Creative synthesis of novel vitamin D analogs for health and disease

Atsushi Kittaka, Nozomi Saito, Shinobu Honzawa, Kazuya Takenouchi, Seiichi Ishizuka, Tai C. Chen, Sara Peleg, Shigeaki Kato, Midori A. Arai

Research output: Contribution to journalArticle

15 Citations (Scopus)

Abstract

We report new analogs of 1α,25-dihydroxyvitamin D3 (1) in three categories. First, design and synthesis of ligands for a mutant vitamin D receptor (VDR)(Arg274Leu), which possess proper functional groups at both C1α and C2α positions of 1 to study the biological activity of the mutant VDR. Among our synthetic analogs, 1α-methyl-2α-(3-hydroxypropyl)-25-hydroxyvitamin D3 (8) showed 7.3-fold greater transcriptional activity for the VDR(Arg274Leu) than that of 1. Next, we examined the antiproliferative activity of 2-substituted 19-norvitamin D3 analogs on an immortalized normal prostate cell line, PZ-HPV-7, and we found MART 10 (14) showed the activity even at very low concentration of 10-10 to 10-11 M. We also synthesized 25-hydroxy-19-norvitamin D3 (13) using Julia-type olefination to connect between the C5 and C6 positions, effectively, to test it as a prohormone type agent for antiprostate diseases. Synthesized compound 13 showed potent antiproliferative activity in PZ-HPV-7, which has high 1α-hydroxylase activity. Finally, we describe design and synthesis of a new TEI-9647 analog, 2α-(3-hydroxypropoxy)-24-propyl-25-dehydro-1α-hydroxyvitamin D3-26,23-lactone (17), which showed the strongest VDR antagonism. Its IC50 value is 7.4 pM to inhibit differentiation of HL-60 cells induced by 10 nM of 1.

Original languageEnglish
Pages (from-to)269-276
Number of pages8
JournalJournal of Steroid Biochemistry and Molecular Biology
Volume103
Issue number3-5
DOIs
Publication statusPublished - 2007 Mar 1
Externally publishedYes

Keywords

  • Antagonist
  • Chemical synthesis
  • Structure-activity relationships
  • Vitamin D analogs
  • Vitamin D receptor

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Endocrinology
  • Clinical Biochemistry
  • Cell Biology

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