Glebocka Agnieszka, Sicinski Rafal R, DeLuca Hector F
Department of Biochemistry, University of Wisconsin-Madison, 433 Babcock Drive, Madison, WI 53706, USA.
J Steroid Biochem Mol Biol. 2004 May;89-90(1-5):25-30. doi: 10.1016/j.jsbmb.2004.03.105.
In pursuit of novel biologically active Vitamin D compounds of potential therapeutic value, 1alpha,25-dihydroxy-2-[3'-(methoxymethoxy)propylidene]-19-norvitamin D(3) (7) was efficiently prepared in a convergent synthesis, starting with (-)-quinic acid and the protected 25-hydroxy Grundmann ketone 16. The key synthetic step involved Lythgoe type Wittig-Horner coupling of 16, with the phosphine oxide 15. Molecular modeling was employed to establish the A-ring conformation of the synthesized Vitamin 7. Also, preliminary modeling of its complex with the rVDR was performed and interactions between ligand and the binding domain analyzed. Analog 7 was found to be only six times less potent than 1alpha,25-(OH)(2)D(3) (1) in binding to the rat recombinant Vitamin D receptor (VDR). In comparison with hormone 1, it also showed slightly lower cellular HL-60-differentiation activity. Preliminary in vivo tests indicated unusually high calcemic activity of 7.
为了寻找具有潜在治疗价值的新型生物活性维生素D化合物，以（-）-奎尼酸和受保护的25-羟基格伦德曼酮16为起始原料，通过汇聚合成法高效制备了1α,25-二羟基-2-[3'-(甲氧基甲氧基)亚丙基]-19-去甲维生素D(3)（7）。关键的合成步骤涉及16与氧化膦15的Lythgoe型维蒂希-霍纳偶联反应。采用分子建模来确定合成的维生素7的A环构象。此外，还对其与rVDR的复合物进行了初步建模，并分析了配体与结合域之间的相互作用。发现类似物7与大鼠重组维生素D受体（VDR）结合的活性仅比1α,25-(OH)(2)D(3)（1）低六倍。与激素1相比，它还表现出略低的细胞HL-60分化活性。初步体内试验表明7具有异常高的血钙活性。
