, sulfoxyl, sulfonyl, phosphinyl, and phosphonyl, and CO 2 H, SO 2 H, SO 3 H, PO 2 H, and PO 3 H, and alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, cycloalkenyl, cycloheteroalkyl, cycloheteroalkenyl, aryl, arylalkyl, arylalkenyl, and arylalkynyl, each of which is optionally substituted; or R A represents at least two adjacent substituents that are taken together with the attached carbons to form an optionally substituted heterocycle;
R D represents three substituents each independently selected from the group consisting of hydrogen, halo, azido, and nitro, and hydroxy, amino, and thio, and acyl, sulfoxyl, sulfonyl, phosphinyl, and phosphonyl, and CO 2 H, SO 2 H, SO 3 H, PO 2 H, and PO 3 H, and alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, cycloalkenyl, cycloheteroalkyl, cycloheteroalkenyl, aryl, arylalkyl, arylalkenyl, and arylalkynyl, each of which is optionally substituted; or R D represents at least two adjacent substituents that are taken together with the attached carbons to form an optionally substituted heterocycle;
X and Y are each independently selected from the group consisting of hydrogen, hydroxy, amino, hydroxylamino, and hydrazino, and alkyl, heteroalkyl, cycloalkyl, cycloheteroalkyl, aryl, and arylalkyl, each of which is optionally substituted; or X and Y are taken together with the attached carbon to form carbonyl, imino, oximino, hydrazono, and alkylidenyl, each of which is optionally substituted; and
W is a secondary or tertiary branched alkanol or cyclic alkanol or W is a ketone.
2. The compound of claim 1 wherein W is a polyhydroxyalkane, or a diol, or a carbohydrate, or a sugar alcohol, or a C 3 -C 6 sugar alcohol, or a C 4 -C 6 sugar alcohol, or a C 5 -C 6 sugar alcohol.
3. The compound of claim 1 wherein W includes a branched alkyl.
4. The compound of claim 1 wherein W is CH 2 CH(OH)—R, where R is alkyl, heteroalkyl, cycloalkyl, cycloheteroalkyl, carbaryl, carbarylalkyl, heteroaryl, or heteroarylalkyl, each of which is optionally substituted.
5. The compound of claim 1 wherein W is CH 2 CH(OH)—CH(OH)—R, where R is hydrogen, alkyl, heteroalkyl, cycloalkyl, cycloheteroalkyl, carbaryl, carbarylalkyl, heteroaryl, or heteroarylalkyl, each of which is optionally substituted.
6. The compound of claim 1 wherein W is a ketoalkanol.
7. The compound of claim 1 wherein W further includes an amino group.
8. The compound of claim 1 wherein W includes the following divalent radical
where R is alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, cycloalkenyl, cycloheteroalkyl, cycloheteroalkenyl, aryl, arylalkyl, arylalkenyl, or arylalkynyl, each of which is optionally substituted.
9. The compound of claim 1 wherein W is a hydroxy ketone.
10. The compound of claim 1 wherein W is a hydrogen bond forming group.
11. The compound of claim 1 wherein W is capable of forming one or more hydrogen bonds with residues in the DNA major groove.
12. The compound of claim 1 wherein W is capable of forming a hydrogen bond with Asn352 of a topoisomerase I.
13. The compound of claim 1 wherein R A represents four substituents each independently selected from the group consisting of hydrogen, halo, and nitro, and hydroxy, amino, and thio, and acyl, sulfoxyl, and sulfonyl, and CO 2 H, and SO 2 H, and alkyl, heteroalkyl, cycloalkyl, cycloheteroalkyl, carbaryl, carbarylalkyl, heteroaryl, and heteroarylalkyl, each of which is optionally substituted; or R A represents at least two adjacent substituents that are taken together with the attached carbons to form an optionally substituted heterocycle.
14. The compound of claim 1 wherein R A represents four substituents each independently selected from the group consisting of, halo, and nitro, and hydroxy, amino, and thio, and acyl, sulfoxyl, and sulfonyl, and CO 2 H, and alkyl, heteroalkyl, cycloalkyl, cycloheteroalkyl, carbaryl, carbarylalkyl, heteroaryl, and heteroarylalkyl, each of which is optionally substituted.
15. The compound of claim 1 wherein R A represents two adjacent substituents that are taken together with the attached carbons to form an optionally substituted heterocycle.
16. The compound of claim 1 wherein R D represents four substituents each independently selected from the group consisting of hydrogen, halo, and nitro, and hydroxy, amino, and thio, and acyl, sulfoxyl, and sulfonyl, and CO 2 H, and SO 2 H, and alkyl, heteroalkyl, cycloalkyl, cycloheteroalkyl, carbaryl, carbarylalkyl, heteroaryl, and heteroarylalkyl, each of which is optionally substituted; or R D represents at least two adjacent substituents that are taken together with the attached carbons to form an optionally substituted heterocycle.
17. The compound of claim 1 wherein R D represents four substituents each independently selected from the group consisting of, halo, and nitro, and-hydroxy, amino, and thio, and acyl, sulfoxyl, and sulfonyl, and CO 2 H, and alkyl, heteroalkyl, cycloalkyl, cycloheteroalkyl, carbaryl, carbarylalkyl, heteroaryl, and heteroarylalkyl, each of which is optionally substituted.
18. The compound of claim 1 wherein R D represents two adjacent substituents that are taken together with the attached carbons to form an optionally substituted heterocycle.
19. The compound of claim 1 wherein at least one of R A is nitro, or alkoxy or, methoxy.
20. The compound of claim 1 wherein at least two of R A are bismethoxy, or alkyleneoxy, or methyleneoxy.
21. The compound of claim 1 wherein at least one of R D is nitro, or alkoxy, or methoxy.
22. The compound of claim 1 wherein at least two of R D are bismethoxy, or alkylenedioxy, or methylenedioxy.
23. The compound of claim 1 wherein X and Y are taken together with the attached carbon to form carbonyl.
24. A pharmaceutical composition comprising one or more compounds of claim 1 and one or more carriers, diluents, or excipients, or a combination thereof for treating cancer.
25. A method for treating cancer, the method comprising the step of administering to a patient in need of relief from the cancer a composition comprising a therapeutically effective amount of one or more compounds of claim 1 and one or more carriers, diluents, or excipients, or a combination thereof.
26. The compound of claim 1 , wherein said compound has the following formula:
wherein
R 1 is hydrogen or methoxy;
R 2 is hydrogen, methoxy, or nitro; and
W is selected from the group consisting of
27. The compound of claim 26 , wherein said compound is
wherein R 1 is hydrogen and R 2 is nitro.
28. The compound of claim 26 , wherein said compound is