Department of Chemistry, University of Warsaw, Pasteura 1, 02-093 Warsaw, Poland.
J Med Chem. 2011 Oct 13;54(19):6832-42. doi: 10.1021/jm200743p. Epub 2011 Sep 16.
As a continuation of our efforts directed to vitamin D compounds of promising biological properties, 19-norvitamins 9-13, possessing a 3'-hydroxypropylidene fragment attached to C-2 and shortened 17β-alkyl chains, were synthesized. A new synthetic pathway providing the CD-ring ketones 20-24 is described starting from the epimeric aldehydes 25 and 26. The hydrindanones 20-24 were subjected to the Wittig-Horner reaction with the phosphine oxide 14, and the vitamin D compounds 9-13 were obtained after hydroxyl deprotection. In comparison to 1α,25-(OH)(2)D(3) (1), the prepared analogues, except for the 20R-compound 12, were only ca. 3 times less potent in binding to VDR. Compounds 9-11 and 13 exhibited HL-60 cellular activity 5-20 times lower and transcriptional activity ca. 10 times decreased related to those for the hormone 1. When tested in vivo, all the analogues showed no ability to mobilize calcium from bone, and intestinal calcium transport activity was observed only at high doses of the vitamins 10, 12, and 13.
作为我们致力于具有有前途的生物特性的维生素 D 化合物的努力的延续，合成了具有连接到 C-2 的 3'-羟丙叉片段和缩短的 17β-烷基链的 19-降维生素 9-13。描述了一种从差向立体醛 25 和 26 开始提供 CD-环酮 20-24 的新合成途径。将氢茚酮 20-24 进行Wittig-Horner 反应与膦氧化物 14，然后在羟基脱保护后得到维生素 D 化合物 9-13。与 1α,25-(OH)(2)D(3) (1)相比，除了 20R-化合物 12 之外，所制备的类似物与 VDR 的结合能力仅约低 3 倍。化合物 9-11 和 13 的 HL-60 细胞活性比激素 1 低 5-20 倍，转录活性约低 10 倍。在体内测试时，所有类似物均没有从骨骼中动员钙的能力，并且仅在高剂量的维生素 10、12 和 13 时观察到肠钙转运活性。
