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Synthesis of Gonadotropin-Releasing Hormone III Analogs. Structure−Antitumor Activity Relationships

1997; American Chemical Society; Volume: 40; Issue: 21 Linguagem: Inglês

10.1021/jm9700981

1520-4804

Imre Mező, Sándor Lovas, I Pályi, Borbála Vincze, Adrien Kálnay, Gizella Turi, Zsolt Vadász, János Seprődi, Miklós Idei, Géza Tóth, Éva Hunyadi‐Gulyás, Ferenc Ötvös, Mariann Mák, Judit Horváth, István Teplán, Richard F. Murphy,

DNA and Nucleic Acid Chemistry

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.