Elucidation and synthesis of antineoplastic tetrapeptide phenethylamides of dolastatin 10

• US 6,034,065 A
• Filed: 12/03/1992
• Issued: 03/07/2000
• Est. Priority Date: 12/03/1992
• Status: Expired due to Term

• Current Assignee: Arizona Board of Regents (University of Arizona)
• Original Assignee: Arizona Board of Regents (University of Arizona)
• Inventors: Barkoczy, Jozsef, Pettit, George R.
• Primary Examiner(s): Huff, Sheela
• Application Number:
  US07/985,831
• Time in Patent Office: 2,651 Days
• Field of Search: 530/330, 514/18
• US Class Current: 514/19.3
• 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

Dolastatin 10, a linear pentapeptide, has shown potent antineoplastic activity profiles against various experimental cancer systems.

The design and synthesis of structural modifications of dolastatin 10 having significant antineoplastic activity against human cancer cell lines has been accomplished. Members of this group have demonstrated significant antineoplastic activity against selected human cancer cell lines. Especially: Ovarian OVSCAR-3; Central Nervous System ("CNS") SF295; Renal A498; Lung NCI460; Colon KM20L2 and Melanoma SK-MEL-3.

Claims

1. A composition of matter comprising a compound having the general structure:

##STR4## wherein n is selected from the group consisting of 1, 2, and 3.

15. A composition of matter according to claim 1 wherein n=1.

16. A composition of matter according to claim 1 wherein n=2.

17. A composition of matter according to claim 1 wherein n=3.

18. A pharmaceutical preparation comprising a compound having the structure set forth in claim 1.

2. A method of inhibiting the growth of abnormal human cells selected from the group consisting of leukemia, non-small cell lung cancer, colon cancer, CNS cancer, melanoma, ovarian cancer, and renal cancer;

comprising engaging said cells with a growth inhibitory amount of a compound having the following structural formula;

##STR5## wherein n is selected from the group consisting of 1, 2, and 3.

3. A method according to claim 2 wherein said abnormal cells are selected from the group of abnormal cell lines having the following NCI cell line designations:

P-388, OVCAR-3, SF-295, A498, NCI 460, KM20L2, and SK-MEL-3.

4. A method according to claim 3 wherein n=1.

5. A method according to claim 3 wherein n=3.

6. A method according to claim 2 wherein n=2.

7. A method according to claim 6 wherein said abnormal human cells are selected from the group consisting of leukemia cell lines having the NCI Cell Line designations:

CCRF-CEM, HL-60(TB), K-562, MOLT-4, RPM-8226 and SR.

8. A method according to claim 6 wherein said abnormal human cells are selected from the group consisting of Non-Small Cell Lung Cancer Cell Lines having the NCI Cell Line designations:

A549/ATCC, EXVX, HOP-62, HOP-92, NCI-H226, NCI-H23, NCI-H460, NCI-H522, and LXFL-529.

9. A method according to claim 6 wherein said abnormal cells are selected from the group consisting of Colon Cancer Cell Lines having the NCI Cell Line designations:

C0L0 205, DLD-1, HCT-116, HCT-15, KM20L2 and SW-620.

10. A method according to claim 6 wherein said abnormal cells are selected from the group consisting of CNS Cancer Cell Lines having the NCI Cell Line designations:

SF-268, SF-539, SNB-19, SNB-75, SNB-78 and U251.

11. A method according to claim 6 wherein said abnormal cells are selected from the group consisting of Melanoma Cancer Cell Lines having the NCI Cell Line designations:

LOX1MV1, MALMB-3M, M14, M19-MEL, SK-MEL-2, SK-MEL-5, and UACC-62.

12. A method according to claim 6 wherein said abnormal cells are selected from the group consisting of Ovarian Cancer Cell Lines having the NCI Cell Line designations:

1GROV1, OVCAR-5, OVCAR-8, and SK-OV-3.

13. A method according to claim 6 wherein said abnormal cells are selected from the group consisting of Renal Cancer Cell Lines having the NCI Cell Line designations:

786-O, ACHN, CAK1-1, RXP-393, SN12C, TK-10, and UO-31.

14. A method according to claim 3 wherein n=2.