title: Practical synthesis and evaluation of the biological activities of 1alpha,25-dihydroxyvitamin D3 antagonists, 1alpha,25-dihydroxyvitamin D3-26,23-lactams. Designed on the basis of the helix 12-folding inhibition hypothesis.
abstract: A practical synthetic route to novel vitamin D antagonists of DLAM (1alpha,25-dihydroxyvitamin D(3)-26,23-lactam) was developed from vitamin D(2) via the 1,3-dipolar cycloaddition reaction as a key step. Six DLAM derivatives (24 compounds) with a variety of nitrogen substituents and stereochemistries at C23 and C25 were synthesized. Among these new derivatives, (23S,25S)-DLAM isomers bound effectively to VDRs and showed antagonistic activity in the HL-60 cell differentiation inhibition assay. The importance of the substituent on the nitrogen of DLAMs for antagonistic activity was also suggested by computational docking studies.
authors.affiliation: Institute of Molecular and Cellular Biosciences, University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-0032, Japan.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Nakano
authors.forename: Yuko
authors.initials: Y
authors.lastname: Kato
authors.forename: Keisuke
authors.initials: K
authors.lastname: Imai
authors.forename: Eiji
authors.initials: E
authors.lastname: Ochiai
authors.forename: Jun-Ichi
authors.initials: J
authors.lastname: Namekawa
authors.forename: Seiichi
authors.initials: S
authors.lastname: Ishizuka
authors.forename: Kazuya
authors.initials: K
authors.lastname: Takenouchi
authors.forename: Aya
authors.initials: A
authors.lastname: Tanatani
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Hashimoto
authors.forename: Kazuo
authors.initials: K
authors.lastname: Nagasawa
mesh_terms: D000818:Animals; D001665:Binding Sites; D019556:COS Cells; D002117:Calcitriol / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D002454:Cell Differentiation / Q000187:drug effects; D002522:Chlorocebus aethiops; D019295:Computational Biology; D018360:Crystallography, X-Ray; D015195:Drug Design; D018922:HL-60 Cells; D006801:Humans; D007769:Lactams / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D008958:Models, Molecular; D008968:Molecular Conformation; D017433:Protein Structure, Secondary; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014807:Vitamin D / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors* / Q000737:chemistry
chemical_list: C510297:DLAM-1P compound; D007769:Lactams; D014807:Vitamin D; D002117:Calcitriol