Synthesis, Biological Evaluation, and Conformational Analysis of A-Ring Diastereomers of 2-Methyl-1,25-dihydroxyvitamin D3 and Their 20-Epimers: Unique Activity Profiles Depending on the Stereochemistry of the A-Ring and at C-20
| Autor: | Hiroaki Takayama, Shojiro Maki, N. Miyata, Manabu Chokki, Seiichi Ishizuka, Connie Smith, Yukiko Kan, Masaaki Kurihara, Hector F. Deluca, Toshie Fujishima, Zhaopeng Liu, Daishiro Miura, Kentaro Yamaguchi, Katsuhiro Konno |
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| Rok vydání: | 2000 |
| Předmět: |
Male
Magnetic Resonance Spectroscopy Stereochemistry Molecular Conformation Crystallography X-Ray Ring (chemistry) Chemical synthesis Bone and Bones Cell Line Structure-Activity Relationship chemistry.chemical_compound Drug Discovery Animals Humans Intestinal Mucosa Vitamin D Enyne Synthon Diastereomer Biological Transport Cell Differentiation Stereoisomerism Rats chemistry Receptors Calcitriol Molecular Medicine Calcium Cattle Stereoselectivity Epimer Triol |
| Zdroj: | Journal of Medicinal Chemistry. 43:4247-4265 |
| ISSN: | 1520-4804 0022-2623 |
| DOI: | 10.1021/jm000261j |
| Popis: | All eight possible A-ring diastereomers of 2-methyl-1, 25-dihydroxyvitamin D(3) (2) and 2-methyl-20-epi-1, 25-dihydroxyvitamin D(3) (3) were convergently synthesized. The A-ring enyne synthons 19 were synthesized starting with methyl (S)-(+)- or (R)-(-)-3-hydroxy-2-methylpropionate (8). This was converted to the alcohol 14 as a 1:1 epimeric mixture in several steps. After having been separated by column chromatography, each isomer led to the requisite A-ring enyne synthons 19 again as 1:1 mixtures at C-1. Coupling of the resulting A-ring enynes 20a-h with the CD-ring portions 5a,b in the presence of a Pd catalyst afforded the 2-methyl analogues 2a-h and 3a-h in good yield. In this way, all possible A-ring diastereomers were synthesized. The synthesized analogues were biologically evaluated both in vitro and in vivo. The potency was highly dependent on the stereochemistry of each isomer. In particular, the alpha alpha beta-isomer 2g exhibited 4-fold higher potency than 1 alpha,25-dihydroxyvitamin D(3) (1) both in bovine thymus VDR binding and in elevation of rat serum calcium concentration and was twice as potent as the parent compound in HL-60 cell differentiation. Furthermore, its 20-epimer, that is, 20-epi-alpha alpha beta 3g, exhibited exceptionally high activities: 12-fold higher in VDR binding affinity, 7-fold higher in calcium mobilization, and 590-fold higher in HL-60 cell differentiation, as compared to 1 alpha,25-dihydroxyvitamin D(3) (1). Accordingly, the double modification of 2-methyl substitution and 20-epimerization resulted in unique activity profiles. Conformational analysis of the A-ring by (1)H NMR and an X-ray crystallographic analysis of the alpha alpha beta-isomer 2g are also described. |
| Databáze: | OpenAIRE |
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