title: Design, synthesis, and biological studies of the A-ring-modified 1,25-dihydroxyvitamin D3 analogs.
abstract: Antitumor effects of 1alpha,25-dihydroxyvitamin D3 analogs have recently become one of the major topics of the vitamin D research field. We focused on the structure-activity relationships of the A-ring moiety of the vitamin D molecule and found several strong agonists of the vitamin D receptor, using a design of introducing a functional group into the C2 position. In the first step, all eight possible diastereomers of novel 2-methyl-1,25-dihydroxyvitamin D3 were synthesized using the convergent method with palladium catalyzed coupling reaction. We studied conformational analysis of each isomer based on 1H NMR and computer calculations; and biologically, VDR binding affinity, potency of induction of HL-60 cell differentiation, and apoptosis were investigated in detail. The biological effect of double modification in a combination of the CD-ring side chain (20-epi, 20-epi-22R-methyl, and KH-1060 types) and the 2-methyl group was then evaluated. In this context, 5,6-trans derivatives of 2-methyl analogs were also synthesized and tested. Through these experiments, our accumulated knowledge that the 2a-methylated analog with the natural la,3fl-dihydroxyl groups possesses a strong and unique biological profile guided us the next synthetic goal, i.e., three kinds of longer functional groups: 2alpha-alkyl, 2alpha-hydroxyalkyl, and 2alpha-hydroxyalkoxyl groups, which were introduced into 1alpha,25-dihydroxyvitamin D3, stereoselectively. We found that five of our new 2alpha-modified analogs show higher VDR-binding affinity than that of the natural hormone. HL-60 cell differentiation induction activities and calcium mobilization were studied for some of these compounds. These are the first examples, including the pioneer 2a-methyl analog, that exhibit higher VDR-binding affinity than 1alpha,25-dihydroxyvitamin D3 with pure A-ring modifications. To explain the effect, docking studies of the synthetic ligands to VDR are also described. This study could stimulate the development of antitumor medicines of the vitamin D analogs.
authors.affiliation: Faculty of Pharmaceutical Sciences, Teikyo University, Sagamiko, Kanagawa 199-0195, Japan. hi-takay@pharm.teikyo-u.ac.jp
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Takayama
authors.forename: Atsushi
authors.initials: A
authors.lastname: Kittaka
authors.forename: Toshie
authors.initials: T
authors.lastname: Fujishima
authors.forename: Yoshitomo
authors.initials: Y
authors.lastname: Suhara
mesh_terms: D002454:Cell Differentiation / Q000187:drug effects; D018360:Crystallography, X-Ray; D015195:Drug Design; D018922:HL-60 Cells; D006801:Humans; D008968:Molecular Conformation; D015394:Molecular Structure; D011485:Protein Binding; D018167:Receptors, Calcitriol / Q000378:metabolism; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014807:Vitamin D / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000494:pharmacology*
chemical_list: C116441:2-methyl-1,25-dihydroxyvitamin D3; D018167:Receptors, Calcitriol; D014807:Vitamin D