2,3-dihydro-1H,7H-pyrimido[5,6,1-de]acridine-1,3,7-trione derivatives, a class of cytotoxic agents active on multidrug-resistant cell lines: Synthesis, biological evaluation, and structure-activity relationships

A series of DNA-intercalating potential antitumor agents, (amino)alkyl-subs tituted 2,3-dihydro-1H,7H-pyrimido[5,6,1-de]acridine-1,3,7-triones has been prepared by aminolysis of the corresponding 6-chloro derivative with a sui table omega-aminoalkylamine. The noncovalent DNA-binding properties of thes e compounds have been examined using a fluorometric technique. In vitro cyt otoxic potencies of these derivatives toward eight tumor cell lines, includ ing human colon adenocarcinoma (HT29, LoVo sensitive and LoVo/Dx (doxorubic in-resistant)) and human ovarian carcinoma (A2780 sensitive, A2780cisR (cis platin-resistant), CH1, CH1cisR (cisplatin-resistant), and SKOV-3) cells, a re described and compared to that of reference drugs. The cytotoxic activit y often parallels the observed DNA affinities, for almost all the target co mpounds. Interesting structure-activity relationships have been found. The octanol/water partition coefficients have also been calculated, but there w as no correlation either with cytotoxicity values or with resistance index. Three highly DNA-affinic analogues, 9 and 15f,15h, have been identified wi th a useful broad spectrum of cytotoxic activity.