The design, synthesis and biological evaluations of eight 4-substituted 5-methyl-furo[2,3-d]pyrimidines are reported. Synthesis involved N4-alkylation of N-aryl-5-methylfuro[2,3-d]pyrimidin-4-amines, obtained from Ullmann coupling of 4-amino-5-methylfuro[2,3-d]pyrimidine and appropriate aryl iodides. Compounds 3, 4 and 9 showed potent microtubule depolymerizing activities, while compounds 68 had slightly lower potency. Compounds 4, 6, 7 and 9 inhibited tubulin assembly with IC50 values comparable to that of combretastatin A-4 (CA-4). Compounds 3, 4, and 69 circumvented Pgp and betaIII-tubulin mediated drug resistance, mechanisms that can limit the efficacy of paclitaxel, docetaxel and the vinca alkaloids. In the NCI 60-cell line panel, compound 3 exhibited GI50 values less than 10 nM in 47 of the cell lines. In an MDA-MB-435 xenograft model, compound 3 had statistically significant antitumor effects. The biological effects of 3 identify it as a novel, potent microtubule depolymerizing agent with antitumor activity.

中文翻译：

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设计，合成和临床前评估的4-取代的5-甲基-呋喃并[2,3-d]嘧啶类作为微管靶向药物，可有效抵抗多药耐药癌细胞。

报道了八个4-取代的5-甲基-呋喃[2,3-d]嘧啶的设计，合成和生物学评估。合成涉及N-芳基-5-甲基呋喃[2,3-d]嘧啶-4-胺的N4-烷基化反应，该胺是通过4-氨基-5-甲基呋喃[2,3-d]嘧啶与适当的芳基碘化物的乌尔曼偶合获得。化合物3、4和9表现出有效的微管解聚活性，而化合物68的效力稍低。化合物4、6、7和9抑制微管蛋白组装，其IC50值可与康维他汀A-4（CA-4）相比。化合物3、4和69规避了Pgp和βIII-微管蛋白介导的耐药性，这些机制可能会限制紫杉醇，多西紫杉醇和长春花生物碱的功效。在NCI 60细胞株中，化合物3在47个细胞株中的GI50值小于10 nM。在MDA-MB-435异种移植模型中，化合物3具有统计学上显着的抗肿瘤作用。3的生物学效应将其鉴定为具有抗肿瘤活性的新型有效的微管解聚剂。