1-Desoxy analog of 2MD: Synthesis and biological activity of (20S)-25-hydroxy-2-methylene-19-norvitamin D3

During our ongoing structure-activity studies in the vitamin D area, we obtained (20S)-1alpha,25-dihydroxy-2-methylene-19-norvitamin D3 (5). This analog, designated 2MD, is characterized by a significantly enhanced calcemic activity and is currently evaluated as a potential drug for osteoporosis. Th...

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Bibliographic Details
Published in:Journal of steroid biochemistry and molecular biology 2010-07, Vol.121 (1-2), p.51-55
Main Authors: SIBILSKA, Izabela, BARYCKA, Katarzyna M, SICINSKI, Rafal R, PLUM, Lori A, DELUCA, Hector F
Format: Article
Language:English
Subjects:
Animals
Binding, Competitive
Biological and medical sciences
Calcitriol - analogs & derivatives
Calcitriol - chemical synthesis
Calcitriol - pharmacology
Drug Design
Drug Evaluation, Preclinical - methods
Fundamental and applied biological sciences. Psychology
HL-60 Cells
Humans
Male
Oxides - chemistry
Phosphines - chemistry
Rats
Rats, Sprague-Dawley
Receptors, Calcitriol - chemistry
Recombinant Proteins - chemistry
Transcription, Genetic
Vertebrates: endocrinology
Vertebrates: reproduction
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Summary:During our ongoing structure-activity studies in the vitamin D area, we obtained (20S)-1alpha,25-dihydroxy-2-methylene-19-norvitamin D3 (5). This analog, designated 2MD, is characterized by a significantly enhanced calcemic activity and is currently evaluated as a potential drug for osteoporosis. Therefore, it was of interest to synthesize also its 1-desoxy analog and to evaluate its biological action. These studies were aimed at solving an intriguing problem: can such a vitamin also be hydroxylated in vivo at the allylic C-1 position despite lack of the exomethylene moiety at C-10? The Wittig-Horner coupling of the known protected (20S)-25-hydroxy Grundmann ketone 17 and the phosphine oxides 16 and 33, differing in their hydroxyls protection, provided the target 1-desoxy-2MD (6) after removal of the silyl protecting groups. Two synthetic paths have been elaborated leading to the desired A-ring synthons and starting from commercially available compounds: 1,4-cyclohexanedione monoethylene acetal (7) and (-)-quinic acid (19). The biological activity in vitro of the synthesized 1-desoxy-2MD (6) was evaluated and this analog was found to have an affinity for the vitamin D receptor (VDR) similar as its parent compound 2MD (5) while being much less active in the transcriptional assay. The results of the biological tests in vivo are also discussed.
ISSN:0960-0760
1879-1220
DOI:10.1016/j.jsbmb.2010.03.063