19-去甲-1α,25-二羟胆钙化醇脱去 26-甲基后，体内的钙调节活性明显降低，但并不改变维生素 D 受体结合、HL-60 细胞分化和转录的体外活性。
Removal of the 26-methyl group from 19-nor-1α,25-dihydroxyvitamin D₃ markedly reduces in vivo calcemic activity without altering in vitro VDR binding, HL-60 cell differentiation, and transcription.
机构信息
Department of Biochemistry, University of Wisconsin-Madison, Madison, Wisconsin 53706, USA.
出版信息
J Med Chem. 2010 Dec 23;53(24):8642-9. doi: 10.1021/jm1010447. Epub 2010 Nov 24.
Abstract
Twelve new analogues of 19-nor-1α,25-dihydroxyvitamin D₃ (5-16) were prepared by convergent syntheses, employing the Wittig-Horner reaction. The necessary Grundmann type ketones (45-48), possessing fixed configurations of the hydroxyl group at C-25, were obtained by a multistep procedure from commercial vitamin D₂ and enantiomers of 1,3-butanediol (23 and 24). We have examined the influence of removal of one of the methyl groups located at C-25 on the biological in vitro and in vivo activity. The in vivo tests showed that the synthesized vitamin D compounds (5-16) exhibit reduced calcemic activity both in bone and in the intestine. However, in vitro potency of 2-methylene and 2α-methyl compounds (5-10, 13, and 14) remained similar or enhanced as compared to that of 1α,25-(OH)₂D₃.
摘要
12 种新型 19-去甲-1α,25-二羟维生素 D₃（5-16）类似物通过会聚合成法制备，采用 Wittig-Horner 反应。必要的 Grundmann 酮（45-48），具有 C-25 处羟基的固定构型，通过从商业维生素 D₂和 1,3-丁二醇的对映异构体（23 和 24）的多步程序获得。我们研究了去除 C-25 上的一个甲基对生物体外和体内活性的影响。体内试验表明，合成的维生素 D 化合物（5-16）在骨骼和肠道中均表现出降低的钙活性。然而，2-亚甲基和 2α-甲基化合物（5-10、13 和 14）的体外效力与 1α,25-（OH）₂D₃相比保持相似或增强。
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