ChemInform Abstract: Antiproliferative Hybrid Analogues of the Hormone 1α,25‐ Dihydroxyvitamin D3: Design, Synthesis, and Preliminary Biological Evaluation.

Abstract

Antiproliferative Hybrid Analogues of the Hormone 1α,25-Dihydroxyvitamin D3: Design, Synthesis, and Preliminary Biological Evaluation.-Seventeen analogues of the title compound are prepared and tested for in vitro antiproliferative activity. (XIVa) is found to parallel the high activity of natural dihydroxyvitamin D3 even at low nanomolar levels. -(POSNER, G. H.; LEE, J. K.; WHITE, M. C.; HUTCHINGS, R. H.; DAI, H.; KACHINSKI, J. L.; DOLAN, P.; KENSLER, T. W.; J.

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

“…The first approach to prepare 22-methyl-1α,25-(OH) 2 D 3 analogues was based on the stereoselective conjugate addition of organocuprate to the steroidal ( E )- and ( Z )-22-ene-24-ketones . We describe herein a convergent synthesis of all the four diastereomers of 22-methyl-1α,25-(OH) 2 D 3 where the key precursors are nitriles 9 and 10 , readily obtainable from the Inhoffen–Lythgoe diol . In contrast to similar synthetic approaches, independently proposed by Fujishima and Mouriño, we used crystallization, avoiding the expensive separation of the C,D-ring isomers by flash chromatography or HPLC.…”

“…As shown in Scheme , the vitamin D analogues 3a and 3b were prepared from the 20 S -tosylate 7 . Its substitution with cyanide provided the nitrile 9 (in 97% yield) that was alkylated at the α-position with bromide A using LDA as a base to give the compounds 11a , b (93% yield) being a mixture of epimers at C-22.…”

“…The synthesis of the diastereomeric vitamins 4a and 4b started from the 20 R -tosylate 8 and followed the analogous path. Also in this case, fractional crystallization from ethyl acetate of the epimeric pair of 20,22-diols 22a and 22b , obtained in a ratio of 2:1, played a crucial role.…”