Design, synthesis, and biological studies of the A-ring-modified 1,25-dihydroxyvitamin D3 analogs.

Hiroaki Takayama, Atsushi Kittaka, Toshie Fujishima, Yoshitomo Suhara

Research output: Contribution to journalReview articlepeer-review

28 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)289-317
Number of pages29
JournalRecent results in cancer research. Fortschritte der Krebsforschung. Progrès dans les recherches sur le cancer
Publication statusPublished - 2003
Externally publishedYes

ASJC Scopus subject areas

  • Oncology
  • Cancer Research


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