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.

• Authors: I Mezö, S Lovas, I Pályi, B Vincze, A Kálnay, G Turi, Z Vadász, J Seprödi, M Idei, G Tóth, E Gulyás, F Otvös, M Mák, J E Horváth, I Teplán, R F Murphy
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 40 Issue 21 Pg. 3353-8 (Oct 10 1997) ISSN: 0022-2623 [Print] United States
• PMID: 9341910 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Antineoplastic Agents
• Oligopeptides
• Gonadotropin-Releasing Hormone

Topics

• Antineoplastic Agents (chemical synthesis, chemistry, pharmacology)
• Cell Division (drug effects)
• Chromatography, High Pressure Liquid
• Chromatography, Thin Layer
• Gonadotropin-Releasing Hormone (analogs & derivatives, chemical synthesis, chemistry, pharmacology)
• Humans
• Oligopeptides (chemical synthesis, chemistry, pharmacology)
• Protein Conformation
• Structure-Activity Relationship
• Tumor Cells, Cultured