当前位置： SCI文献检索 > JOURNAL OF MEDICINAL CHEMISTRY期刊下所有文献 > A 20S combined with a 22R configuration markedly increases both in vivo and in vitro biological activity of 1α,25-dihydroxy-22-methyl-2-methylene-19-norvitamin D3.

A 20S combined with a 22R configuration markedly increases both in vivo and in vitro biological activity of 1α,25-dihydroxy-22-methyl-2-methylene-19-norvitamin D3.

Abstract：

:Six new analogues of 1α,25-dihydroxy-19-norvitamin D(3) (3a-4b, 5, and 6) were prepared by a convergent synthesis applying the Wittig-Horner reaction as a key step. The influence of methyl groups at C-22 on their biological activity was examined. It was established that both in vitro and in vivo activity is strongly dependent on the configuration of the stereogenic centers at C-20 and C-22. Introduction of the second methyl group at C-22 (analogues 5 and 6) generates the compounds that are slightly more potent than 1α,25-(OH)(2)D(3) in the in vitro tests but much less potent in vivo. The greatest in vitro and in vivo biological activity was achieved when the C-20 is in the S configuration and the C-22 is in the R configuration. The building blocks for the synthesis, the respective (20R,22R)-, (20R,22S)-, (20S,22R)-, and (20S,22S)-diols, were obtained by fractional crystallization of mixtures of the corresponding diastereomers. Structures and absolute configurations of the diols 21a, 21b, and 22a as well as analogues 3a, 5, and 6 were confirmed by the X-ray crystallography.

journal_name

J Med Chem

journal_title

Journal of medicinal chemistry

authors

Flores A,Sicinski RR,Grzywacz P,Thoden JB,Plum LA,Clagett-Dame M,DeLuca HF

doi

10.1021/jm300187x

subject

Has Abstract

pub_date

2012-05-10 00:00:00

pages

4352-66

issue

9

eissn

0022-2623

issn

1520-4804

journal_volume

55

pub_type

杂志文章

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