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Synthesis of gonadotropin-releasing hormone III analogs. Structure-antitumor activity relationships.

Abstract：

:Following the observation that the activity of gonadotropin-releasing hormone III (GnRH-III) in the suppression of growth of MDA-MB-231 and MCF-7 breast cancer cells surpasses that of GnRH and other analogs thereof, analogs of GnRH-III were synthesized to investigate the structural basis for the improved antitumor activity. Compounds synthesized include analogs with changes in the central sequence in which GnRH-III differs from GnRH and in the C- and N-terminal regions. The results indicate that a salt bridge between Asp6 and Lys8 stabilizes the active conformation of GnRH-III and show the importance of the Trp7. Replacement of the C-terminal Gly-NH2 with D-Ala-NH2 was not well tolerated, but replacement with ethylamide was. Replacement of pGlu1 with Ac-D-Trp appears to have a significantly deleterious effect on a unique conformation of GnRH-III which is responsible for its binding to the receptors on cancer cell lines and the resultant antitumor activity.

journal_name

J Med Chem

journal_title

Journal of medicinal chemistry

authors

Mezö I,Lovas S,Pályi I,Vincze B,Kálnay A,Turi G,Vadász Z,Seprödi J,Idei M,Tóth G,Gulyás E,Otvös F,Mák M,Horváth JE,Teplán I,Murphy RF

doi

10.1021/jm9700981

subject

Has Abstract

pub_date

1997-10-10 00:00:00

pages

3353-8

issue

21

eissn

0022-2623

issn

1520-4804

pii

jm9700981

journal_volume

40

pub_type

杂志文章

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