Elucidation and synthesis of selected pentapeptides

• US 5,780,588 A
• Filed: 01/26/1993
• Issued: 07/14/1998
• Est. Priority Date: 01/26/1993
• Status: Expired due to Fees

• Current Assignee: Arizona Board of Regents (University of Arizona)
• Original Assignee: Arizona Board of Regents (University of Arizona)
• Inventors: Srirangam, Jayaram K., Pettit, George R.
• Primary Examiner(s): Hill, Jr., Robert J.
• Assistant Examiner(s): Lukton, David
• Application Number:
  US08/009,296
• Time in Patent Office: 1,995 Days
• Field of Search: 514/15, 514/17, 530/330, 530/323
• US Class Current: 530/330
• CPC Class Codes: A61K 38/00 Medicinal preparations containing peptides peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: C07K 5/0205 containing the structure -NH-(X)3-C(=0)-, e.g. statine or derivatives thereof

Abstract

The sea hare Dolabella auricularia has yielded many structurally distinct peptides which possess antineoplastic activity. Presently the compound denominated "dolastatin 10" represents the most important of such peptides because of its demonstrated potential as an anticancer drug.

The present invention relates to the systematic creation of five unique pentapeptides by selectively coupling a tripeptide-trifluoroacetate salt with a preselected dipeptide-trifluoroacetate salt which provide active molecules capable of emulating the measured therapeutic effect of dolastatin 10. The pentapeptides hereof have the structure shown below: ##STR1## wherein R is selected from the following group of substituents: ##STR2##

Claims

1. A composition of matter having the structural formula designated 3(a-e):

##STR5## wherein R is selected from the following group of substituents;

##STR6##

2. A composition of matter according to claim 1 in which R is the substituent designated a.

3. A composition of matter according to claim 1 in which R is the substituent designated b.

4. A composition of matter according to claim 1 in which R is the substituent designated c.

5. A composition of matter according to claim 1 in which R is the substituent designated d.

6. A composition of matter according to claim 1 in which R is the substituent designated e.

7. A method for inhibiting the growth of human cancer cells wherein said cancer is selected from the group consisting of leukemia, ovarian cancer, CNS cancer, mammary cancer, non-small cell lung cancer, renal cancer, colon cancer, and melanoma consisting of administering an active ingredient selected from the group consisting of:

Dov-Val-Dil-Dap-Phe-OCH₃, Dov-Val-Dil-Dap-Phe-NH₂, Dov-Val-Dil-Dap-Pro-OCH₃, Dov-Val-Dil-Dap-Ile-OCH₃, and Dov-Val-Dil-Dap-Met-OCH₃, to said cells in a quantity sufficient to inhibit the growth of said cells.

8. A method according to claim 7 wherein said active ingredient consists of Dov-Val-Dil-Dap-Phe-OCH₃.

9. A method according to claim 7 wherein said active ingredient consists of Dov-Val-Dil-Dap-Phe-NH₂.

10. A method according to claim 7 wherein said active ingredient consists of Dov-Val-Dil-Dap-Pro-OCH₃.

11. A method according to claim 7 wherein said active ingredient consists of Dov-Val-Dil-Dap-Ile-OCH₃.

12. A method according to claim 7 wherein said active ingredient consists of Dov-Val-Dil-Dap-Met-OCH₃.

13. A method according to claim 7 for inhibiting the growth of human cancer cells selected from the group of cell lines consisting of P388 Lymphotic Leukemia, L1210 Lumphatic Leukemia, B16 Melanoma, M5076 Ovary Sarcoma, LOX Human Melanoma, Human Mammary MX-7, and OVCAR-3, consisting of administering an active ingredient selected from the group consisting of Dov-Val-Dil-Dap-Phe-OCH₃, Dov-Val-Dil-Dap-Phe-NH₂, Dov-Val-Dil-Dap-Pro-OCH₃, Dov-Val-Dil-Dap-Ile-OCH₃, and Dov-Val-Dil-Dap-Met-OCH₃, to said cells in a quantity sufficient to inhibit the growth of said cells.

14. A method according to claim 7 wherein said cancer is selected from the group of cell lines consisting of P388, OVCAR-3, SF-295, A498, NCI-H460, KM20L2, and SK-MEL-3.

15. A method according to claim 14 wherein said active ingredient consists of Dov-Val-Dil-Dap-Phe-OCH₃.

16. A method according to claim 14 wherein said active ingredient consists of Dov-Val-Dil-Dap-Phe-NH₂.

17. A method according to claim 14 wherein said active ingredient consists of Dov-Val-Dil-Dap-Pro-OCH₃.

18. A method according to claim 14 wherein said active ingredient consists of Dov-Val-Dil-Dap-Ile-OCH₃.

19. A method according to claim 14 wherein said active ingredient consists of Dov-Val-Dil-Dap-Met-OCH₃.