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Discovery of Substituted N -Phenyl Nicotinamides as Potent Inducers of Apoptosis Using a Cell- and Caspase-Based High Throughput Screening Assay

2003; American Chemical Society; Volume: 46; Issue: 12 Linguagem: Inglês

10.1021/jm0205200

1520-4804

Sui Xiong Cai, Bao Nguyen, Shaojuan Jia, John Herich, John Guastella, Sanjeeva Reddy, Ben Tseng, John Drewe, Shailaja Kasibhatla,

Synthesis and biological activity

By applying a novel cell- and caspase-based HTS assay, a series of N-phenyl nicotinamides has been identified as a new class of potent inducers of apoptosis. Through SAR studies, a 20-fold increase in potency was achieved from a screening hit N-(4-methoxy-2-nitrophenyl)pyridine-3-carboxamide (1) to lead compound 6-methyl-N-(4-ethoxy-2-nitrophenyl)pyridine-3-carboxamide (10), with an EC(50) of 0.082 microM in the caspase activation assay in T47D breast cancer cells. The N-phenyl nicotinamides also were found to be active in the growth inhibition assay where compound 10 had a GI(50) value of 0.21 microM in T47D cells. More importantly, compound 10 was found to be equipotent in MES-SA cells and paclitaxel-resistant, p-glycoprotein overexpressed MES-SA/DX5 cells. Compounds 1 and 6-chloro-N-(4-ethoxy-2-nitrophenyl)pyridine-3-carboxamide (8), a more potent analogue, were found to arrest T47D cells in G(2)/M phase of the cell cycle followed by induction of apoptosis as measured by flow cytometry. Compound 8, which was more potent than 1 in the caspase activation assay, also was found to be more potent in G(2)/M arrest and apoptosis assay. These data confirm that the cell-based caspase activation assay is useful for screening for inducers of apoptosis, as well as for SAR studies and lead optimization. Upon further characterization, N-phenyl nicotinamides were found to be inhibitors of microtubule polymerization in vitro. The identification of N-phenyl nicotinamides as a novel series of inducers of apoptosis demonstrates that our cell- and caspase-based HTS assay is useful for the discovery and optimization of potentially novel anticancer agents.