Rational design, synthesis, and biological activity of novel conformationally restricted vitamin D analogues, (22R)- and (22S)-22-ethyl-1,25-dihydroxy-23,24-didehydro-24a,24b-dihomo-20-epivitamin D3

Hiroyuki Masuno, Keiko Yamamoto, Xinxiang Wang, Mihwa Choi, Hiroshi Ooizumi, Toshimasa Shinki, Sachiko Yamada

Research output: Contribution to journalArticle

31 Citations (Scopus)

Abstract

Two new vitamin D analogues, (22R)- and (22S)-22-ethyl-1,25-dihydroxy-23,24-didehydro-24a,24b-dihomo-20-epivitamin D3 (3 and 4), were rationally designed on the basis of the active space group concept previously proposed by us. The 22R ethyl group of 3 restricts the mobility of the side chain to active space regions, whereas the 22S ethyl group of 4 confines the side chain to an inactive region. The double bond at C(23) further restricts the side chain flexibility. These compounds (3 and 4) were synthesized using ortho ester Claisen rearrangement as the key step. As expected, the 22R isomer 3 has nearly 100 times higher efficacy than 1,25-dihydroxyvitamin D3 (1) in cell differentiation, although its affinity for the vitamin D receptor (VDR) was one-seventh of that of 1. The 22S isomer 4 has significantly lower efficacy than 3. A docking study in combination with site-directed mutation analysis revealed that two carbon elongated side chain analogue 3 could be fitted in the ligand binding pocket of the VDR by adopting a stable conformation.

Original languageEnglish (US)
Pages (from-to)1825-1834
Number of pages10
JournalJournal of Medicinal Chemistry
Volume45
Issue number9
DOIs
StatePublished - Apr 25 2002
Externally publishedYes

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Calcitriol Receptors
Vitamin D
Calcitriol
Cell Differentiation
Esters
Carbon
Ligands
Mutation

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

Cite this

Rational design, synthesis, and biological activity of novel conformationally restricted vitamin D analogues, (22R)- and (22S)-22-ethyl-1,25-dihydroxy-23,24-didehydro-24a,24b-dihomo-20-epivitamin D3. / Masuno, Hiroyuki; Yamamoto, Keiko; Wang, Xinxiang; Choi, Mihwa; Ooizumi, Hiroshi; Shinki, Toshimasa; Yamada, Sachiko.

In: Journal of Medicinal Chemistry, Vol. 45, No. 9, 25.04.2002, p. 1825-1834.

Research output: Contribution to journalArticle

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abstract = "Two new vitamin D analogues, (22R)- and (22S)-22-ethyl-1,25-dihydroxy-23,24-didehydro-24a,24b-dihomo-20-epivitamin D3 (3 and 4), were rationally designed on the basis of the active space group concept previously proposed by us. The 22R ethyl group of 3 restricts the mobility of the side chain to active space regions, whereas the 22S ethyl group of 4 confines the side chain to an inactive region. The double bond at C(23) further restricts the side chain flexibility. These compounds (3 and 4) were synthesized using ortho ester Claisen rearrangement as the key step. As expected, the 22R isomer 3 has nearly 100 times higher efficacy than 1,25-dihydroxyvitamin D3 (1) in cell differentiation, although its affinity for the vitamin D receptor (VDR) was one-seventh of that of 1. The 22S isomer 4 has significantly lower efficacy than 3. A docking study in combination with site-directed mutation analysis revealed that two carbon elongated side chain analogue 3 could be fitted in the ligand binding pocket of the VDR by adopting a stable conformation.",
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