Meier Christopher, Steinhauer Tamara N, Koczian Fabian, Plitzko Birte, Jarolim Katharina, Girreser Ulrich, Braig Simone, Marko Doris, Vollmar Angelika M, Clement Bernd
Department of Pharmaceutical and Medicinal Chemistry, Pharmaceutical Institute of the Christian Albrechts University in Kiel, Gutenbergstraße 76, 24118, Kiel, Germany.
Department of Pharmacy, Center for Drug Research, Pharmaceutical Biology, University of Munich, Butenandtstraße 5-13, 81377, Munich, Germany.
ChemMedChem. 2017 Mar 7;12(5):347-352. doi: 10.1002/cmdc.201700026. Epub 2017 Feb 8.
Classic cytotoxic drugs remain indispensable instruments in antitumor therapy due to their effectiveness and a more prevalent insensitivity toward tumor resistance mechanisms. Herein we describe the favorable properties of 6-(N,N-dimethyl-2-aminoethoxy)-11-(3,4,5-trimethoxyphenyl)pyrido[3,4-c][1,9]phenanthroline (P8-D6), a powerful inducer of apoptosis caused by an equipotent inhibition of human topoisomerase I and II activities. A broad-spectrum effect against human tumor cell lines at nanomolar concentrations, as well as strong antileukemic effects, were shown to be superior to those of marketed topoisomerase-targeting drugs and dual topoisomerase inhibitors in clinical trials. The facile four-step synthesis, advantageous drugability properties, and initial in vivo data encourage the application of P8-D6 in appropriate animal tumor models and further drug development.
经典的细胞毒性药物因其有效性以及对肿瘤耐药机制普遍具有的不敏感性，在抗肿瘤治疗中仍然是不可或缺的手段。在此，我们描述了6-(N,N-二甲基-2-氨基乙氧基)-11-(3,4,5-三甲氧基苯基)吡啶并[3,4-c][1,9]菲咯啉（P8-D6）的良好特性，它是一种强大的凋亡诱导剂，可通过同等抑制人类拓扑异构酶I和II的活性来引发凋亡。在临床试验中，P8-D6在纳摩尔浓度下对人类肿瘤细胞系具有广谱效应，以及强大的抗白血病作用，均显示优于市售的靶向拓扑异构酶的药物和双重拓扑异构酶抑制剂。简便的四步合成方法、有利的成药特性以及初步的体内数据，促使P8-D6在合适的动物肿瘤模型中得到应用，并进一步推动药物研发。
