Camptothecin derivatives

1. A compound of Formula I:

wherein

u is 0 or 1;

R 1a , R 1b , and R 1c independently are H, halogen, hydroxyl, nitrile, amino, substituted amino, nitro, carboxyl ester, aminocarbonyl, substituted sulfonyl, aminosulfonyl, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 2 -C 6 alkynyl, substituted or unsubstituted C 2 -C 6 alkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocycloalkyl, or substituted or unsubstituted C 1 -C 6 alkoxy group, or R 1a and R 1b together with the carbon atoms to which they are bonded form a 5-7 membered heterocycle, or R 1b and R 1c together with the carbon atoms to which they are bonded form a 5-7 membered heterocycle;

R 2 is H, halogen, nitrile, formyl, oxime, hydrazone, imine, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted C 2 -C 6 alkenyl, or substituted or unsubstituted C 2 -C 6 alkynyl group; or R 2 and R 1a together with the carbon atoms to which they are attached form a 5-7 membered substituted cycloalkyl ring;

X is nitro or —NR 3 R 4 ;

each R 3 and R 4 are independently H, substituted or unsubstituted C 1 -C 6 alkyl, —CO 2 R 5 , or —COR 6 ;

R 5 is substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;

R 6 is H, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;

or a carboxyl ester or a pharmaceutically acceptable salt thereof, provided however that the compound is not 14-nitro-20-acetoxycamptothecin.

2. The compound of claim 1 , wherein R 1a , R 1b , and R 1c independently are H, OH, methyl, fluoro, dimethylaminomethyl, —NH 2 , —NO 2 ,

or R 2 and R 1a together are

or R 1b and R 1c together are

3. The compound of claim 1 or 2 , wherein R 1a , R 1b , and R 1c are H.

4. The compound of claim 1 , wherein X is —NO 2 , —NH 2 , or —NHCHO.

5. The compound of claim 1 , wherein u is 0.

6. The compound of claim 1 that is a compound of Formula III:

wherein

R 2 is halo, cyano, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclyl group, or —CH═Y 1 ;

Y 1 is O, N—R 10 , or CR 11 R 12 ;

R 10 is —OR 13 , —NR 14 R 15 , or substituted or unsubstituted aryl or heteroaryl group;

R 11 is H or substituted or unsubstituted C 1 -C 3 alkyl;

R 12 is H, —COR 16 , substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 3 -C 8 cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl group;

R 13 is H, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 1 -C 6 alkenyl, substituted or unsubstituted C 3 -C 8 cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl group;

R 14 and R 15 independently are H, —SO 2 R 17 , —COR 18 , substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 3 -C 8 cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl group, or R 14 and R 15 together with the nitrogen atom to which they are bonded form a 5-7 membered heterocycle;

R 16 is —OH, —OR 19 , —NR 26 R 27 , substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 3 -C 8 cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl group;

R 17 is substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 3 -C 8 cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl group;

R 18 is H or substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 3 -C 8 cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl group;

R 19 is substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 3 -C 8 cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl group; and

R 26 and R 27 independently are H, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 3 -C 8 cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl group, or R 26 and R 27 together with the carbon atom to which they are bonded form a 5-7 membered heterocycle.

7. The compound of claim 1 , wherein R 2 is unsubstituted C 1 -C 6 alkyl.

8. The compound of claim 1 that is a compound of Formula IVA:

wherein

R 14 is H, SO 2 R 17 , or COR 18 ;

R 17 is a substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 3 -C 8 cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl group;

R 18 is H or a substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 3 -C 8 cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl group;

R 15 is -L 2 -Z 2 ; or R 14 and R 15 together with the nitrogen atom to which they are bonded form a 5-7 membered heterocycle;

L 2 is substituted or unsubstituted C 1 -C 6 alkylene;

Z 2 is H, —OH, —NR 22 R 23 , or a leaving group; and

R 22 and R 23 independently are H, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 3 -C 8 cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl group, or R 22 and R 23 together with the nitrogen atom to which they are bonded form a 5-7 membered heterocycle.

9. The compound of any one of claims 1 - 5 , wherein R 2 is —CH(OR 20 ) 2 or —CHO, wherein R 20 is substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 3 -C 8 cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl group, or the two R 20 groups together with the oxygen atoms to which they are bonded form a 5-6 membered heterocycle.

10. A compound prepared by the process comprising contacting a compound of Formula IX:

wherein

u is 0 or 1;

R 1a , R 1b , and R 1c each independently are H, halogen, hydroxyl, amino, substituted amino, nitro, carboxyl ester, aminocarbonyl, substituted sulfonyl, aminosulfonyl, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 2 -C 6 alkynyl, substituted or unsubstituted C 2 -C 6 alkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclyl, or substituted or unsubstituted C 1 -C 6 alkoxy group, or R 1a and R 1b together with the carbon atoms to which they are bonded form a 5-7 membered heterocycle, or R 1b and R 1c together with the carbon atoms to which they are bonded form a 5-7 membered heterocycle; and

R 2 is H, halogen, nitrile, formyl, oxime, hydrazone, imine, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted C 2 -C 6 alkenyl, or substituted or unsubstituted C 2 -C 6 alkynyl group; or R 2 and R 1a together with the carbon atoms to which they are bonded form a 5-7 membered substituted cycloalkyl ring; or

a carboxyl ester or salt thereof

with fuming nitric acid, provided however that the compound prepared excludes 14-nitro-20-acetoxycamptothecin.

11. The compound of claim 1 selected from the group consisting of

12. The compound of claim 11 selected from the group consisting of:

13. A method of synthesis comprising contacting a compound of Formula IX:

wherein

u is 0 or 1;

R 1a , R 1b , and R 1c independently are H, halogen, hydroxyl, amino, substituted amino, nitro, carboxyl ester, aminocarbonyl, substituted sulfonyl, aminosulfonyl, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 2 -C 6 alkynyl, substituted or unsubstituted C 2 -C 6 alkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclyl, or substituted or unsubstituted C 1 -C 6 alkoxy group, or R 1a and R 1b together with the carbon atoms to which they are bonded form a 5-7 membered heterocycle, or R 1b and R 1c together with the carbon atoms to which they are bonded form a 5-7 membered heterocycle; and

R 2 is H, halogen, nitrile, formyl, oxime, hydrazone, imine, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted C 2 -C 6 alkenyl, or substituted or unsubstituted C 2 -C 6 alkynyl group; or R 2 and R 1a together with the carbon atoms to which they are bonded form a 5-7 membered substituted cycloalkyl ring; or

a carboxyl ester or a salt thereof

with fuming nitric acid to provide a compound of Formula IXA:

14. The method of claim 13 , wherein the contacting is performed in acetic anhydride.

15. A pharmaceutical composition comprising the compound of claim 1 or 14-nitro-20-acetoxycamptothecin and a pharmaceutically acceptable carrier, excipient, or diluent.

16. A method of inhibiting growth of a hyperproliferative cell comprising contacting the hyperproliferative cell with an effective amount of the compound of claim 1 or 14-nitro-20-acetoxycamptothecin, wherein the hyperproliferative cell is a cancer cell selected from lung cancer, melanoma, prostate cancer, colon cancer, and ovarian cancer.

17. A method of treating a cancer selected from lung cancer, melanoma, prostate cancer, colon cancer, and ovarian cancer comprising administering a therapeutically effective amount of the compound of claim 1 or 14-nitro-20-acetoxycamptothecin to a patient in need of such treatment thereby treating the cancer.