Department of Chemistry and Analytical and Biological Chemistry Research Facility, University College Cork, Cork, Ireland.
Org Biomol Chem. 2013 Feb 28;11(8):1334-44. doi: 10.1039/c2ob27186a.
Drugs that inhibit DNA topoisomerase I and DNA topoisomerase II have been widely used in cancer chemotherapy. We report herein the results of a focused medicinal chemistry effort around novel ellipticinium salts which target topoisomerase I and II enzymes with improved solubility. The salts were prepared by reaction of ellipticine with the required alkyl halide and evaluated for DNA intercalation, topoisomerase inhibition and growth inhibition against 12 cancer cell lines. Results from the topoisomerase I relaxation assay indicated that all novel ellipticine derivatives behaved as intercalating agents. At a concentration of 100 μM, specific topoisomerase I inhibition was not observed. Two of the derivatives under investigation were found to fully inhibit the DNA decatenation reaction at a concentration of 100 μM, indicative of topoisomerase II inhibition. N-Alkylation of ellipticine was found to enhance the observed growth inhibition across all cell lines and induce growth inhibition comparable to that of Irinotecan (CPT-11; GI(50) 1-18 μM) and in some cell lines better than Etoposide (VP-16; GI(50) = 0.04-5.2 μM). 6-Methylellipticine was the most potent growth inhibitory compound assessed (GI(50) = 0.47-0.9 μM). N-Alkylation of 6-methylellipticine was found to reduce this response with GI(50) values in the range of 1.3-28 μM.
抑制 DNA 拓扑异构酶 I 和 DNA 拓扑异构酶 II 的药物已广泛用于癌症化疗。我们在此报告了一项集中药物化学研究的结果，该研究围绕新型椭圆素盐展开，这些盐针对拓扑异构酶 I 和 II 酶，具有改善的溶解性。这些盐是通过椭圆素与所需的烷基卤化物反应制备的，并评估了它们对 DNA 嵌入、拓扑异构酶抑制和对 12 种癌细胞系的生长抑制作用。拓扑异构酶 I 松弛测定的结果表明，所有新型椭圆素衍生物均表现为嵌入剂。在 100 μM 的浓度下，未观察到特定的拓扑异构酶 I 抑制。研究中的两种衍生物在 100 μM 的浓度下完全抑制了 DNA 解链反应，表明拓扑异构酶 II 抑制。椭圆素的 N-烷基化被发现增强了所有细胞系中观察到的生长抑制作用，并诱导了与伊立替康（CPT-11；GI(50) 1-18 μM）相当的生长抑制，并且在一些细胞系中优于依托泊苷（VP-16；GI(50) = 0.04-5.2 μM）。6-甲基椭圆素是评估的最有效的生长抑制化合物（GI(50) = 0.47-0.9 μM）。6-甲基椭圆素的 N-烷基化被发现降低了这种反应，GI(50)值在 1.3-28 μM 的范围内。
