Recent Results on A-Ring Modification of 1α,25-Dihydroxyvitamin D3: Design and Synthesis of VDR-Agonists and Antagonists with High Biological Activity

Author(s): Nozomi Saito , Shinobu Honzawa , Atsushi Kittaka .

Journal Name: Current Topics in Medicinal Chemistry

Volume 6 , Issue 12 , 2006

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Abstract:

The structure-activity relationships of 1α,25-dihydroxyvitamin D3 on simultaneous modification at both C2α and CD-ring side chain, including 20-epimerization, double side chain (gemini), and vitamin D receptor (VDR) antagonists TEI-9647 and TEI-9648 lactone rings, and also on simultaneous modifications at both C2 and C10 positions, i.e., C2 modified active 19-norvitamin D3, have been studied in our laboratory to find new seeds of B-seco-steroidal medicine for treating bone diseases, psoriasis, secondary hyperparathyroidism, and certain kinds of cancers. We developed an efficient and systematic route to the 2α-substituted 1α,25-dihydroxyvitamin D3 analogs, i.e., VDR-agonists (20-epi-2-4, double side chain 13a-c, 19-nor 15a-c) and antagonists (36a-c, 37a-c). The A-ring precursors (11a-o) for these analogs were synthesized from D-glucose as a chiral template. In the 19-nor series, we used radical coupling reaction for preparing the A-ring parts from (-)-quinic acid, and the resulting 2-substituted A-ring moiety was coupled with 25-hydroxy Grundmanns ketone utilizing Julia olefination to connect between the C5 and C6 positions. We also synthesized the highly potent VDR-antagonists by introducing the 2α-functional group to the TEI-9647 and TEI-9648 skeletons.

Keywords: palladium coupling, B-seco steroidal, HL-60 Cell Differentiation, Docking, CD-ring lactones

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Article Details

VOLUME: 6
ISSUE: 12
Year: 2006
Page: [1273 - 1288]
Pages: 16
DOI: 10.2174/156802606777864953
Price: $58

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