Fuska J, Fusková A, Rosazza J P, Nicholas A W
Neoplasma. 1984;31(1):31-6.
In vitro effects of withaferin A and its 9 new derivatives on P388 cells have been studied. The cytotoxicity was calculated from the utilization of precursors in protein and nucleic acid (NA) synthesis and from capacity to suppress cell proliferation. The most potent agents proved to be 4-dehydrowithaferin A and withaferin A diacetate exhibited an equal inhibitory effect on thymidine, uridine, and L-valine incorporation. They stopped cell proliferation and, at the same time, killed the cells. Cytotoxicity was found to be due to a double bond at position C2-3, by dissociating this bond the cytotoxicity markedly decreased in all derivatives. A dissociation of the double bond at C24-25 or a removal of OH group from C27 did not cause any significant changes in the biological effects of the derivatives. An addition of a carbonyl group at C4 increased the effects of the agent. An addition of OH groups to the molecule of withaferin A resulted chiefly in a qualitative change in the action of derivatives manifested by a significant decrease in L-valine inhibition. As withaferin A promptly reacted with L-cysteine, it was presumed that one of the possible target sites in the cell might be the SH groups of enzymes which react with the lactone and epoxide groups of the agent.
已研究了睡茄内酯A及其9种新衍生物对P388细胞的体外作用。细胞毒性是根据蛋白质和核酸（NA）合成中前体的利用情况以及抑制细胞增殖的能力来计算的。最有效的药物是4-脱氢睡茄内酯A，睡茄内酯A二乙酸酯对胸苷、尿苷和L-缬氨酸掺入表现出同等的抑制作用。它们停止细胞增殖，同时杀死细胞。发现细胞毒性是由于C2-3位的双键，通过断开此键，所有衍生物的细胞毒性均显著降低。C24-25位双键的断开或C27位羟基的去除对衍生物的生物学效应未引起任何显著变化。在C4位添加羰基增强了药物的作用。在睡茄内酯A分子中添加羟基主要导致衍生物作用的定性变化，表现为L-缬氨酸抑制作用显著降低。由于睡茄内酯A能迅速与L-半胱氨酸反应，推测细胞中可能的靶位点之一可能是与该药物的内酯和环氧基团反应的酶的SH基团。
