Novobiocin analogues as anticancer agents

1. A compound according to Formula I

wherein R 1 is hydrogen, alkyl, aryl or amido;

wherein R 2 is hydrogen; hydroxy or —R 8 —OR 9 , wherein R 8 is a covalent bond or alkyl, and R 9 is C-amido or acyl; or R 2 together with R 3 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 R 3 is hydrogen; hydroxy or —R 10 —OR 11 , wherein R 10 is a covalent bond or alkyl, and R 11 is C-amido or acyl; or R 3 together with R 2 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 R 4 is hydrogen or methyl;

wherein R 5 is hydrogen or alkyl;

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 are hydrogen, alkyl, alkenyl, or alkynyl;

wherein X 4 is —CR 20 —, wherein R 20 is hydrogen, alkyl, alkenyl, or alkynyl;

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

wherein X 6 is —CR 22 —, wherein R 22 is hydrogen, alkyl, alkenyl, alkynyl, alkoxy, aryl, aralkyl, halogen, or nitro;

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

wherein X 9 is ether;

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

wherein n is 1; and

wherein R 2 and R 3 are not simultaneously hydroxy.

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

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

4. The compound of claim 2 wherein R 4 and R 5 are both methyl.

5. The compound of claim 2 wherein X 4 is —CR 20 — and R 20 is hydrogen, and wherein X 8 is —CR 23 — and R 23 is hydrogen or alkyl.

6. The compound of claim 5 wherein R 1 is amido.

7. The compound of claim 6 selected from the group consisting of:

N-(7-((3aR,4R,7R,7aR)-7-methoxy-6,6-dimethyl-2-oxo-tetrahydro-3aH-[1,3]dioxolo[4,5-c]pyran-4-yloxy)-2-oxo-2H-chromen-3-yl)acetamide (A1);

(2R,3R,4R,5R)-2-(3-acetamido-2-oxo-2H-chromen-7-yloxy)-4-hydroxy-5-methoxy-6,6-dimethyl-tetrahydro-2H-pyran-3-yl carbamate (A2);

(3R,4S,5R,6R)-6-(3-acetamido-2-oxo-2H-chromen-7-yloxy)-5-hydroxy-3-methoxy-2,2-dimethyl tetrahydro-2H-pyran-4-yl carbamate (A3); and

4-deshydroxy-8-desmethylnovobiocin.

8. The compound of claim 5 wherein R 1 is hydrogen.

9. The compound of claim 8 selected from the group consisting of:

7-((3aR,4R,7R,7aR)-7-methoxy-6,6-dimethyl-2-oxo-tetrahydro-3 aH-[1,3]dioxolo[4,5-c]pyran-4-yloxy)-2H-chromen-2-one (B1);

(3R,4S,5R,6R)-5-hydroxy-3-methoxy-2,2-dimethyl-6-(2-oxo-2H-chromen-7-yloxy)-tetrahydro-2H-pyran-4-yl carbamate (B2);

(2R,3R,4R,5R)-4-hydroxy-5-methoxy-6,6-dimethyl-2-(2-oxo-2H-chromen-7-yloxy)-tetrahydro-2H-pyran-3-yl carbamate (B3).

10. The compound of claim 2 wherein X 4 , is —CR 20 — and R 20 is alkyl and wherein R 1 is aryl.

11. The compound of claim 10 selected from the group consisting of:

7-((3aR,4R,7R,7aR)-7-methoxy-6,6-dimethyl-2-oxo-tetrahydro-3 aH-[1,3]dioxolo[4,5-c]pyran-4-yloxy)-4-methyl-3-phenyl-2H-chromen-2-one (C1);

(3R,4S,5R,6R)-5-hydroxy-3-methoxy-2,2-dimethyl-6-(4-methyl-2-oxo-3-phenyl-2H-chromen-7-yloxy)-tetrahydro-2H-pyran-4-yl carbamate (C2); and

(2R,3R,4R,5R)-4-hydroxy-5-methoxy-6,6-dimethyl-2-(4-methyl-2-oxo-3-phenyl-2H-chromen-7-yloxy)-tetrahydro-2H-pyran-3-yl carbamate (C3).

12. The compound of claim 2 wherein X 4 is —CR 20 — and R 20 is hydrogen, and wherein X 8 is —CR 23 — and R 23 is alkyl.

13. The compound of claim 12 wherein R 1 is amido.

14. The compound of claim 13 selected from the group consisting of:

4-deshydroxynovobiocin (DHN1); and

(3R,4S,5R,6R)-6-(3-acetamido-2-oxo-2H-chromen-7-yloxy)-8-methyl-5-hydroxy-3-methoxy-2,2-dimethyltetrahydro-2H-pyran-4-yl carbamate (8-methyl A3).

15. A compound according to Formula II:

wherein R 2 is hydrogen; hydroxy or —R 8 —OR 9 , wherein R 8 is a covalent bond or alkyl, and R 9 is C-amido or acyl; or R 2 together with R 3 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; and

wherein R 3 is hydrogen; hydroxyl or —R 10 —OR 11 , wherein R 10 is a covalent bond or alkyl, and R 11 is C-amido or acyl; or R 3 together with R 2 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.

16. The compound of claim 15 selected from the group consisting of:

8-(7-Methoxy-6,6-dimethyl-2-oxo-tetrahydro-[1,3]dioxolo[4,5-c]pyran-4-yloxy)-chromen-2-one (D1);

Carbamic acid 4-hydroxy-5-methoxy-6,6-dimethyl-2-(2-oxo-2H-chromen-8-yloxy)-tetrahydro-pyran-3-yl ester (D2);

Carbamic acid 5-hydroxy-3-methoxy-2,2-dimethyl-6-(2-oxo-2H-chromen-8-yloxy)-tetrahydro-pyran-4-yl ester (D3); and

8-(3,4-Dihydroxy-5-methoxy-6,6-dimethyl-tetrahydro-pyran-2-yloxy)-chromen-2-one (D4).

17. A compound according to Formula III:

wherein R 2 is hydrogen; hydroxy or —R 8 —OR 9 , wherein R 8 is a covalent bond or alkyl, and R 9 is C-amido or acyl; or R 2 together with R 3 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; and

wherein R 3 is hydrogen; hydroxyl or —R 10 —OR 11 , wherein R 10 is a covalent bond or alkyl, and R 11 is C-amido or acyl; or R 3 together with R 2 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.

18. The compound of claim 17 selected from the group consisting of:

6-(7-Methoxy-6,6-dimethyl-2-oxo-tetrahydro-[1,3]dioxolo[4,5-c]pyran-4-yloxy)-chromen-2-one [E1];

Carbamic acid 5-hydroxy-3-methoxy-2,2-dimethyl-6-(2-oxo-2H-chromen-6-yloxy)-tetrahydro-pyran-4-yl ester (E2);

Carbamic acid 4-hydroxy-5-methoxy-6,6-dimethyl-2-(2-oxo-2H-chromen-6-yloxy)-tetrahydro-pyran-3-yl ester (E3); and

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