Seriniquinones, melanoma-specific anticancer agents

1. A compound of Formula (I):

or pharmaceutically acceptable salt thereof,

wherein

A is N or —CR 4 ;

X is —S—;

R 1 , R 4 , R 5 , R 6 , R 7 , and R 8 are independently hydrogen, halogen, —NH 2 , —OH, —NO 2 , —C(O)CH 3 , —NHC(O)CF 3 , —OC(O)CH 3 , or unsubstituted C 1-4 alkyl;

R 2 and R 3 are independently hydrogen, halogen, —N 3 , —CF 3 , —CCl 3 , —CBr 3 , —CI 3 , —CN, —CHO, —OH, —NH 2 , —COOH, —CONH 2 , —NO 2 , —SH, —SO 2 , —SO 2 Cl, —SO 3 H, —SO 4 H, —SO 2 NH 2 , —NHNH 2 , —ONH 2 , —NHC(O)NHNH 2 , R 2a -substituted or unsubstituted C 1 -C 8 alkyl, R 2a -substituted or unsubstituted 2-8 membered heteroalkyl, R 2a -substituted or unsubstituted C 3 -C 8 cycloalkyl, R 2a -substituted or unsubstituted 3-6 membered heterocycloalkyl, R 2a -substituted or unsubstituted phenyl, or R 2a -substituted or unsubstituted 5or 6 membered heteroaryl;

R 2a is independently hydrogen, halogen, —N 3 , —CF 3 , —CCl 3 , —CBr 3 , —CI 3 , —CN, —CHO, —OH, —NH 2 , —COOH, —CONH 2 , —NO 2 , —SH, —SO 2 , —SO 2 Cl, —SO 3 H, —SO 4 H, —SO 2 NH 2 , —NHNH 2 , —ONH 2 , —NHC(O)NHNH 2 , R 2b -substituted or unsubstituted C 1 -C 8 alkyl, R 2b -substituted or unsubstituted 2-8 membered heteroalkyl, R 2b -substituted or unsubstituted C 3 -C 8 cycloalkyl, R 2b -substituted or unsubstituted 3-6 membered heterocycloalkyl, R 2b -substituted or unsubstituted phenyl, or R 2b -substituted or unsubstituted 5or 6 membered heteroaryl; and

R 2b is independently hydrogen, halogen, —N 3 , —CF 3 , —CCl 3 , —CBr 3 , —CI 3 , —CN, —CHO, —OH, —NH 2 , —COOH, —CONH 2 , —NO 2 , —SH, —SO 2 , —SO 2 Cl, —SO 3 H, —SO 4 H, —SO 2 NH 2 , —NHNH 2 , —ONH 2 , —NHC(O)NHNH 2 , an unsubstituted C 1 -C 8 alkyl, an unsubstituted 2-8 membered heteroalkyl, an unsubstituted C 3 -C 8 cycloalkyl, an unsubstituted 3-6 membered heterocycloalkyl, an unsubstituted phenyl, or an unsubstituted 5or 6 membered heteroaryl;

wherein if A is —CR 4 then at least one of R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , and R 8 is not hydrogen or alkyl.

2. The compound of claim 1 , wherein A is —CR 4 ; and R 1 , R 4 , R 5 , and R 8 are hydrogen.

3. The compound of claim 1 , wherein

A is —CR 4 —;

R 1 , R 3 , R 4 , R 5 , R 6 , R 7 , and R 8 are hydrogen; and

R 2 is halogen, —N 3 , —CF 3 , —CCl 3 , —CBr 3 , —CI 3 , —CN, —CHO, —OH, —NH 2 , —COOH, —CONH 2 , —NO 2 , —SH, —SO 2 , —SO 2 Cl, —SO 3 H, —SO 4 H, —SO 2 NH 2 , —NHNH 2 , —ONH 2 , —NHC(O)NHNH 2 , R 2a -substituted or unsubstituted C 1 -C 8 alkyl, R 2a -substituted or unsubstituted 2-8 membered heteroalkyl, R 2a -substituted or unsubstituted C 3 -C 8 cycloalkyl, R 2a -substituted or unsubstituted 3-6 membered heterocycloalkyl, R 2a -substituted or unsubstituted phenyl, or R 2a -substituted or unsubstituted 5 or 6 membered heteroaryl.

4. The compound of claim 1 , wherein the compound is:

wherein R 2 is R 2a -substituted or unsubstituted C 1 -C 8 alkyl, R 2a -substituted or unsubstituted 2-8 membered heteroalkyl, R 2a -substituted or unsubstituted C 3 -C 8 cycloalkyl, R 2a -substituted or unsubstituted 3-6 membered heterocycloalkyl, R 2a -substituted or unsubstituted phenyl, or R 2a -substituted or unsubstituted 5or 6 membered heteroaryl.

