Creation of Potent Vitamin D Receptor Agonists and Antagonists with 2?-(?-Hydroxyalkylation) Concept to the seco-Steroid Skeleton

Authors

  • Atsushi Kittaka Faculty of Pharmaceutical Sciences Teikyo University 2-11-1 Kaga, Itabashi, Tokyo 173-8605, Japan;, Email: akittaka@pharm.teikyo-u.ac.jp

DOI:

https://doi.org/10.2533/chimia.2018.859

Keywords:

Agonist, Antagonist, Tachysterol, Vitamin d, Vitamin d receptor

Abstract

2?-modification on the vitamin D skeleton with a 2?-(?-hydroxyalkyl) or 2?-(?-hydroxyalkoxy) group improves vitamin D receptor (VDR) binding affinity, lengthens the half-life in target cells because of increased resistance to CYP24A1 metabolism, and enhances biological activity. The introduced terminal hydroxy group forms an additional hydrogen bond to Arg274, which is the most important amino acid residue for recognizing the ligand hormone 1?,25-dihydroxyvitamin D3 of human VDR. According to our 2?-functionalization concept, we synthesized several hundred vitamin D analogs, and some had selective potent biological activity, such as bone formation (by AH-1) or anticancer activity (by MART-10), without the side-effects of vitamin D such as hypercalcemia. A potent hVDR antagonist NS-74c and stable 14-epi-tachysterol derivatives are also described in this short review.

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Published

2018-12-19

How to Cite

[1]
A. Kittaka, Chimia 2018, 72, 859, DOI: 10.2533/chimia.2018.859.