title: Design and synthesis of potent vitamin D receptor antagonists with A-ring modifications: remarkable effects of 2alpha-methyl introduction on antagonistic activity.
abstract: Novel A-ring analogues of the vitamin D receptor (VDR) antagonist (3a), ZK-159222, and its 24-epimer (3b) were convergently synthesized. Preparation of the CD-ring portions with the side chains of 3a,b, followed by palladium-catalyzed cross-coupling with the A-ring enyne precursors (15a,b), (3S,4S,5R)- and (3S,4S,5S)-bis[(tert-butyldimethylsilyl)oxy]-4-methyloct-1-en-7-yne, afforded the 2alpha-methyl-introduced analogues (4a,b) and their 3-epimers (5a,b). The biological profiles of the hybrid analogues were assessed in terms of affinity for VDR, and antagonistic activity to inhibit HL-60 cell differentiation induced by the natural hormone, 1alpha,25-dihydroxyvitamin D(3). The analogue 4a showed an approximately fivefold higher antagonistic activity compared with 3a. The 2alpha-methyl introduction into 3a increased the receptor affinity, thereby enhancing VDR antagonism. This approach to design potent antagonists based on hybridization of structural motifs in the A-ring and in the side chain may prove to be valuable.
authors.affiliation: Faculty of Pharmaceutical Sciences, Teikyo University, 199-0195, Sagamiko, Kanagawa, Japan. akittaka@pharm.teikyo-u.ac.jp
authors.forename: Toshie
authors.initials: T
authors.lastname: Fujishima
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Kojima
authors.forename: Isao
authors.initials: I
authors.lastname: Azumaya
authors.forename: Atsushi
authors.initials: A
authors.lastname: Kittaka
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Takayama
mesh_terms: D000818:Animals; D002117:Calcitriol / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D002417:Cattle; D015195:Drug Design; D015394:Molecular Structure; D010165:Palladium / Q000737:chemistry; D018167:Receptors, Calcitriol / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D018167:Receptors, Calcitriol; C410228:ZK159222; D010165:Palladium; D002117:Calcitriol