5. The compound of claim 1 , wherein R 2 is —(CH 2 ) 2 C(O)—R 2b .

6. The compound of claim 1 , wherein

A is —CR 4 —; and

R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , and R 8 are independently hydrogen, halogen, —NH 2 , —OH, —NO 2 , —C(O)CH 3 , —NHC(O)CF 3 , —OC(O)CH 3 , or unsubstituted C 1-4 alkyl.

7. The compound of claim 6 , wherein

R 1 , R 4 , R 5 , and R 8 are hydrogen;

one of R 2 and R 3 is hydrogen and the other of R 2 and R 3 is halogen, —NH 2 , —OH, —NO 2 , —C(O)CH 3 , —NHC(O)CF 3 , or —OC(O)CH 3 ; and

one of R 6 and R 7 is hydrogen and the other of R 6 and R 7 is halogen, —NH 2 , —OH, —NO 2 , —C(O)CH 3 , —NHC(O)CF 3 , or —OC(O)CH 3 .

8. A method of treating melanoma or prostate cancer in a subject in need thereof, said method comprising administering to a subject a therapeutically effective amount of a compound of claim 1 to treat the melanoma or prostate cancer.

9. A compound of Formula (VII):

or pharmaceutically acceptable salt thereof,

wherein

X is —S— or —NR 21 ;

R 1 , R 4 , R 5 , R 6 , R 7 and R 8 are independently hydrogen, halogen, —NH 2 , —OH, —NO 2 , —C(O)CH 3 , —NHC(O)CF 3 , —OC(O)CH 3 , or unsubstituted C 1-4 alkyl;

R 2 and R 3 are independently hydrogen, halogen, —N 3 , —CF 3 , —CCl 3 , —CBr 3 , —CI 3 , —CN, —CHO, —OH, —NH 2 , —COOH, —CONH 2 , —NO 2 , —SH, —SO 2 , —SO 2 Cl, —SO 3 H, —SO 4 H, —SO 2 NH 2 , —NHNH 2 , —ONH 2 , —NHC(O)NHNH 2 , R 2a -substituted or unsubstituted C 1 -C 8 alkyl, R 2a -substituted or unsubstituted 2-8 membered heteroalkyl, R 2a -substituted or unsubstituted C 3 -C 8 cycloalkyl, R 2a -substituted or unsubstituted 3-6 membered heterocycloalkyl, R 2a -substituted or unsubstituted phenyl, or R 2a -substituted or unsubstituted 5or 6 membered heteroaryl;

R 2a is independently hydrogen, halogen, —N 3 , —CF 3 , —CCl 3 , —CBr 3 , —CI 3 , —CN, —CHO, —OH, —NH 2 , —COOH, —CONH 2 , —NO 2 , —SH, —SO 2 , —SO 2 Cl, —SO 3 H, —SO 4 H, —SO 2 NH 2 , —NHNH 2 , —ONH 2 , —NHC(O)NHNH 2 , R R2b -substituted or unsubstituted C 1 -C 8 alkyl, R 2b -substituted or unsubstituted 2-8 membered heteroalkyl, R 2b -substituted or unsubstituted C 3 -C 8 cycloalkyl, R 2b -substituted or unsubstituted 3-6 membered heterocycloalkyl, R 2b -substituted or unsubstituted phenyl, or R 2b -substituted or unsubstituted 5or 6 membered heteroaryl;

R 2b is independently hydrogen, halogen, —N 3 , —CF 3 , —CCl 3 , —CBr 3 , —CI 3 , —CN, —CHO, —OH, —NH 2 , —COOH, —CONH 2 , —NO 2 , —SH, —SO 2 , —SO 2 Cl, —SO 3 H, —SO 4 H, —SO 2 NH 2 , —NHNH 2 , —ONH 2 , —NHC(O)NHNH 2 , unsubstituted C 1 -C 8 alkyl, unsubstituted 2 -8 membered heteroalkyl, unsubstituted C 3 -C 8 cycloalkyl, unsubstituted 3-6 membered heterocycloalkyl, unsubstituted phenyl, or unsubstituted 5or 6 membered heteroaryl;

R 2 and R 3 are independently hydrogen, halogen, —N 3 , —CF 3 , —CCl 3 , —CBr 3 , —CI 3 , —CN, —CHO, —OH, —NH 2 , —COOH, —CONH 2 , —NO 2 , —SH, —SO 2 , —SO 2 Cl, —SO 3 H, —SO 4 H, —SO 2 NH 2 , —NHNH 2 , —ONH 2 , —NHC(O)NHNH 2 , R 2a -substituted or unsubstituted C 1 -C 8 alkyl, R 2a -substituted or unsubstituted 2-8 membered heteroalkyl, R 2a -substituted or unsubstituted C 3 -C 8 cycloalkyl, R 2a -substituted or unsubstituted 3-6 membered heterocycloalkyl, R 2a -substituted or unsubstituted phenyl, or R 2a -substituted or unsubstituted 5or 6 membered heteroaryl; and

R 21 is hydrogen or unsubstituted C 1 -C 5 alkyl;

wherein at least one of R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , and R 8 is not hydrogen or alkyl.

