22-Alkyl-20-epi-1α,25-dihydroxyvitamin D3 compounds of superagonistic activity: Syntheses, biological activities and interaction with the receptor

Keiko Yamamoto, Yuka Inaba, Nobuko Yoshimoto, Mihwa Choi, Hector F. DeLuca, Sachiko Yamada

Research output: Contribution to journalArticle

17 Scopus citations

Abstract

We previously reported that 22R-methyl-20-epi-1,25-(OH)2D 3 (3) possesses strong binding affinity for the vitamin D receptor (VDR) and shows superagonistic biological activities. To examine the effect of the length of an alkyl substituent at C(22) and to extend our compound library, we successfully synthesized 22R-ethyl-20-epi-1,25-(OH)2D3 (4) and 22R-butyl-20-epi-1,25-(OH)2D3 (5). Surprisingly, 22-ethyl analogue 4 showed stronger VDR binding affinity and transactivation potency than the superagonist of methyl analogue 3, but its calcemic activity in vivo was weaker than that of both the methyl analogue 3 and the natural hormone (1), while 22-butyl analogue 5 showed activities comparable to those of the hormone (1). A study of the docking of these new analogues to the VDR-LBD and alanine scanning mutational analysis demonstrated that 22-methyl and 22-ethyl substituents enhance the favorable hydrophobic interactions with residues lining the ligand binding pocket of the VDR, and that 22-butyl analogue 5 binds to the VDR by an induced fit mechanism.

Original languageEnglish (US)
Pages (from-to)932-939
Number of pages8
JournalJournal of Medicinal Chemistry
Volume50
Issue number5
DOIs
StatePublished - Mar 8 2007
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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