Novobiocin analogues as anticancer agents

1. The compounds according to Formula I

wherein R 1 is hydrogen, alkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl, aralkyl, carboxyl, amido, amino, sulfanyl, sulfenyl, sulfonyl, or ether; or R 1 together with X 2 and the atom to which R 1 is attached form a heterocyclic ring having 4 to 8 ring members with at least one heteroatom selected from oxygen or nitrogen; or R 1 together with X 4 and the atom to which R 1 is attached form a heterocyclic ring having 4 to 8 ring members with at least one heteroatom selected from oxygen or nitrogen;

wherein R 2 is hydrogen or hydroxy;

wherein R 3 is hydrogen or hydroxy;

wherein R 4 is hydrogen, methyl, hydroxy, carboxyl, —R 12 —O—R 13 , or —R 12 —R 14 ,

wherein R 12 is a covalent bond or alkyl, and R 13 is C-amido or acyl, and R 14 is N-amido, —POR 15 R 16 , —SO 2 R 17 , or sulfonamido and wherein R 15 , R 16 , R 17 are independently alkoxy;

wherein R 5 is hydrogen, alkyl, alkenyl, alkynyl, aryl, or aralkyl;

wherein R 6 is hydrogen, alkyl, alkenyl, alkynyl, aryl, aralkyl, alkoxy, aryloxy, or aralkoxy;

wherein X 1 is —O—, —CO—, or —N—;

wherein X 2 is —O—, —N—, —NR 18 —, —CR 19 —, or —CO—,

wherein R 18 and R 19 is hydrogen, alkyl, alkenyl, alkynyl; or X 2 together with R 1 and the atom to which R 1 is attached form a heterocyclic ring having 4 to 8 ring members with at least one heteroatom selected from oxygen or nitrogen;

wherein X 4 is —O—, —CR 20 —, —CO—, or —N—, wherein R 20 is hydrogen, alkyl, alkenyl, alkynyl, or wherein X 4 together with R 1 and the atoms to which they are attached form a heterocyclic ring having 4 to 8 ring members with at least one heteroatom selected from oxygen or nitrogen;

wherein X 5 , is —CR 21 — or —N—, wherein R 21 is hydrogen, alkyl, alkenyl, alkynyl;

wherein X 6 , is —CR 22 — or —N—, wherein R 22 is hydrogen, alkyl, alkenyl, alkynyl, alkoxy, aryl, aralkyl, halogen, or nitro; or X 6 together with X 9 and the carbon at position 7 form a heterocyclic ring having 4 to 8 ring members with at least one heteroatom selected from oxygen or nitrogen;

wherein X 8 , is —CR 23 — or —N—, wherein R 23 is hydrogen, alkyl, alkenyl, alkynyl;

wherein X 9 is alkyl, alkenyl, alkynyl, ether, secondary or tertiary amino, or sulfanyl; or X 9 together with X 6 and the carbon at position 7 form a heterocyclic ring having 4 to 8 ring members with at least one heteroatom selected from oxygen or nitrogen;

and wherein at least one of X 1 , X 2 , X 4 , X 5 , X 6 , X 8 is not —CR—;

wherein n is 0, 1, 2, or 3.

2. The coumarin compounds of claim 1 wherein X 1 is —O— and X 2 is —CO—.

3. The isocoumarin compounds of claim 1 wherein X 1 is —CO— and X 2 is —O—.

4. The compounds of claim 1 wherein R 4 and R 5 are both hydrogen.

5. The compounds of claim 1 wherein R 4 and R 5 are independently hydrogen or methyl, and R 6 is hydrogen.

6. The compounds of claim 1 such X 1 is nitrogen, R 1 together with X 2 and the atom to which R 1 is attached form a heterocyclic ring according to the following Formula I(F):

wherein R a , R b and R c are independently hydrogen, alkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl, or aralkyl; and wherein R b may also be oxidized to form a carbonyl.

7. The compounds according to claim 6 wherein X 4 , X 5 , X 6 , and X 8 are all —CH—, R b is oxidized to form a carbonyl, and n is 1 according to the Formula I(F)(i):

8. The compounds according to claim 6 wherein X 9 is —O—, and R 2 and R 3 are hydroxyl, R 4 and R 5 are methyl, R 6 is methoxy, and n is 1 according to the Formula I(F)(ii):

9. The compounds of claim 1 such that X 1 is nitrogen, X 2 is —CO—, and R 1 together with X 4 and the atom to which R 1 is attached form a heterocyclic ring according to the following Formula I(G):

wherein R a , R b and R c are independently hydrogen, alkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl, or aralkyl; and wherein R b may also be oxidized to form a carbonyl.

