Karapidaki Irini, Papageorgiou Athanasios, Geromichalos George, Fousteris Manolis, Papaconstadinou Ioanna, Pairas George, Koutsourea Anna, Mourelatos Denis, Nikolaropoulos Sotiris, Lialiaris Theodoros
Laboratory of Biology and Genetics, Medical School, Aristotle University of Thessaloniki, Thessaloniki, Greece.
Genet Test Mol Biomarkers. 2010 Feb;14(1):93-7. doi: 10.1089/gtmb.2009.0059.
The aim of this study was to design new potentially antineoplastic agents by combining nitrogen mustard with steroidal skeleton, in an effort to improve specificity and simultaneously to reduce systemic toxicity. The steroidal part is aimed to act as a biological platform enabling the alkylating moiety to approach its site of action by altering its physicochemical properties.
The compounds tested have, as alkylating agents, either p-N,N-bis(2-chloroethyl)aminophenyl-butyrate or p-N,N-bis(2-chloroethyl)aminophenyl-acetate esterified with a modified steroidal nucleus. The four newly synthesized compounds were compared on a molar basis, regarding their ability to induce sister chromatid exchanges and modify proliferation rate indices in cultured human lymphocytes. Life span of BDF1 mice inoculated with L1210 leukemia was also estimated (antileukemic activity).
A compound having p-N,N-bis(2-chloroethyl)aminophenyl-acetate as the alkylator and two ketone groups in the steroidal part demonstrated the highest statistically significant enhancement of sister chromatid exchanges and suppression of proliferation rate indices, and also caused significant antineoplastic activity. The other compounds proved less active.
These results suggest that cytogenetic and antileukemic activity of alkylating steroidal esters depends on the configuration of the whole molecule and the appropriate combination of the alkylator with the steroidal molecule.
本研究的目的是通过将氮芥与甾体骨架相结合来设计新型潜在抗肿瘤药物，以提高特异性并同时降低全身毒性。甾体部分旨在作为一个生物平台，通过改变其物理化学性质使烷基化部分接近其作用位点。
所测试的化合物作为烷基化剂，是用修饰的甾体核酯化的对 - N,N - 双（2 - 氯乙基）氨基苯基丁酸酯或对 - N,N - 双（2 - 氯乙基）氨基苯基乙酸酯。在摩尔基础上比较了四种新合成的化合物在诱导培养的人淋巴细胞姐妹染色单体交换和改变增殖率指数方面的能力。还评估了接种L1210白血病的BDF1小鼠的寿命（抗白血病活性）。
一种以对 - N,N - 双（2 - 氯乙基）氨基苯基乙酸酯为烷基化剂且甾体部分有两个酮基的化合物在统计学上显示出姐妹染色单体交换的最高显著增强和增殖率指数的抑制，并且还具有显著的抗肿瘤活性。其他化合物活性较低。
这些结果表明，烷基化甾体酯的细胞遗传学和抗白血病活性取决于整个分子的构型以及烷基化剂与甾体分子的适当组合。
