title: Synthesis and metabolic studies of 1α,2α,25-, 1α,4α,25- and 1α,4β,25-trihydroxyvitamin D3.
abstract: Three different A-ring perhydroxylated trihydroxyvitamin D3 metabolites were synthesized from their appropriate A-ring precursors and CD-ring for their potential therapeutic applications. We first chemically synthesized 1α,2α,25-trihydroxyvitamin D3 [1α,2α,25(OH)3D3] to study its VDR binding affinity because this metabolite is a product of recombinant human CYP3A4 catalysis when 2α-(3-hydroxypropoxy)-1α,25-dihydroxyvitamin D3 (O2C3), a more potent vitamin D receptor (VDR) binder than 1α,25-dihydroxyvitamin D3 [1α,25(OH)2D3], is used as the substrate. We found that this metabolite retained 27.3% of the VDR binding affinity compared to 1α,25(OH)2D3. The kcat/Km value of CYP24A1 for 1α,2α,25(OH)3D3 is 60% of that for 1α,25(OH)2D3. Since the biological activity and the metabolic fate of a naturally occurring C4-hydroxylated vitamin D2 metabolite found in the serum of rats treated with pharmacological doses of vitamin D2 have never been described, we next synthesized 1α,4α,25-trihydroxyvitamin D3 and its diastereoisomer, 1α,4β,25-trihydroxyvitamin D3, to study their metabolism and biological activities. Both 4-hydroxylated isomers showed weaker VDR binding affinity than 1α,25(OH)2D3. Although either 4-hydroxylated isomer can be metabolized by CYP24A1 almost at the same level as 1α,25(OH)2D3, their metabolic patterns catalyzed by uridine 5'-diphosphoglucuronosyltransferase (UGT) are different; only the 4α-hydroxylated analog can be metabolized by UGT to produce a glucuronate conjugate. The results provide important information for the synthesis of new novel chemotherapeutic vitamin D analogs which would be less subjective to degradation and therefore more bioavailable than 1α,25(OH)2D3. This article is part of a Special Issue entitled '17th Vitamin D Workshop'.
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 Pharmaceutical Sciences, Teikyo University, 2-11-1 Kaga, Itabashi, Tokyo 173-8605, Japan.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Sawada
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: Miyu
authors.initials: M
authors.lastname: Nishikawa
authors.affiliation: Teijin Institute for Bio-medical Research, Teijin Pharma Ltd., Hino, Tokyo 191-8512, Japan.
authors.forename: Akiko
authors.initials: A
authors.lastname: Takeuchi
authors.affiliation: Teijin Institute for Bio-medical Research, Teijin Pharma Ltd., Hino, Tokyo 191-8512, Japan.
authors.forename: Ken-Ichiro
authors.initials: K
authors.lastname: Takagi
authors.affiliation: Teijin Institute for Bio-medical Research, Teijin Pharma Ltd., Hino, Tokyo 191-8512, Japan.
authors.forename: Kyohei
authors.initials: K
authors.lastname: Horie
authors.affiliation: Epimer LLC, North Smithfield, RI 02906, USA.
authors.forename: G Satyanarayana
authors.initials: GS
authors.lastname: Reddy
authors.affiliation: Section of Endocrinology, Diabetes & Nutrition, Boston University School of Medicine, Boston, MA 02118, USA.
authors.forename: Tai C
authors.initials: TC
authors.lastname: Chen
authors.affiliation: Faculty of Engineering, Toyama Prefectural University, Imizu, Toyama 939-0398, Japan.
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* / Q000494:pharmacology*; D006801:Humans; D015394:Molecular Structure; D051381:Rats; D013237:Stereoisomerism; D014815:Vitamins / Q000138:chemical synthesis* / Q000494:pharmacology*
chemical_list: D014815:Vitamins; D002117:Calcitriol
keywords: CYP24A1; CYP3A4; Trihydroxyvitamin D(3); UGT; Vitamin D receptor; Vitamin D(3)