10. The compounds according to claim 9 wherein X 4 , X 5 , X 6 , X 8 are all —CH—, and n is 1 according to the Formula I(G)(i):

11. The compounds according to claim 10 , wherein X 9 , is —O— and R 2 and R 3 are hydroxyl, R 4 and R 5 are methyl, R 6 is methoxy, and n is 1 according to the Formula I(G)(iii):

12. The compounds of claim 1 wherein that X 5 is nitrogen, X 1 is oxygen, and X 2 is —CO— according to the Formula I(H):

13. The compounds according to claim 12 wherein X 4 , X 6 , X 8 are all —CH—, and n is 1 according to the Formula I(H)(i):

14. The compounds according to claim 1 wherein R 5 is hydrogen, and R 2 and R 3 are independently —OH.

15. The compounds according to claim 1 wherein X 6 , is —CR 21 —, and R 21 is methoxy, ethoxy, or nitro, and R 2 and R 3 are independently —OH.

16. The compounds of claim 1 such that X 6 is carbon and X 9 is nitrogen, and X 6 together with X 9 and the carbon at position 7 form a heterocyclic ring according to the following Formula I(J):

wherein R a and R b are independently hydrogen, alkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl, or aralkyl; and wherein R b may also be oxidized to form a carbonyl.

17. The compounds according to claim 16 wherein R b is oxidized to form a carbonyl according to the Formula I(J)(i):

18. The compounds according to claim 17 wherein X 1 is —O— and X 2 is —CO—.

19. The compounds of claim 1 wherein X 1 is —CO— and X 2 is —NR 18 — according to the Formula I(K):

20. The compounds according to claim 19 wherein X 4 , X 5 , X 6 , X 8 are all —CH—, and n is 1 according to the Formula I(K)(i):

21. The compounds of claim 1 wherein X 4 , is —CR 20 — and R 20 is hydrogen and wherein X 8 is —CR 23 — and R 23 is hydrogen.

22. The compounds of claim 1 wherein that X 1 is —N— and X 2 is —CH— according to the Formula I(L):

23. The compounds according to claim 22 wherein X 4 , X 5 , X 6 , X 8 are all —CH— and n is 1 according to the Formula I(L)(i):

24. Dimers of the compounds of claim 1 , which are shown below:

wherein X is alkyl, alkenyl, alkynyl, aryl, alkylaryl, carbocylic, or heterocyclic.

25. Dimers of the compounds of claim 24 wherein R 2 and R 3 are both hydroxyl, and R 4 and R 5 are both methyl, and R 6 is methoxy according to the formula shown below:

26. A method of inhibiting heat-shock protein 90 activity by administering one of more of the compounds of claim 1 to a cell, and observing a decrease in the expression of a heat-shock protein 90 client protein.

27. The method of claim 26 wherein said client protein comprises Her-2, phospho-AKT, or HIF-1alpha.

28. The compounds of claim 1 selected from the group consisting of:

7-((2R,3R,4S,5R)-3,4-dihydroxy-5-methoxy-6,6-dimethyl-tetrahydro-2H-pyran-2-yloxy)-2H -chromen-2-one (B4);

7-((2R,3R,4S,5R)-3,4-dihydroxy-5-methoxy-6,6-dimethyl-tetrahydro-2H-pyran-2-yloxy)-4-methyl-3-phenyl-2H-chromen-2-one (C4);

8-(3,4-Dihydroxy-5-methoxy-6,6-dimethyl-tetrahydro-pyran-2-yloxy)-chromen-2-One (D4); and

6-(3,4-Dihydroxy-5-methoxy-6,6-dimethyl-tetrahydro-pyran-2-yloxy)-chromen-2-one (E4).

29. The compounds of claim 1 wherein R 1 is amido.

30. The compounds of claim 1 wherein R 1 is amido which is an N-amido according to —NR′COR″, wherein R′ and R″ are independently hydrogen, alkyl, alkenyl, alkynyl, alkoxy, carbocyclic, heterocyclic, aryl, or aralkyl.

31. The compounds of claim 1 wherein R 1 amido which is —NHCOCH 3 .

32. The compound of claim 1 which is

33. The compounds of claim 1 wherein X 4 is —CR 20 — and wherein R 20 is hydrogen.

34. The compound N-(7-((2R,3R,4S,5R)-3,4-dihydroxy-5-methoxy-6,6-dimethyl-tetrahydro-2H-py-ran-2-yloxy)-2-oxo-2H-chromen-3-yl) acetamide (A4).