Allewaert K, Zhao X Y, Zhao J, Glibert F, Branisteanu D, De Clercq P, Vandewalle M, Bouillon R
Laboratory of Experimental Medicine and Endocrinology, Gasthuisberg, Katholieke Universiteit Leuven, Belgium.
Steroids. 1995 Apr;60(4):324-32. doi: 10.1016/0039-128x(94)00072-k.
The biological activity of 16-epoxy side-chain analogs of 1 alpha,25-dihydroxyvitamin D3, (1 alpha,25(OH)2D3) was evaluated in vitro and in vivo. Compared to 1 alpha,25(0H)2D3, all analogs had lower affinities for the pig duodenal vitamin D receptor and also for the human serum vitamin D binding protein. The in vitro effects on cell proliferation or differentiation of human promyeloid leukemia (induction of superoxide production in HL-60 cells), human osteosarcoma MG-63 cells (osteocalcin secretion), or human breast cancer cells (incorporation of thymidine in MCF-7 cells), was markedly inhibited by several epoxy analogs, compared to 1 alpha,25(OH)2D3, but the rank order of their activity widely varied among different cancer cells. The most potent analogs (24S,25S-24-hydroxy-25,26-epoxy-22-ene-1 alpha-OHD3, 25,26-epoxy-23-yne-1 alpha-OHD3, and 25,26-epoxy-23-yne-20-epi-1 alpha-OHD3 or compounds, 16, 5, and 7, respectively) were equipotent (16 and 5) or 30-fold (compound 7 on MG-63 cells) to 40-fold (compound 7 on MCF-7 cells) more active than 1 alpha,25-(OH)2D3. These analogs were nevertheless poorly antirachitic (< 3%) when tested in vitamin D-deficient chicks (using serum and bone calcium, serum osteocalcin and duodenal calbindin D-28K, as end points). Compound 7 was also 100-fold more active than 1 alpha,25-(OH)2D3 in inhibition of proliferation of human foreskin keratinocytes. Some epoxy analogs of 1 alpha,25-(OH)2D3 thus display interesting dissociations between their receptor affinity and their potency to induce cell differentiation, whereas their effect on cell proliferation/differentiation exceed their calcemic effects more than 100- to 1000-fold.
对1α,25 - 二羟基维生素D3（1α,25(OH)2D3）的16 - 环氧侧链类似物的生物活性进行了体外和体内评估。与1α,25(OH)2D3相比，所有类似物对猪十二指肠维生素D受体以及人血清维生素D结合蛋白的亲和力都较低。与1α,25(OH)2D3相比，几种环氧类似物对人早幼粒细胞白血病（HL - 60细胞中超氧化物产生的诱导）、人骨肉瘤MG - 63细胞（骨钙素分泌）或人乳腺癌细胞（MCF - 7细胞中胸苷掺入）的细胞增殖或分化的体外作用受到明显抑制，但其活性的排序在不同癌细胞之间差异很大。最有效的类似物（分别为24S,25S - 24 - 羟基 - 25,26 - 环氧 - 22 - 烯 - 1α - OHD3、25,26 - 环氧 - 23 - 炔 - 1α - OHD3和25,26 - 环氧 - 23 - 炔 - 20 - 表 - 1α - OHD3或化合物16、5和7）与1α,25 - (OH)2D3相比，活性相当（化合物16和5）或高30倍（化合物7对MG - 63细胞）至40倍（化合物7对MCF - 7细胞）。然而，在维生素D缺乏的雏鸡中进行测试时（以血清和骨钙、血清骨钙素和十二指肠钙结合蛋白D - 28K为终点），这些类似物的抗佝偻病活性很差（<3%）。化合物7在抑制人包皮角质形成细胞增殖方面的活性也比1α,25 - (OH)2D3高100倍。因此，1α,25 - (OH)2D3的一些环氧类似物在其受体亲和力与其诱导细胞分化的效力之间表现出有趣的差异，而它们对细胞增殖/分化的影响比其血钙作用高出100至1000倍以上。
