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

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• 作者：Ravi Kumar Vyas Devambatla ; Ojas A. Namjoshi ; Shruti Choudhary ; Ernest Hamel ; Corena V. Shaffer ; Cristina C. Rohena ; Susan L. Mooberry ; Aleem Gangjee
• 刊名：Journal of Medicinal Chemistry
• 出版年：2016
• 出版时间：June 23, 2016
• 年：2016
• 卷：59
• 期：12
• 页码：5752-5765
• 全文大小：729K
• 年卷期：0
• ISSN：1520-4804

文摘

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.