Spicer J A, Gamage S A, Rewcastle G W, Finlay G J, Bridewell D J, Baguley B C, Denny W A
Auckland Cancer Society Research Centre, Faculty of Medical and Health Sciences, The University of Auckland, Private Bag 92019, Auckland 1000, New Zealand.
J Med Chem. 2000 Apr 6;43(7):1350-8. doi: 10.1021/jm990423f.
Ring-substituted bis(phenazine-1-carboxamides), linked by a -(CH(2))(3)NMe(CH(2))(3)- chain, were prepared from the corresponding substituted phenazine-1-carboxylic acids by reaction of the intermediate imidazolides with bis(3-aminopropyl)methylamine. The compounds were evaluated for growth inhibitory activity in a panel of tumor cell lines, including P388 leukemia, Lewis lung carcinoma, and wild-type (JL(C)) and mutant (JL(A) and JL(D)) forms of human Jurkat leukemia. The latter mutant lines are resistant to topoisomerase (topo) II targeted agents because of lower levels of the enzyme. Analogues with small, lipophilic substituents (e.g., Me, Cl) at the 9-position were the most potent inhibitors, superior to the corresponding dimeric bis(acridine-4-carboxamides) (bis-DACA analogues). Several of the compounds were preferentially (up to 2-fold) more cytotoxic toward the mutant Jurkat lines than the wild-type. To test whether this selectivity was related to topoisomerase action, the most potent of the compounds (9-methyl) was evaluated in a cell-free system. It poisoned topo I at drug concentrations of 0.25 and 0.5 microM and inhibited the catalytic activity of both topo I and topo II at concentrations of 1 and 5 microM, respectively. Results from the NCI human tumor cell line panel showed the compounds had preferential activity toward colon tumor lines (on average 9.5-fold more active in the HT29 line than in the cell line panel as a whole). Several analogues produced significant growth delays in the relatively refractory subcutaneous colon 38 tumor model in vivo. In particular, the 9-methyl compound was substantially more potent in this tumor model than the clinical dual topo I/II poison DACA (total dose 90 versus 400 mg/kg) with comparable activity. The bis(phenazine-1-carboxamides) are a new and interesting class of dual topo I/II-directed anticancer drugs.
通过中间体咪唑化物与双（3 - 氨丙基）甲胺反应，由相应的取代吩嗪 - 1 - 羧酸制备了由 -（CH₂）₃NMe（CH₂）₃ - 链连接的环取代双（吩嗪 - 1 - 甲酰胺）。在一组肿瘤细胞系中评估了这些化合物的生长抑制活性，包括P388白血病、Lewis肺癌以及人Jurkat白血病的野生型（JL（C））和突变型（JL（A）和JL（D））。后一种突变系由于拓扑异构酶（topo）II水平较低而对topo II靶向药物耐药。在9位带有小的亲脂性取代基（如Me、Cl）的类似物是最有效的抑制剂，优于相应的二聚体双（吖啶 - 4 - 甲酰胺）（双 - DACA类似物）。几种化合物对突变的Jurkat系的细胞毒性比对野生型的优先（高达2倍）更高。为了测试这种选择性是否与拓扑异构酶作用有关，在无细胞系统中评估了最有效的化合物（9 - 甲基）。它在药物浓度为0.25和0.5 microM时使topo I中毒，在浓度分别为1和5 microM时抑制topo I和topo II的催化活性。美国国立癌症研究所（NCI）人类肿瘤细胞系面板的结果表明，这些化合物对结肠肿瘤系具有优先活性（在HT29系中平均活性比整个细胞系面板高9.5倍）。几种类似物在相对难治的皮下结肠38肿瘤体内模型中产生了显著的生长延迟。特别是，9 - 甲基化合物在该肿瘤模型中比临床双topo I/II毒药DACA（总剂量90对400 mg/kg）效力更强，活性相当。双（吩嗪 - 1 - 甲酰胺）是一类新型且有趣的双topo I/II导向抗癌药物。
