TY - JOUR
T1 - 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
AU - Devambatla, Ravi Kumar Vyas
AU - Namjoshi, Ojas A.
AU - Choudhary, Shruti
AU - Hamel, Ernest
AU - Shaffer, Corena V.
AU - Rohena, Cristina C.
AU - Mooberry, Susan L.
AU - Gangjee, Aleem
N1 - Funding Information:
This work was supported, in part, by a grant from the National Institutes of Health, National Cancer Institute (CA142868 (to A.G., S.L.M.)); by the Presidents Council Research Excellence Award (to S.L.M.), Duquesne University Adrian Van Kaam Chair in Scholarly Excellence (to A.G.); the CTRC Cancer Center Support Grant P30 CA054174 and the Flow Cytometry Shared Resource; and by an NSF equipment grant for NMR instrumentation (NMR: CHE 0614785).
PY - 2016/6/23
Y1 - 2016/6/23
N2 - 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.
AB - 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.
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U2 - 10.1021/acs.jmedchem.6b00237
DO - 10.1021/acs.jmedchem.6b00237
M3 - Article
C2 - 27213719
AN - SCOPUS:84975815223
VL - 59
SP - 5752
EP - 5765
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
SN - 0022-2623
IS - 12
ER -