title: Systematic studies on synthesis, structural elucidation, and biological evaluation of A-ring diastereomers of 2-methyl-1alpha,25-dihydroxyvitamin D(3) and 20-epi-2-methyl-1alpha,25-dihydroxyvitamin D(3).
abstract: All possible A-ring diastereomers of 2-methyl-1alpha,25-dihydroxyvitamin D(3) (2) and 20-epi-2-methyl-1alpha,25-dihydroxyvitamin D(3) (3) were synthesized by palladium-catalyzed coupling reaction of A-ring 'enyne' synthons with CD-ring portions. The A-ring synthons were rationally synthesized via a novel and practical route, starting with methyl (R)-(+)- and (S)-(-)-3-hydroxy-2-methyl-propionate, in good yields. X-ray crystallographic analysis of 2alpha-methyl-1alpha,25-dihydroxyvitamin D(3) (2b) and conformational analysis of the A-ring of 2alpha-methyl-(2b) and 2beta-methyl-1alpha,25-dihydroxyvitamin D(3) (2f) were carried out, and the results are described. All A-ring diastereomers (2 and 3), thus synthesized, were biologically evaluated both in vitro and in vivo. The biologic potency was highly dependent on the stereochemistry of the A-ring substituents. In particular, 2b showed 4-fold higher vitamin D receptor [VDR] binding activity than the natural hormone, and its 20-epimer (3b) exhibited exceptionally high activity, 12-fold more potent in VDR binding, 7-fold in calcium mobilization, and 590-fold in induction of human promyelocytic leukemia (HL-60) cell differentiation as compared with the natural hormone. Further, the 20-epi-2beta-Me-1beta, 3alpha(OH)(2) isomer (3g) had significant biologic potencies compared to the natural hormone despite having 1beta-OH configuration. The transcriptional activities on human osteocalcin gene promoter, including VDRE in transfected mammalian cells, were also evaluated. Finally, there was a clear contrast between the effects of the 2-methyl group on the HL-60 cell differentiation- and apoptosis-inducing activities of 2 and 3.
authors.affiliation: Faculty of Pharmaceutical Sciences, Teikyo University, Sagamiko, 199-0195, Kanagawa, Japan. hi-takay@pharm.Teikyo-u.ac.jp
authors.forename: H
authors.initials: H
authors.lastname: Takayama
authors.forename: K
authors.initials: K
authors.lastname: Konno
authors.forename: T
authors.initials: T
authors.lastname: Fujishima
authors.forename: S
authors.initials: S
authors.lastname: Maki
authors.forename: Z
authors.initials: Z
authors.lastname: Liu
authors.forename: D
authors.initials: D
authors.lastname: Miura
authors.forename: M
authors.initials: M
authors.lastname: Chokki
authors.forename: S
authors.initials: S
authors.lastname: Ishizuka
authors.forename: C
authors.initials: C
authors.lastname: Smith
authors.forename: H F
authors.initials: HF
authors.lastname: DeLuca
authors.forename: K
authors.initials: K
authors.lastname: Nakagawa
authors.forename: M
authors.initials: M
authors.lastname: Kurobe
authors.forename: T
authors.initials: T
authors.lastname: Okano
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001692:Biological Transport / Q000187:drug effects; D001842:Bone and Bones / Q000378:metabolism; D002118:Calcium / Q000097:blood; D002417:Cattle; D002454:Cell Differentiation / Q000187:drug effects; D018360:Crystallography, X-Ray; D018922:HL-60 Cells; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism; D015394:Molecular Structure; D015675:Osteocalcin / Q000235:genetics; D011485:Protein Binding; D051381:Rats; D018167:Receptors, Calcitriol / Q000378:metabolism; D013237:Stereoisomerism; D015533:Transcriptional Activation / Q000187:drug effects; D014407:Tumor Cells, Cultured; D014807:Vitamin D / Q000031:analogs & derivatives / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*
chemical_list: C116441:2-methyl-1,25-dihydroxyvitamin D3; D018167:Receptors, Calcitriol; D015675:Osteocalcin; D014807:Vitamin D; D002118:Calcium