Structure-activity relationships for pyrido-, imidazo-, pyrazolo-, pyrazino-, and pyrrolophenazinecarboxamides as topoisomerase-targeted anticancer agents
Structure-activity relationships for pyrido-, imidazo-, pyrazolo-, pyrazino-, and pyrrolophenazinecarboxamides as topoisomerase-targeted anticancer agents
复制标题
DOI：
10.1021/jm010330
复制
发表时间：
2002-01-31
影响因子：
7.3
通讯作者：
Denny, WA
中科院分区：
文献类型：
--
作者：
Gamage, SA;Spicer, JA;Denny, WA
以氨基杂环化合物和2-卤代-3-硝基苯甲酸为原料，经缩合、还原关环、酰胺化反应合成了杂环吩嗪酰胺类化合物。他们表现出类似的抑制配对的细胞系，低表达拓扑异构酶II或过度表达P-糖蛋白，表明非拓扑异构酶II的细胞毒性机制和漠不关心的P-糖蛋白介导的多药耐药。具有稠合五元杂环的化合物通常不如吡啶并[4，3-α]吩嗪有效。4-甲氧基吡啶并[4，3-a]吩嗪（IC（50）s 2.5-26 nM）给出了适度的（约1.5 nM）。5天）的生长延迟。
Heterocyclic phenazinecarboxamides were prepared by condensation of aminoheterocycles and 2-halo-3-nitrobenzoic acids, followed by reductive ring closure and amidation. They showed similar inhibition of paired cell lines that underexpressed topo II or overexpressed P-glycoprotein, indicating a non topo II mechanism of cytotoxicity and indifference to P-glycoprotein mediated multidrug resistance. Compounds with a fused five-membered heterocyclic ring were generally less potent than the pyrido[4,3-alpha]phenazines. A 4-methoxypyrido[4,3-alpha]phenazine (IC(50)s 2.5-26 nM) gave modest (ca. 5 day) growth delays in H69/P xenografts with oral dosing.