title: 22-Alkyl-20-epi-1alpha,25-dihydroxyvitamin D3 compounds of superagonistic activity: syntheses, biological activities and interaction with the receptor.
abstract: We previously reported that 22R-methyl-20-epi-1,25-(OH)2D3 (3) possesses strong binding affinity for the vitamin D receptor (VDR) and shows superagonistic biological activities. To examine the effect of the length of an alkyl substituent at C(22) and to extend our compound library, we successfully synthesized 22R-ethyl-20-epi-1,25-(OH)2D3 (4) and 22R-butyl-20-epi-1,25-(OH)2D3 (5). Surprisingly, 22-ethyl analogue 4 showed stronger VDR binding affinity and transactivation potency than the superagonist of methyl analogue 3, but its calcemic activity in vivo was weaker than that of both the methyl analogue 3 and the natural hormone (1), while 22-butyl analogue 5 showed activities comparable to those of the hormone (1). A study of the docking of these new analogues to the VDR-LBD and alanine scanning mutational analysis demonstrated that 22-methyl and 22-ethyl substituents enhance the favorable hydrophobic interactions with residues lining the ligand binding pocket of the VDR, and that 22-butyl analogue 5 binds to the VDR by an induced fit mechanism.
authors.affiliation: Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University, 2-3-10 Kanda-Surugadai, Tokyo 101-0062, Japan. yamamoto.mr@tmd.ac.jp
authors.forename: Keiko
authors.initials: K
authors.lastname: Yamamoto
authors.forename: Yuka
authors.initials: Y
authors.lastname: Inaba
authors.forename: Nobuko
authors.initials: N
authors.lastname: Yoshimoto
authors.forename: Mihwa
authors.initials: M
authors.lastname: Choi
authors.forename: Hector F
authors.initials: HF
authors.lastname: DeLuca
authors.forename: Sachiko
authors.initials: S
authors.lastname: Yamada
mesh_terms: D000818:Animals; D001665:Binding Sites; D001692:Biological Transport; D001842:Bone and Bones / Q000378:metabolism; D019556:COS Cells; D002117:Calcitriol / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D002417:Cattle; D002454:Cell Differentiation / Q000187:drug effects; D002522:Chlorocebus aethiops; D018922:HL-60 Cells; D006801:Humans; D066298:In Vitro Techniques; D007413:Intestinal Mucosa / Q000378:metabolism; D008024:Ligands; D008958:Models, Molecular; D009154:Mutation; D011869:Radioligand Assay; D051381:Rats; D018167:Receptors, Calcitriol / Q000037:antagonists & inhibitors* / Q000235:genetics; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D015533:Transcriptional Activation / Q000187:drug effects
chemical_list: C518985:22-butyl-1,25-dihydroxyvitamin D3; C518984:22-ethyl-1,25-dihydroxyvitamin D3; D008024:Ligands; D018167:Receptors, Calcitriol; D002117:Calcitriol; D002118:Calcium