1 research outputs found
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-furoÂ[2,3-<i>d</i>]Âpyrimidines are reported. Synthesis
involved <i>N</i><sup>4</sup>-alkylation of <i>N</i>-aryl-5-methylfuroÂ[2,3-<i>d</i>]Âpyrimidin-4-amines, obtained
from Ullmann coupling of 4-amino-5-methylfuroÂ[2,3-<i>d</i>]Âpyrimidine 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 IC<sub>50</sub> 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 GI<sub>50</sub> 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