Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 54, Issue 7, Pages 2012-2021Publisher
AMER CHEMICAL SOC
DOI: 10.1021/jm1009428
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Funding
- U.S. National Institutes of Health [RR-16480, CA-135579]
- NIH [1U54MH084690]
- Fonds National de la Recherche Scientifique (FNRS, Belgium)
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After the initial discovery of antiproliferative and apoptosis-inducing properties of a camptothecin-inspired pentacycle based on a 1H-indeno[2',1':5,6]dihydropyrido[2,3-d]pyrimidine scaffold, a library of its analogues as well as their oxidized planar counterparts were prepared utilizing a practical multicomponent synthetic protocol. The synthesized compounds exhibited submicromolar to low micromolar antiproliferative potencies toward a panel of human cancer cell lines. Biochemical experiments are consistent with the dihydropyridine library members undergoing intracellular oxidation to the corresponding planar pyridines, which then inhibit topoisomerase II activity, leading to inhibition of proliferation and cell death. Because of facile synthetic preparation and promising antitopoisomerase activity, both the dihydropyridine and planar pyridine-based compounds represent a convenient starting point for anticancer drug discovery.
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