2-Substituted-16-ene-22-thia-1α,25-dihydroxy-26,27-dimethyl-19-norvitamin D3 analogs: Synthesis, biological evaluation, and crystal structure

Masato Shimizu, Yukiko Miyamoto, Hajime Takaku, Mayumi Matsuo, Makoto Nakabayashi, Hiroyuki Masuno, Nobuyuki Udagawa, Hector F. DeLuca, Teikichi Ikura, Nobutoshi Ito

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    52 Citations (Scopus)


    Recently, we have found that 16-ene-22-thia-26,27-dimethyl-19-norvitamin D3 analogs 1a (n = 2, 3) are 20 times more active than the natural hormone 1α,25-dihydroxyvitamin D3 in terms of transcriptional activity. To further investigate the effects of the A-ring modification of 1a, b on the biological activity profile, novel 22-thia-19-norvitamin D analogs 2-11 bearing a hydroxyethoxy-, hydroxyethylidene- or methyl group at C-2 in combination with 20S- and 20R-isomers were prepared and tested for their in vitro biological activities. All of the synthesized analogs showed 0.5-140% of the activity of the natural hormone in binding to the vitamin D receptor (VDR). When compared with the transcriptional activity of C-2 or C-20 isomeric pairs of the 22-thia analogs, the 20S-isomers 2-11a were more potent than the 20R-isomers 2, 3, 8-11b, and the 2β-hydroxyethoxy, 2E-hydroxyethylidene, and 2α-methyl-2β-hydroxy-22-thia isomers showed higher potency than their corresponding counterparts. In particular, 3a exhibited an extremely higher level of potency (210-fold) than the natural hormone. To elucidate the action mode of superagonist 3a at the molecular level, we determined the crystal structures of the rat VDR-ligand-binding domain complexed with 3a or 3b in the presence of peptide containing a nuclear box motif (LxxLL) at 1.9-2.0 Å resolution. The crystal structures demonstrated that the 1α-OH, 3β-OH, and 25-OH groups of the natural hormone and 3a were anchored by the same amino acid residues in the ligand-binding pocket, and the terminal OH moiety of the substituent at C-2 formed hydrogen bonds with Arg270 and a water molecule to create a tight water molecule network. Moreover, the methyl groups at C-26a and C-27a make additional contact with hydrophobic residues such as Leu223, Ala227, Val230, and Ala299. These hydrophilic and hydrophobic interactions in 3a may underlie the induction of superagonistic activity.

    Original languageEnglish
    Pages (from-to)6949-6964
    Number of pages16
    JournalBioorganic and Medicinal Chemistry
    Issue number14
    Publication statusPublished - Jul 15 2008


    • 16-Ene-22-thia-19-norvitamin D
    • Crystal structure
    • Structure-activity relationships
    • Transcriptional activity
    • VDR-binding affinity

    ASJC Scopus subject areas

    • Biochemistry
    • Molecular Medicine
    • Molecular Biology
    • Pharmaceutical Science
    • Drug Discovery
    • Clinical Biochemistry
    • Organic Chemistry


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