Synthesis and biological activities of new 1alpha,25-dihydroxy-19-norvitamin D3 analogs with modifications in both the A-ring and the side chain.
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) compared with 1e. Elongation of the side chain at the C-24, C-26, and C-27 positions and introduction of a 22,24-diene moiety strongly increased transcriptional activity, as seen in the 20-epi analogs 3-6f.
Shimizu
Masato
M
Laboratory of Medicinal Chemistry, School of Biomedical Science, Tokyo Medical and Dental University, 2-3-10 Kandasurugadai, Tokyo 101-0062, Japan. shimizu.mr@tmd.ac.jp
Miyamoto
Yukiko
Y
Kobayashi
Emi
E
Shimazaki
Mika
M
Yamamoto
Keiko
K
Reischl
Wolfgang
W
Yamada
Sachiko
S
D000818:Animals; D001665:Binding Sites; D019556:COS Cells; D002117:Calcitriol / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D002522:Chlorocebus aethiops; D004353:Drug Evaluation, Preclinical; D066298:In Vitro Techniques; D008024:Ligands; D008968:Molecular Conformation; D051381:Rats; D018167:Receptors, Calcitriol / Q000187:drug effects*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014158:Transcription, Genetic / Q000187:drug effects
D008024:Ligands; D018167:Receptors, Calcitriol; C083610:1,25-dihydroxy-19-norvitamin D3; D002117:Calcitriol