title: Synthesis of the CYP24A1 major metabolite of 2α-[2-(tetrazol-2-yl)ethyl]-1α,25-dihydroxyvitamin D3.
abstract: Previously, we found that 2α-[2-(tetrazol-2-yl)ethyl]-1α,25-dihydroxyvitamin D3(AH-1) showed higher osteocalcin promoter transactivation activity in human osteosarcoma (HOS) cells and a greater therapeutic effect on ovariectomized (OVX) rats for enhancing bone mineral density than those of 1α,25(OH)2D3without hypercalcemic side effects in vivo. Although CYP24A1 catalyzes multi-step oxidations toward the CD-ring side chain of the active vitamin D3[1α,25(OH)2D3], the CYP24A1-dependent metabolism of AH-1 tended to stop at the first step hydroxylation at the C24-position of AH-1. Interestingly, the metabolite 24-hydroxy-AH-1 [24(OH)AH-1] showed potent VDR binding affinity, and the new chiral center of the 24-position might be the 24R configuration compared with the process of the natural 1α,25(OH)2D3catabolism. This time, (24R)-2α-[2-(tetrazol-2-yl)ethyl]-1α,24,25-trihydroxyvitamin D3[(24R-OH)AH-1] was synthesized as a candidate for the major metabolite of AH-1 using the Trost Pd-mediated coupling reaction between A-ring and CD-ring precursors to identify the metabolite and evaluate its biological activity. We confirmed that the CYP24A1-dependent major metabolite of AH-1 was (24R-OH)AH-1 by HPLC analyses.
authors.affiliation: Faculty of Pharmaceutical Sciences, Teikyo University, 2-11-1 Kaga, Itabashi, Tokyo 173-8605, Japan.
authors.forename: Masashi
authors.initials: M
authors.lastname: Takano
authors.affiliation: Faculty of Engineering, Toyama Prefectural University, Imizu, Toyama 939-0398, Japan.
authors.forename: Kaori
authors.initials: K
authors.lastname: Yasuda
authors.affiliation: Faculty of Engineering, Toyama Prefectural University, Imizu, Toyama 939-0398, Japan.
authors.forename: Eri
authors.initials: E
authors.lastname: Tohyama
authors.affiliation: Faculty of Pharmaceutical Sciences, Teikyo University, 2-11-1 Kaga, Itabashi, Tokyo 173-8605, Japan.
authors.forename: Erika
authors.initials: E
authors.lastname: Higuchi
authors.affiliation: Faculty of Engineering, Toyama Prefectural University, Imizu, Toyama 939-0398, Japan. Electronic address: tsakaki@pu-toyama.ac.jp.
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Sakaki
authors.affiliation: Faculty of Pharmaceutical Sciences, Teikyo University, 2-11-1 Kaga, Itabashi, Tokyo 173-8605, Japan. Electronic address: akittaka@pharm.teikyo-u.ac.jp.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Kittaka
mesh_terms: D000818:Animals; D002117:Calcitriol / Q000031:analogs & derivatives / Q000138:chemical synthesis* / Q000378:metabolism*; D002384:Catalysis; D060326:Chemistry Techniques, Synthetic / Q000379:methods; D010165:Palladium / Q000737:chemistry; D051381:Rats; D011994:Recombinant Proteins / Q000378:metabolism; D013237:Stereoisomerism; D065668:Vitamin D3 24-Hydroxylase / Q000378:metabolism*; D014815:Vitamins / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism*
chemical_list: D011994:Recombinant Proteins; D014815:Vitamins; D010165:Palladium; D065668:Vitamin D3 24-Hydroxylase; D002117:Calcitriol
keywords: AH-1; CYP24A1; Metabolism; Synthesis; Vitamin D(3) analog