Isolation and structural elucidation of the cytostatic linear and cyclo-depsipeptides dolastatin 16, dolastatin 17, and dolastatin 18

• US 6,239,104 B1
• Filed: 12/01/1999
• Issued: 05/29/2001
• Est. Priority Date: 02/25/1997
• Status: Expired due to Term

• Current Assignee: Arizona Board of Regents (University of Arizona)
• Original Assignee: Arizona Board of Regents (University of Arizona)
• Inventors: Xu, Jun-ping, Pettit, George R.
• Primary Examiner(s): Low, Christopher S. F.
• Assistant Examiner(s): Tu, Stephen
• Application Number:
  US09/380,016
• Time in Patent Office: 545 Days
• Field of Search: 424/520, 514/9, 514/16, 514/17, 514/19, 530/323, 530/329, 530/330, 530/333, 548/204
• US Class Current: 514/19.2
• 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 11/00 Depsipeptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
• CPC Class Codes: C07K 5/06043 Leu-amino acid

Abstract

Cytostatic linear and cyclo-depsipeptides, “Dolastatin 16”, “Dolastatin 18”, and “Dolastatin 17”, are disclosed which are obtained from Indian Ocean shelless mollusk Dolabella auricularia. Methods of using the substances to inhibit malignant cell growth associated with neoplastic diseases in animals and humans are also disclosed, as well as pharmaceutical preparations containing Dolastatin 16, Dolastatin 17, and Dolastatin 18.

Claims

1. An isolated and purified substance which inhibits neoplastic cell growth denominated Dolastatin 16 and having the following characteristics:

Physical Data for Dolastatin 16

IR (cm<sup>−

1</sup>), KBr;

3300, 1600 and 1540;

UV (nm), MeOH;

250, and 240-210;

MS, HRFAB;

871.525713 [M+H]⁺; and

NMR, 500 MHZ, CLCl₃;

2. An isolated cell growth inhibitory substance according to claim 1 and having the structural formula (HMBC () and nOe () correlations):

3. An isolated and purified substance which inhibits neoplastic cell growth denominated Dolastatin 17 and having the following characteristics:

Physical Data for Dolastatin 17

IR (cm<sup>−

1</sup>), KBr;

3350,2900,2116,1740,1643, and 1520;

MS, HRFAB;

774.500914 [M+H]⁺; and

NMR, 500 MHZ, CDCl₃;

4. An isolated cell growth inhibitory substance according to claim 3 and having the structural formula (HMBC () and nOe () correlations):

5. An isolated and purified substance which inhibits neoplastic cell growth denominated Dolastatin 18 and having the following characteristics:

Physical Data for Dolastatin 18

MS, HRFAB;

619 [M+H]⁺; and

NMR, 500 MHZ, CDCl₃;

6. An isolated cell growth inhibitory substance according to claim 5 and having the structural formula (HMBC () correlations):

7. A method of inhibiting the growth of neoplastic cells in a host afflicted therewith comprising administering to said host an amount effective to inhibit the growth of said cells of an active ingredient selected from the group consisting of dolastatin 16, dolastatin 17, dolastatin 18 or a pharmaceutically active derivative thereof and a pharmaceutically acceptable carrier.

8. A method according to claim 7 in which active ingredient has the structural formula;

9. A method according to claim 7 in which active ingredient has the structural formula:

10. A method according to claim 7 in which active ingredient has the structural formula: