Biomolecules (Jan 2022)

Lithocholic Acid Amides as Potent Vitamin D Receptor Agonists

  • Ayana Yoshihara,
  • Haru Kawasaki,
  • Hiroyuki Masuno,
  • Koki Takada,
  • Nobutaka Numoto,
  • Nobutoshi Ito,
  • Naoya Hirata,
  • Yasunari Kanda,
  • Michiyasu Ishizawa,
  • Makoto Makishima,
  • Hiroyuki Kagechika,
  • Aya Tanatani

DOI
https://doi.org/10.3390/biom12010130
Journal volume & issue
Vol. 12, no. 1
p. 130

Abstract

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1α,25-Dihydroxyvitamin D3 [1α,25(OH)2D3, 1] is an active form of vitamin D3 and regulates various biological phenomena, including calcium and phosphate homeostasis, bone metabolism, and immune response via binding to and activation of vitamin D receptor (VDR). Lithocholic acid (LCA, 2) was identified as a second endogenous agonist of VDR, though its potency is very low. However, the lithocholic acid derivative 3 (Dcha-20) is a more potent agonist than 1α,25(OH)2D3, (1), and its carboxyl group has similar interactions to the 1,3-dihydroxyl groups of 1 with amino acid residues in the VDR ligand-binding pocket. Here, we designed and synthesized amide derivatives of 3 in order to clarify the role of the carboxyl group. The synthesized amide derivatives showed HL-60 cell differentiation-inducing activity with potency that depended upon the substituent on the amide nitrogen atom. Among them, the N-cyanoamide 6 is more active than either 1 or 3.

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