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Design, Synthesis, and Biological Studies of the A-Ring-Modified 1,25-Dihydroxyvitamin D3 Analogs

  • Hiroaki Takayama
  • Atsushi Kittaka
  • Toshie Fujishima
  • Yoshitomo Suhara
Part of the Recent Results in Cancer Research book series (RECENTCANCER, volume 164)

Abstract

Antitumor effects of 1α,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 2α-methylated analog with the natural 1α,3β-dihydroxyl groups possesses a strong and unique biological profile guided us the next synthetic goal, i.e., three kinds of longer functional groups: 2a-alkyl, 2α-hydroxyalkyl, and 2α-hydroxyalkoxyl groups, which were introduced into 1α,25-dihydroxyvitamin D3, stereoselectively. We found that five of our new 2α-modified analogs show higher VDR-binding affinity than that of the natural hormone.

Keywords

Chair Conformer Acetylene Unit Polar Isomer Benzylidene Acetal 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

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Copyright information

© Springer-Verlag Berlin Heidelberg 2003

Authors and Affiliations

  • Hiroaki Takayama
    • 1
  • Atsushi Kittaka
  • Toshie Fujishima
  • Yoshitomo Suhara
  1. 1.Faculty of Pharmaceutical SciencesTeikyo UniversitySagamiko, KanagawaJapan

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