Synthesis and use of .beta.-lapachone analogs

• US 5,763,625 A
• Filed: 04/25/1995
• Issued: 06/09/1998
• Est. Priority Date: 04/25/1995
• Status: Expired due to Fees

• Current Assignee: Wisconsin Alumni Research Foundation (University of Wisconsin System)
• Original Assignee: Wisconsin Alumni Research Foundation (University of Wisconsin System)
• Inventors: Boothman, David A., Witiak, Donald T., Frydman, Benjamin J.
• Primary Examiner(s): Richter, Johann
• Assistant Examiner(s): Oswecki, Jane C.
• Application Number:
  US08/428,574
• Time in Patent Office: 1,141 Days
• Field of Search: 549/390, 549/391, 549/393, 549/395
• US Class Current: 549/390
• CPC Class Codes: C07D 311/92 Naphthopyrans; Hydrogenated naphthopyrans

Abstract

3-Substituted-β-lapachone analogs and their use either alone or to augment chemotherapy or radiotherapy to induce programmed neoplastic cell death without exhibiting toxicity to surrounding normal cells are disclosed. In particular, 3-allyl-β-lapachones, 3-alkyl-β-lapachones and 3-halo-β-lapachones were found to be Topoisomerase (Topo I) inhibitors. When these analogs are used alone there is a reversible single-strand break in the DNA of neoplastic cells causing apoptosis and cell death in some cells. However, when these analogs are combined with chemotherapy or X-irradiation, an irreversible Topo I-mediated break is achieved. A new and more efficient chemical synthesis of the compounds is also disclosed.

Claims

1. A compound having the structure:

##STR5## wherein R is allyloxy, ethoxycarbonylmethyl, or ethoxycarbonylmethyl.

2. The compound of claim 1 wherein said compound is 3-ethoxycarbonylmethyl-β

-lapachone.

3. The compound of claim 1 wherein said compound is 3-ethoxycarbonylmethyloxy-β

-lapachone.

4. The compound of claim 1 wherein said compound is 3-allyloxy-β

-lapachone.

5. A method of enhancing the lethality of a DNA damaging agent in neoplastic cells comprising the steps of:

a. exposing a neoplastic cell to a DNA damaging agent, and

b. subjecting the neoplastic cell to a 3-substituted 3-lapachone selected from the group consisting of ##STR6## wherein R is allyloxy, --O--(CH₂)_n --R₁, or (CH₂)_n --R₁ where n is an integer from 0-10 and R₁ is hydroxy, an alklcarboxy, a heteroaromatic, a heterocyclic, an amine, a thiol, an amide, or a halogen.

6. The method of claim 5 wherein said DNA damaging agent is radiotherapy.

7. The method of claim 5 wherein said DNA damaging agent is chemotherapy.

8. The method of claim 5 wherein said 3-substituted β

-lapachone is 3-allyl-β

-lapachone.

9. The method of claim 5 wherein said 3-substituted β

-lapachone is 3-ethoxycarbonylmethyl-β

-lapachone.

10. The method of claim 5 wherein said 3-substituted β

-lapachone is 3-(2'"'"'-Hydroxyethyl)-β

-lapachone.

11. The method of claim 5 wherein said 3-substituted β

-lapachone is 3-methyl-β

-lapachone.

12. The method of claim 5 wherein said 3-substituted β

-lapachone is 3-(2'"'"'-aminoethyl)-β

-lapachone.

13. The method of claim 5 wherein said 3-substituted β

-lapachone is 3-hydroxy-β

-lapachone.

14. The method of claim 5 wherein said 3-substituted β

-lapachone is 3-methoxy-β

-lapachone.

15. The method of claim 5 wherein said 3-substituted β

-lapachone is 3-benzyloxy-β

-lapachone.

16. The method of claim 5 wherein said 3-substituted β

-lapachone is 3-ethoxycarbonylmethoxy-β

-lapachone.

17. The method of claim 5 wherein said 3-substituted-β

-lapachone is 3-allyloxy-β

-lapachone.

18. A method of chemotherapy comprising the step of:

exposing a neoplastic cell to a 3-substituted-β

-lapachone in sufficient amounts to induce cell death.

19. The method of claim 18 wherein the 3-substituted β

-lapachone is present in an amount of from about 0.7 μ

M to about 10 μ

M.

20. The method of claim 18 wherein the neoplastic cell is selected from human neoplastic melanoma, lung, breast, prostate, leukemia and colon cells.

21. The method of claim 18 wherein said 3-substituted β

-lapachone has the structure;

##STR7## wherein R is allyloxy, --O--(CH₂)_n --R₁, or (CH₂)_n --R₁ where n is an integer from 0-10 and R₁ is hydroxy, an alkylcarboxy, a heteroaromatic, a heterocyclic, an amine, a thiol, an amide, or a halogen.

22. The method of claim 18 wherein said cell death is via apoptosis.

23. The method of claim 18 wherein said cell death is via necrosis.

24. The method of claim 18 wherein said 3-substituted-β

-lapachone is 3-allyl-β

-lapachone.

25. The method of claim 18 wherein said 3-substituted-β

-lapachone is 3-ethoxycarbonylmethyl-β

-lapachone.

26. The method of claim 18 wherein said 3-substituted-β

-lapachone is 3-(2'"'"'-hydroxyethyl)-β

-lapachone.

27. The method of claim 18 wherein said 3-substituted-β

-lapachone is 3-methyl-β

-lapachone.

28. The method of claim 18 wherein said 3-substituted β

-lapachone is 3-hydroxy-β

-lapachone.

29. The method of claim 18 wherein said 3-substituted-β

-lapachone is 3-methoxy-β

-lapachone.

30. The method of claim 18 wherein said 3-substituted-β

-lapachone is 3-benzyloxy-β

-lapachone.

31. The method of claim 18 wherein said 3-substituted-β

-lapachone is 3-ethoxycarbonylmethoxy-β

-lapachone.

32. The method of claim 18 wherein said 3-substituted-β

-lapachone is 3-allyloxy-β

-lapachone.