Posner G H, Lee J K, Wang Q, Peleg S, Burke M, Brem H, Dolan P, Kensler T W
Department of Chemistry, Johns Hopkins University, Baltimore, Maryland 21218, Department of Medical Specialities, The University of Texas, M. D. Anderson Cancer Center, Houston, Texas 77030, USA.
J Med Chem. 1998 Jul 30;41(16):3008-14. doi: 10.1021/jm980031t.
Four new hybrid analogues of 1alpha,25-dihydroxyvitamin D3 (1) have been synthesized in a convergent manner by joining A-ring and C, D-ring fragments. Each hybrid analogue, having a noncalcemic 1-hydroxymethyl group and a potentiating 16-ene 24,24-difluorinated C,D-ring side chain, was designed to be lipophilic and inert toward 24-hydroxylase enzyme catabolism. Each hybrid analogue with 1beta, 3alpha-substituent stereochemistry (i.e., analogues 3b and 4b) showed a pharmacologically desirable combination of in vitro high antiproliferative activity in two different cell lines and high transcriptional activity with also low calcemic activity in vivo.
通过连接A环和C、D环片段，以汇聚方式合成了四种新的1α,25-二羟基维生素D3（1）杂合类似物。每个杂合类似物都具有一个非致高钙血症的1-羟甲基基团和一个增强活性的16-烯24,24-二氟代C、D环侧链，设计使其具有亲脂性且对24-羟化酶分解代谢呈惰性。具有1β, 3α-取代基立体化学的每个杂合类似物（即类似物3b和4b）在两种不同细胞系中显示出体外高抗增殖活性、高转录活性以及体内低致高钙血症活性的药理学上理想的组合。
