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-<i>d</i>]­pyrimidines are reported. Synthesis involved <i>N</i>⁴-alkylation of <i>N</i>-aryl-5-methylfuro­[2,3-<i>d</i>]­pyrimidin-4-amines, obtained from Ullmann coupling of 4-amino-5-methylfuro­[2,3-<i>d</i>]­pyrimidine and appropriate aryl iodides. Compounds <b>3</b>, <b>4</b>, and <b>9</b> showed potent microtubule depolymerizing activities, while compounds <b>6</b>–<b>8</b> had slightly lower potency. Compounds <b>4</b>, <b>6</b>, <b>7</b>, and <b>9</b> inhibited tubulin assembly with IC₅₀ values comparable to that of combretastatin A-4 (CA-4). Compounds <b>3</b>, <b>4</b>, and <b>6</b>–<b>9</b> 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 <b>3</b> exhibited GI₅₀ values less than 10 nM in 47 of the cell lines. In an MDA-MB-435 xenograft model, compound <b>3</b> had statistically significant antitumor effects. The biological effects of <b>3</b> identify it as a novel, potent microtubule depolymerizing agent with antitumor activity