Arsenou Evaggelia S, Fousteris Manolis A, Koutsourea Anna I, Papageorgiou Athanasios, Karayianni Venetia, Mioglou Eleftheria, Iakovidou Zafiria, Mourelatos Dionysios, Nikolaropoulos Sotiris S
Laboratory of Pharmaceutical Chemistry, School of Health Sciences, Department of Pharmacy, University of Patras, Rion-Patras, Greece.
Anticancer Drugs. 2004 Nov;15(10):983-90. doi: 10.1097/00001813-200411000-00008.
We have investigated the role of the allylic 7-ketone in oxidized Delta5-steroids on antileukemic activity. We synthesized and studied a series of oxidized and non-oxidized steroidal esters of p-N,N-bis(2-chloroethyl)aminophenylacetic acid (PHE), chlorambucil's active metabolite. In a comparative study of these 7-keto derivatives, on a molecular basis, regarding their ability to induce sister chromatid exchanges (SCEs) and to inhibit cell proliferation in normal human lymphocytes in vitro, the results with these 7-keto derivatives, on a molecular basis, correlated well with their antileukemic potency against leukemia P388- and L1210-bearing mice, which proved to be significantly increased compared to that of the non-oxidized derivatives. Our results indicate that the role of the steroidal skeleton it is not only for the transportation of the alkylating agent into the cell, but also contributes directly to the mechanism of antileukemic action, by an as-yet unknown way. The main conclusion from this study is that the existence of the allylic 7-keto group in the skeleton of the Delta5-steroidal esters impressively enhances their antileukemic activity, while the toxicity remains at clinically acceptable levels, suggesting that this structural modification should be further investigated.
我们研究了氧化Δ5-甾体中烯丙基7-酮在抗白血病活性方面的作用。我们合成并研究了一系列对-N,N-双(2-氯乙基)氨基苯乙酸（PHE，苯丁酸氮芥的活性代谢产物）的氧化和未氧化甾体酯。在对这些7-酮衍生物的分子水平比较研究中，考察它们在体外诱导正常人淋巴细胞姐妹染色单体交换（SCEs）和抑制细胞增殖的能力，这些7-酮衍生物的研究结果在分子水平上与它们对携带白血病P388和L1210的小鼠的抗白血病效力密切相关，与未氧化衍生物相比，其抗白血病效力显著增强。我们的结果表明，甾体骨架的作用不仅在于将烷化剂转运到细胞中，还以一种尚不清楚的方式直接促成抗白血病作用机制。这项研究的主要结论是，Δ5-甾体酯骨架中烯丙基7-酮基团的存在显著增强了它们的抗白血病活性，而毒性仍处于临床可接受水平，这表明这种结构修饰应进一步研究。
