Catalytic asymmetric syntheses and biological activities of singly dehydroxylated 19-nor-1α,25-dihydroxyvitamin D3 A-ring analogs in cancer cell differentiation and apoptosis

Toshio Okano, Kimie Nakagawa, Noboru Kubodera, Keiichi Ozono, Akira Isaka, Ayako Osawa, Masahiro Terada, Koichi Mikami

Research output: Contribution to journalArticlepeer-review

32 Citations (Scopus)

Abstract

Background: 1α,25-Dihydroxyvitamin D3 (1α,25(OH)2D3) has been shown to modulate not only proliferation and differentiation, but also apoptosis in malignant cells, indicating that it could be useful for treating cancer. Little information is available concerning the structural motifs of the 1α,25(OH)2D3 molecule responsible for modulation of differentiation and apoptosis, however. We set out to synthesize singly dehydroxylated A-ring analogs of 19-nor-1α,25(OH)2D3 in a catalytic asymmetric fashion, and to investigate their biological activities in leukemia HL-60 cells. Results: A series of singly dehydroxylated 19-nor-1α,25-dihydroxyvitamin D3 A-ring analogs were synthesized using a combinatorial sequence of regioselective propiolate-ene reaction and catalytic asymmetric carbonyl-ene cyclization. Surprisingly, the analogs could be clearly divided into two categories; one group, bearing 1α-hydroxy or 3β-hydroxy groups in the A-ring, were potent differentiators and the second group, bearing 1β-hydroxy or 3α-hydroxy groups, were potent stimulators of apoptosis. Conclusions: We have clearly identified the structural motifs of 19-nor-1α,25(OH)2D3 analogs responsible for differentiation and apoptosis in HL-60 cells. These findings will provide useful information not only for development of therapeutic agents for treatment of leukemia and other cancers, but also for structure-function studies of 1α,25(OH)2D3.

Original languageEnglish
Pages (from-to)173-184
Number of pages12
JournalChemistry and Biology
Volume7
Issue number3
DOIs
Publication statusPublished - 2000 Mar 1
Externally publishedYes

Keywords

  • Apoptosis
  • Asymmetric catalysis
  • Cancer-cell differentiation
  • Carbonylene reaction

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmacology
  • Drug Discovery
  • Clinical Biochemistry

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