Synthesis and biological activities of new 1alpha,25-dihydroxy-19-norvitamin D3 analogs with modifications in both the A-ring and the side chain

Bioorganic & Medicinal Chemistry
Masato ShimizuSachiko Yamada

Abstract

In a series of studies on structure-activity relationships of 2-substituted 19-norvitamin D analogs, we found that 1alpha,25-dihydroxy-19-norvitamin D3 analogs with 2beta-hydroxyethoxy or 2E-hydroxyethylidene moieties show strong binding affinity for the vitamin D receptor (VDR) as well as marked transcriptional activity. To further examine the effects of side chain structure on the activity of 2-substituted 19-norvitamin D analogs, we have synthesized new 19-norvitamin D3 analogs with modifications in both the A-ring at the C(2) position and the side chain. The side chains of these analogs contained a double bond between C(22) and C(23) or an oxygen atom at C(22). The biological activity of the analogs was evaluated in vitro. All the side chain-modified analogs were less active than 1alpha,25-dihydroxyvitamin D31e and the parent compounds 3-6e possessing a natural 20R-configuration in binding to the VDR, but, except for the (20R)-22-oxa analogs 3-6d, were significantly more potent in transcriptional activity. Of the side-chain-modified analogs 4 and 5, the 2beta-hydroxyethoxy- and 2E-hydroxyethylidene-22,24-diene-24a,26a,27a-trihomo analogs showed markedly higher transcriptional activity (25- and 17.5-fold, respectively) compa...Continue Reading

References

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May 10, 2001·Proceedings of the National Academy of Sciences of the United States of America·G Tocchini-ValentiniD Moras
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Oct 11, 2002·Proceedings of the National Academy of Sciences of the United States of America·Nirupama K ShevdeHector F DeLuca
Nov 9, 2002·Medicinal Research Reviews·Sachiko YamadaKeiko Yamamoto
May 1, 2004·Proceedings of the National Academy of Sciences of the United States of America·Lori A PlumHector F DeLuca
Feb 17, 2005·Bioorganic & Medicinal Chemistry Letters·Masato ShimizuSachiko Yamada

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Citations

Feb 14, 2015·Chemical Biology & Drug Design·Yan ChenWei-Min Chen
Jul 28, 2020·Pharmaceuticals·Susana Fernández, Miguel Ferrero
Mar 28, 2019·Journal of Medicinal Chemistry·Miguel A MaestroCarsten Carlberg

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