Karthikeyan Chandrabose, Jharia Pramod, Waiker Digambar Kumar, Nusbaum Amy Catherine, Amawi Haneen, Kirwen Erin Marie, Christman Ryann, Arudra Sri Krishna Chaitanya, Meijer Laurent, Tiwari Amit K, Trivedi Piyush
School of Pharmaceutical Sciences, Rajiv Gandhi ProudyogikiVishwavidyalaya, Bhopal 462033, MP, India.
Department of Pharmacology and Experimental Therapeutics, College of Pharmacy & Pharmaceutical Sciences, University of Toledo, OH, USA.
Bioorg Med Chem Lett. 2017 Jun 15;27(12):2663-2667. doi: 10.1016/j.bmcl.2017.04.080. Epub 2017 Apr 27.
Described herein is the design, synthesis and biological evaluation of a series of N-(1H-pyrazol-3-yl)quinazolin-4-amines against a panel of eight disease relevant protein kinases. The kinase inhibition results indicated that two compounds inhibited casein kinase 1δ/ε (CK1δ/ε) with some selectivity over related kinases, namely CDK5/p25, GSK-3α/β, and DYRK1A. Docking studies with 3c and 3d revealed the key interactions with desired amino acids in the ATP binding site of CK1δ. Furthermore, compound 3c also elicited selective cytotoxic activity against the pancreas ductal adenocarcinoma (PANC-1) cell line. Taken together, the results of this study establish N-(1H-pyrazol-3-yl)quinazolin-4-amines especially 3c and 3d as valuable lead molecules with great potential for CK1δ/ε inhibitor development targeting neurodegenerative disorders and cancer.
本文描述了一系列N-(1H-吡唑-3-基)喹唑啉-4-胺针对一组八种与疾病相关的蛋白激酶的设计、合成及生物学评价。激酶抑制结果表明，有两种化合物对酪蛋白激酶1δ/ε（CK1δ/ε）具有抑制作用，且对相关激酶（即细胞周期蛋白依赖性激酶5/p25、糖原合成酶激酶-3α/β和双重特异性酪氨酸磷酸化调节激酶1A）具有一定的选择性。对3c和3d进行的对接研究揭示了其与CK1δ的ATP结合位点中所需氨基酸的关键相互作用。此外，化合物3c对胰腺导管腺癌（PANC-1）细胞系也具有选择性细胞毒性活性。综上所述，本研究结果确立了N-(1H-吡唑-3-基)喹唑啉-4-胺，尤其是3c和3d作为有价值的先导分子，在开发针对神经退行性疾病和癌症的CK1δ/ε抑制剂方面具有巨大潜力。
