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
Current Topics in Medicinal Chemistry
Title: Recent Results on A-Ring Modification of 1α,25-Dihydroxyvitamin D3: Design and Synthesis of VDR-Agonists and Antagonists with High Biological Activity
Volume: 6 Issue: 12
Author(s): Nozomi Saito, Shinobu Honzawa and Atsushi Kittaka
Affiliation:
Keywords: palladium coupling, B-seco steroidal, HL-60 Cell Differentiation, Docking, CD-ring lactones
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.
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Saito Nozomi, Honzawa Shinobu and Kittaka Atsushi, Recent Results on A-Ring Modification of 1α,25-Dihydroxyvitamin D3: Design and Synthesis of VDR-Agonists and Antagonists with High Biological Activity, Current Topics in Medicinal Chemistry 2006; 6 (12) . https://dx.doi.org/10.2174/156802606777864953
DOI https://dx.doi.org/10.2174/156802606777864953 |
Print ISSN 1568-0266 |
Publisher Name Bentham Science Publisher |
Online ISSN 1873-4294 |
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