Recent results on A-ring modification of 1alpha,25-dihydroxyvitamin D3: design and synthesis of VDR-agonists and antagonists with high biological activity.
The structure-activity relationships of 1alpha,25-dihydroxyvitamin D3 on simultaneous modification at both C2alpha 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 2alpha-substituted 1alpha,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 Grundmann's ketone utilizing Julia olefination to connect between the C5 and C6 positions. We also synthesized the highly potent VDR-antagonists by introducing the 2alpha-functional group to the TEI-9647 and TEI-9648 skeletons.
Saito
Nozomi
N
Faculty of Pharmaceutical Sciences, Teikyo University, Sagamiko, Sagamihara, Kanagawa 199-0195, Japan.
Honzawa
Shinobu
S
Kittaka
Atsushi
A
D002117:Calcitriol / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D015394:Molecular Structure; D018167:Receptors, Calcitriol / Q000819:agonists* / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
D018167:Receptors, Calcitriol; D002117:Calcitriol