Isolation and structural elucidation of the cytostatic linear depsipeptides dolastatin 13 and dehydrodolastatin 13

• US 4,986,988 A
• Filed: 05/18/1989
• Issued: 01/22/1991
• Est. Priority Date: 05/18/1989
• Status: Expired due to Term

• Current Assignee: Arizona Board of Regents (University of Arizona)
• Original Assignee: Arizona Board of Regents (University of Arizona)
• Inventors: Kamano, Yoshiaki, Pettit, George R.
• Primary Examiner(s): Cashion, Jr., Merrell C.
• Assistant Examiner(s): AZPURU, CARLOS A
• Application Number:
  US07/353,960
• Time in Patent Office: 614 Days
• Field of Search: 424/95, 424/104, 514/764-765
• US Class Current: 424/520
• 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: A61P 35/02 specific for leukemia
• CPC Class Codes: C07K 11/02 cyclic, e.g. valinomycins ; Derivatives thereof

Abstract

The Indian Ocean sea hare Dolabella auricularia has been found to contain a new cell growth inhibitory and antineoplastic (P388 leukemia) cyclodepsipeptide designated dolastatin 13.sup.(1) and a companion substance dehydrodolastatin 13.sup.(2). A series of high field (400 MHz) 2D-NMR experiments including sequential analyses by HMBC and NOE techniques and tandem mass spectrometry provided structural determinations. Dolastatin 13 and dehydrodolastatin 13 represent a new class of cyclodepsipeptides. Pharmaceutical preparations and therapeutic regimens employing these new cytostatic depsipeptides are disclosed. The depsipeptides have the following structure: ##STR1##

Claims

1. A cell growth inhibitory substance denominated dolastatin 13 having the structural formula:

##STR5## wherein;

R₁ =OH;

R₂ =H.

2. A cell growth inhibitory substance denominated dehydrodolastation 13 having the structural formula:

##STR6## wherein;

R₁ =R₂ =Δ

¹³,15.

3. A pharmaceutical preparation comprising a pharmaceutically acceptable carrier and an amount effective to inhibit cell growth of a natural or synthetic substance or a non-toxic pharmaceutically active derivative thereof, said substance having the structural formula:

##STR7## wherein;

R₁ =OH;

R₂ =H.

4. A pharamaceutical preparation comprising a pharmaceutically acceptable carrier and an amount effective to inhibit cell growth of a natural or synthetic substance or a non-toxic pharmaceutically active derivative thereof, said substance having the structural formula:

##STR8## wherein;

R₁ =R₂ =Δ

¹⁴,15.