Roth T, Tang W, Eisenbrand G
Department of Chemistry, University of Kaiserlautern, Germany.
Anticancer Drug Des. 1995 Dec;10(8):655-66.
Two steroid-linked phosphoramide mustard prodrugs, 7a and 7b, synthesized. The androgens testosterone and 19-nortestosterone were linked through the 17beta-position via an acetal bond to aldophosphamide (3). Proton-catalyzed, as well as cytochrome P450-mediated cleavage of the acetal bond resulted in the release of 3 which decays into the ultimate cytotoxic species, phosphoramide mustard. In a competitive cellular binding assay, the new prodrugs displayed approximately 10-12% affinity to androgen binding proteins in breast cancer cells, relative to testosterone (100%). In the sex hormone receptor-negative cell line MDA-MB231, the testosterone conjugate 7a and the 19-nortestosterone conjugate 7b have been found to be as effective as 4-hydroperoxycyclophosphamide (5). Both compounds were more active than 5 in receptor-positive cell lines. No significant differences in response were observed, however, between receptor-negative and receptor-positive cell lines.
合成了两种与甾体相连的磷酰胺氮芥前药，即7a和7b。雄激素睾酮和19-去甲睾酮通过缩醛键在17β位与醛磷酰胺（3）相连。质子催化以及细胞色素P450介导的缩醛键裂解导致3的释放，3分解为最终的细胞毒性物质磷酰胺氮芥。在竞争性细胞结合试验中，相对于睾酮（100%），新前药对乳腺癌细胞中的雄激素结合蛋白显示出约10 - 12%的亲和力。在性激素受体阴性细胞系MDA - MB231中，已发现睾酮缀合物7a和19 - 去甲睾酮缀合物7b与4 - 氢过氧环磷酰胺（5）一样有效。在受体阳性细胞系中，这两种化合物均比5更具活性。然而，在受体阴性和受体阳性细胞系之间未观察到反应的显著差异。
