title: Structure-activity studies of lGnRH-III through rational amino acid substitution and NMR conformational studies.
abstract: Lamprey gonadotropin-releasing hormone type III (lGnRH-III) is an isoform of GnRH isolated from the sea lamprey (Petromyzon marinus) with negligible endocrine activity in mammalian systems. Data concerning the superior direct anticancer activity of lGnRH-III have been published, raising questions on the structure-activity relationship. We synthesized 21 lGnRH-III analogs with rational amino acid substitutions and studied their effect on PC3 and LNCaP prostate cancer cell proliferation. Our results question the importance of the acidic charge of Asp⁶ for the antiproliferative activity and indicate the significance of the stereochemistry of Trp in positions 3 and 7. Furthermore, conjugation of an acetyl-group to the side chain of Lys⁸ or side chain cyclization of amino acids 1-8 increased the antiproliferative activity of lGnRH-III demonstrating that the proposed salt bridge between Asp⁶ and Lys⁸ is not crucial. Conformational studies of lGnRH-III were performed through NMR spectroscopy, and the solution structure of GnRH-I was solved. In solution, lGnRH-III adopts an extended backbone conformation in contrast to the well-defined β-turn conformation of GnRH-I.
authors.affiliation: Department of Pharmacy, University of Patras, Greece. el2pappa@yahoo.gr
authors.forename: Eleni V
authors.initials: EV
authors.lastname: Pappa
authors.forename: Aikaterini A
authors.initials: AA
authors.lastname: Zompra
authors.forename: Zoi
authors.initials: Z
authors.lastname: Diamantopoulou
authors.forename: Zinovia
authors.initials: Z
authors.lastname: Spyranti
authors.forename: George
authors.initials: G
authors.lastname: Pairas
authors.forename: Fotini N
authors.initials: FN
authors.lastname: Lamari
authors.forename: Panagiotis
authors.initials: P
authors.lastname: Katsoris
authors.forename: George A
authors.initials: GA
authors.lastname: Spyroulias
authors.forename: Paul
authors.initials: P
authors.lastname: Cordopatis
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D007987:Gonadotropin-Releasing Hormone / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D011471:Prostatic Neoplasms / Q000188:drug therapy; D011487:Protein Conformation; D011761:Pyrrolidonecarboxylic Acid / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; C448022:gonadotropin-releasing hormone-III; D007987:Gonadotropin-Releasing Hormone; D011761:Pyrrolidonecarboxylic Acid