Design, Synthesis, and Preclinical Evaluation of 4‑Substituted-5-methyl-furo[2,3‑<i>d</i>]pyrimidines as Microtubule Targeting Agents That Are Effective against Multidrug Resistant Cancer Cells

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 6–8 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 6–9 circumvented Pgp and βIII-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.本研究报道了8种4-取代-5-甲基呋喃并[2,3-d]嘧啶类化合物的设计、合成及生物学评价。该类化合物的合成以4-氨基-5-甲基呋喃并[2,3-d]嘧啶与相应芳基碘化物经乌尔曼（Ullmann）偶联反应得到N-芳基-5-甲基呋喃并[2,3-d]嘧啶-4-胺，随后对其进行N4位烷基化修饰完成。活性测试结果显示，化合物3、4与9表现出强效的微管解聚活性，化合物6至8的活性稍弱；化合物4、6、7与9对微管蛋白聚合的抑制活性半数抑制浓度（IC50）与康普瑞汀A-4（combretastatin A-4, CA-4）相当。化合物3、4及6至8可规避P-糖蛋白（Pgp）与βIII-微管蛋白介导的多药耐药性，该机制可限制紫杉醇、多西他赛及长春花生物碱类药物的临床疗效。在美国国家癌症研究所（NCI）60株细胞系筛选模型中，化合物3在47株细胞系中的生长抑制半数浓度（GI50）低于10 nM；在MDA-MB-435细胞异种移植瘤模型中，化合物3展现出具有统计学显著性的抗肿瘤活性。综上，化合物3的生物学效应表明其是一类结构新颖、活性强效的微管解聚剂，兼具抗肿瘤活性。