DESIGN AND SYNTHESIS OF TWO CYCLIC ANALOGUES OF GONADOTROPIN RELEASING HORMONE (GNRH) FOR THE TREATMENT OF CANCER

摘要

Gonadotropin releasing hormone (GnRH) stimulates production of gonadotropin hormones (FSH and LH) through interaction with specific receptors triggering important biological functions. A vast number of linear analogues of GnRH has been synthesized and tested for several medicinal uses. Triptorelin, Leuprolide, Buserelin, Goserelin, Nafarelin, Histrelin, are used in cancer treatment and reproductive disorders . In order to improve leuprolide's biological activity and bioavailability, two cyclic peptide analogues were designed and synthesized. Non natural amino-acid azetidine (Aze) at position 9 was used in order to reduce the proteolytic degradation of analogues. Moreover, substitution of Tyr~5 with Tyr(OMe) aimed at avoiding desensitization of GnRH receptors and introduction of D-Leu at position 6 intented to stabilize P-turn between aminoacids 5 to 8 (Tyr~5-Gly~6-Leu~7-Arg~8) of GnRH. Also, the usage of Pro and 3-aminobutyric acid at the N and C terminal respectively, simulates the important for activity residues pGlu and ethylamide of leuprolide (Fig. 1).