Arizona State University

Arizona Board of Regents, a Body Corporate

Jayaram K Srirangam

George R Pettit

Michael D Williams

Darko Kantoci

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##

Elucidation and synthesis of selected pentapeptides

This application discloses seven newly synthesized pentapeptide amides and our tetrapeptide amides. The synthesis utilized both naturally occurring and modified amino acids; the modified amino acids are constituents of the well known dolastatin 10 and dolastatin 15 which are structurally distinct peptides with excellent antineoplastic activity. These peptides were constructed by introducing a peptide bond between selected amino acids and modified amino acids and coupling the resulting di- and tri-peptides to obtain peptides having a high anticancer activity against a series of human cancer cell lines. ##STR1##

Human cancer inhibitory peptide amides

The synthesis and elucidation of nineteen heterocyclic or halophenyl amide erivatives of dolastatin 10 are disclosed. These compounds and the methods of producing those compounds offer demonstrated significant in vitro activity against several human cancer cell lines. These compounds and the methods of producing those compounds offer a commercially viable alternative to natural and synthetic dolastatin 10.

Human cancer inhibitory pentapeptide heterocyclic and halophenyl amides

The sea hare Dolabella auricularia has yielded many structurally distinct ptides 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 seven 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.

Cancer inhibitory peptides

The isolation, elucidation and synthetic replication of novel pentapeptide mides and esters are described. The compounds have the general structure ##STR1## in which R.sub.1 and R.sub.2 are selected as shown below: ##STR2##

Human cancer inhibitory pentapeptide amides and esters

Herein disclosed are several pentapeptide methyl ester derivatives of dolatin 10, using both naturally occurring and modified amino acids. The selected modified amino acids are constituents of dolastatin 10 which is a structurally distinct peptide with excellent in vitro and in vivo antineoplastic activity. The structures of these compounds are as shown below: ##STR1##

Human cancer inhibitory pentapeptide methyl esters

The cytostatic cycloheptapeptide stylostatin 2 was isolated respectively, from the South and Western Pacific Ocean sponges Stylotella sp. and Phakellia costata. Structural determination was accomplished by utilizing high-field (500 MHz) 2D-NMR experiments and confirmed by an X-ray crystal structure determination to provide the assignment cyclo(Pro-Leu-Ile-Phe-Ser-Pro-Ile). The absolute configuration was established by chiral gas chromatographic analytical technique. The cyclic heptapeptide backbone was found to include a .beta.-turn, type VIa, incorporating a cis peptide bond, at -Ser-Pro.

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Tempe, AZ, United States of America

Jayaram K Srirangam