10. A method of treating melanoma or prostate cancer in a subject in need thereof, said method comprising administering to a subject a therapeutically effective amount of a compound of claim 9 to treat the melanoma or prostate cancer.

11. A compound of Formula (VIII):

or pharmaceutically acceptable salt thereof,

wherein

X is —S— or —O—;

R 1 , R 4 , R 5 , R 6 , R 7 , and R 8 are independently hydrogen, halogen, —NH 2 , —OH, —NO 2 , —C(O)CH 3 , —NHC(O)CF 3 , —OC(O)CH 3 , or unsubstituted C 1 -C 4 alkyl;

R 2 and R 3 are independently hydrogen, halogen, —N 3 , —CF 3 , —CCl 3 , —CBr 3 , —CI 3 , —CN, —CHO, —OH, —NH 2 , —COOH, —CONH 2 , —NO 2 , —SH, —SO 2 , —SO 2 Cl, SO 3 H, —SO 4 H, —SO 2 NH 2 , —NHNH 2 , —ONH 2 , —NHC(O)NHNH 2 , R 2a -substituted or unsubstituted C 1 -C 8 alkyl, R 2a -substituted or unsubstituted 2-8 membered heteroalkyl, R 2a -substituted or unsubstituted C 3 -C 8 cycloalkyl, R 2a -substituted or unsubstituted 3-6 membered heterocycloalkyl, R 2a -substituted or unsubstituted phenyl, or R 2a -substituted or unsubstituted 5or 6 membered heteroaryl;

R 2a is independently hydrogen, halogen, —N 3 , —CF 3 , —CCl 3 , —CBr 3 , —CI 3 , —CN, —CHO, —OH, —NH 2 , —COOH, —CONH 2 , —NO 2 , —SH, —SO 2 , —SO 2 Cl, —SO 3 H, —SO 4 H, —SO 2 NH 2 , —NHNH 2 , —NHC(O)NHNH 2 , R 2b -substituted or unsubstituted C 1 -C 8 alkyl, R 2b -substituted or unsubstituted 2-8 membered heteroalkyl, R 2b -substituted or unsubstituted C 3 -C 8 cycloalkyl, R 2b -substituted or unsubstituted 3-6 membered heterocycloalkyl, R 2b -substituted or unsubstituted phenyl, or R 2b -substituted or unsubstituted 5or 6 membered heteroaryl;

R 2b is independently hydrogen, halogen, —N 3 , —CF 3 , —CCl 3 , —CBr 3 , —CI 3 , —CN, —CHO, —OH, —NH 2 , —COOH, —CONH 2 , —NO 2 , —SH, —SO 2 , —SO 2 Cl, —SO 3 H, —SO 4 H, —SO 2 NH 2 , —NHNH 2 , —ONH 2 , —NHC(O)NHNH 2 , unsubstituted C 1 -C 8 alkyl, unsubstituted 2-8 membered heteroalkyl, unsubstituted C 3 -C 8 cycloalkyl, unsubstituted 3-6 membered heterocycloalkyl, unsubstituted phenyl, or unsubstituted 5or 6 membered heteroaryl; and

R 17 , R 18 , R 19 , and R 20 are independently hydrogen or substituted or unsubstituted alkyl.

12. The compound of claim 11 , wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , and R 8 are hydrogen.

13. The compound of claim 11 , wherein R 17 , R 18 , R 19 , and R 20 are identical.

14. The compound of claim 11 , wherein R 17 , R 18 , R 19 , and R 20 are hydrogen, methyl, or acetyl.

15. The compound of claim 11 , wherein R 17 , R 18 , R 19 , and R 20 are acetyl.

16. A method of treating melanoma or prostate cancer in a subject in need thereof, said method comprising administering to a subject a therapeutically effective amount of a compound of claim 11 to treat the melanoma or prostate cancer.

17. A method of inhibiting a dermcidin protein in vitro, comprising:

(i) contacting a dermcidin protein having at least 75% sequence identity to SEQ ID NO:1, 2, 3, or 4 in vitro with a compound of claim 1 ; and

(ii) detecting formation of a dermcidin—seriniquinone complex, wherein formation of the complex is indicative of inhibition of the dermcidin protein, and further wherein the complex is detected using fluorescence detection.

18. A compound selected from the group consisting of:

19. A compound selected from the group consisting of: