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Structure-activity relationship study of vitamin D analogs with oxolane group in their side chain.

Belorusova AY, Martínez A, Gándara Z, Gómez G, Fall Y, Rochel N
Eur J Med Chem 134 86-96 (2017)
Related entries: 5nky, 5nma

Cited: 3 times
EuropePMC logo PMID: 28399453

Abstract

Synthetic analogs of 1α,25-dihydroxyvitamin D3 (1,25(OH)2D3) have been developed with the goal of improving the biological profile of the natural hormone for therapeutic applications. Derivatives of 1,25(OH)2D3 with the oxolane moiety branched in the side chain at carbon C20, act as Vitamin D nuclear Receptor (VDR) superagonists being several orders of magnitude more active than the natural ligand. Here, we describe the synthesis and biological evaluation of three diastereoisomers of (1S, 3R)-Dihydroxy-(20S)-[(2″-hydroxy-2″-propyl)-tetrahydrofuryl]-22,23,24,25,26,27-hexanor-1α-hydroxyvitamin D3, with different stereochemistry at positions C2 and C5 of the oxolane ring branched at carbon C22 (1, C2RC5S; 2, C2SC5R; 3, C2SC5S). These compounds act as weak VDR agonist in transcriptional assays with compound 3 being the most active. X-ray crystallographic analysis of the VDR ligand-binding domain accommodating the three compounds indicates that the oxolane group branched at carbon C22 is not constrained as in case of compound with oxolane group branched at C20 leading to the loss of interactions of the triene group and increased flexibility of the C/D-rings and of the side chain.

Reviews citing this publication (1)

  1. Vitamin D and Its Synthetic Analogs. Maestro MA, Molnár F, Carlberg C. J Med Chem 62 6854-6875 (2019)

Articles citing this publication (2)

  1. eModel-BDB: a database of comparative structure models of drug-target interactions from the Binding Database. Naderi M, Govindaraj RG, Brylinski M. Gigascience 7 (2018)
  2. Novel calcitriol analogue with an oxolane group: In vitro, in vivo, and in silico studies. Obiol DJ, Martínez A, Ferronato MJ, Quevedo MA, Grioli SM, Alonso EN, Gómez G, Fall Y, Facchinetti MM, Curino AC. Arch Pharm (Weinheim) 352 e1800315 (2019)


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