title: Synthesis and biological evaluation of all A-ring stereoisomers of 5,6-trans-2-methyl-1,25-dihydroxyvitamin D(3) and their 20-epimers: possible binding modes of potent A-ring analogues to vitamin D receptor.
abstract: BACKGROUND
  The secosteroid 1 alpha,25-dihydroxyvitamin D(3) (1) has a wide variety of biological activities, which makes it a promising therapeutic agent for the treatment of cancer, psoriasis and osteoporosis. Insight into the structure-activity relationships of the A-ring of 1 is still needed to assist the development of more potent and selective analogues as candidate chemotherapeutic agents, as well as to define the molecular mode of action.
  
  
  RESULTS
  All possible A-ring stereoisomers of 5,6-trans-2-methyl-1,25-dihydroxyvitamin D(3) (6a-h) and their 20-epimers (7a-h) were designed and efficiently synthesized. The dependence of the affinities for vitamin D receptor (VDR) and vitamin D binding protein (DBP), as well as the HL-60 cell differentiation-inducing activity, upon the stereochemistry of the A-ring and at C20 in the side chain was evaluated.
  
  
  CONCLUSIONS
  The binding affinities and potency of the 5,6-trans and 5,6-cis analogues were enhanced by a 2-methyl substituent in a certain orientation. Molecular docking studies based upon the X-ray crystal structure of VDR suggested that the axial 2-methyl group would be accommodated in a pocket surrounded by hydrophobic amino acid residues in the ligand binding domain, resulting in enhanced interaction.
authors.affiliation: Faculty of Pharmaceutical Sciences, Teikyo University, Sagamiko, Kanagawa, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Fujishima
authors.forename: K
authors.initials: K
authors.lastname: Konno
authors.forename: K
authors.initials: K
authors.lastname: Nakagawa
authors.forename: M
authors.initials: M
authors.lastname: Tanaka
authors.forename: T
authors.initials: T
authors.lastname: Okano
authors.forename: M
authors.initials: M
authors.lastname: Kurihara
authors.forename: N
authors.initials: N
authors.lastname: Miyata
authors.forename: H
authors.initials: H
authors.lastname: Takayama
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D001665:Binding Sites; D002417:Cattle; D002454:Cell Differentiation / Q000187:drug effects; D018922:HL-60 Cells; D006801:Humans; D011485:Protein Binding; D011487:Protein Conformation; D018167:Receptors, Calcitriol / Q000737:chemistry / Q000378:metabolism; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013950:Thymus Gland; D014807:Vitamin D / Q000031:analogs & derivatives* / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D014809:Vitamin D-Binding Protein / Q000737:chemistry / Q000378:metabolism
chemical_list: C116441:2-methyl-1,25-dihydroxyvitamin D3; D000970:Antineoplastic Agents; D018167:Receptors, Calcitriol; D014809:Vitamin D-Binding Protein; D014807:Vitamin D