Beck Daniel E, Abdelmalak Monica, Lv Wei, Reddy P V Narasimha, Tender Gabrielle S, O'Neill Elizaveta, Agama Keli, Marchand Christophe, Pommier Yves, Cushman Mark
†Department of Medicinal Chemistry and Molecular Pharmacology, College of Pharmacy, and the Purdue Center for Cancer Research, Purdue University, 575 Stadium Mall Drive, West Lafayette, Indiana 47907, United States.
‡Laboratory of Molecular Pharmacology, Center for Cancer Research, National Cancer Institute, NCI-Frederick, Frederick, Maryland 21702, United States.
J Med Chem. 2015 May 14;58(9):3997-4015. doi: 10.1021/acs.jmedchem.5b00303. Epub 2015 Apr 24.
3-Nitroindenoisoquinoline human topoisomerase IB (Top1) poisons have potent antiproliferative effects on cancer cells. The undesirable nitro toxicophore could hypothetically be replaced by other functional groups that would retain the desired biological activities and minimize potential safety risks. Eleven series of indenoisoquinolines bearing 3-nitro bioisosteres were synthesized. The molecules were evaluated in the Top1-mediated DNA cleavage assay and in the National Cancer Institute's 60 cell line cytotoxicity assay. The data reveal that fluorine and chlorine may substitute for the 3-nitro group with minimal loss of Top1 poisoning activity. The new information gained from these efforts can be used to design novel indenoisoquinolines with improved safety.
3-硝基茚并异喹啉类人拓扑异构酶IB（Top1）抑制剂对癌细胞具有强大的抗增殖作用。理论上，不良的硝基毒性基团可以被其他官能团取代，这些官能团将保留所需的生物活性并将潜在的安全风险降至最低。合成了11个带有3-硝基生物电子等排体的茚并异喹啉系列。这些分子在Top1介导的DNA切割试验和美国国立癌症研究所的60细胞系细胞毒性试验中进行了评估。数据表明，氟和氯可以替代3-硝基，而Top1抑制活性的损失最小。这些研究获得的新信息可用于设计安全性更高的新型茚并异喹啉类化合物。
