Abstract
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.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 5752-5765 |
| Number of pages | 14 |
| Journal | Journal of Medicinal Chemistry |
| Volume | 59 |
| Issue number | 12 |
| DOIs | |
| State | Published - Jun 23 2016 |
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ASJC Scopus subject areas
- Molecular Medicine
- Drug Discovery
Cite this
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. / Devambatla, Ravi Kumar Vyas; Namjoshi, Ojas A.; Choudhary, Shruti; Hamel, Ernest; Shaffer, Corena V.; Rohena, Cristina C.; Mooberry, Susan L; Gangjee, Aleem.
In: Journal of Medicinal Chemistry, Vol. 59, No. 12, 23.06.2016, p. 5752-5765.Research output: Contribution to journal › Article
}
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
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.
UR - http://www.scopus.com/inward/record.url?scp=84975815223&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84975815223&partnerID=8YFLogxK
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 -