Dual inhibitors of epidermal growth factor receptor and topoisomerase II alpha derived from a quinoline scaffold

作者：Chauhan Monika; Joshi Gaurav; Kler Harveen; Kashyap Archana; Amrutkar Suyog M; Sharma Praveen; Bhilare Kiran D; Banerjee Uttam Chand; Singh Sandeep; Kumar Raj

来源：RSC Advances, 2016, 6(81): 77717-77734.

DOI：10.1039/c6ra15118c

Based on the quinazoline bearing EGFR inhibitors, a series of thirty four compounds having a quinoline scaffold were synthesised and evaluated in vitro for EGFR kinase inhibitory activity. A structure-activity relationship study revealed that 2,4-bis(arylamino) substituted quinolines possessed better anti-EGFR kinase activity. Compounds 3f and 3m emerged as potent EGFR kinase inhibitors (200 and 210 nM, respectively) and showed excellent anticancer activity at the micromolar level against a panel of cancer cell lines comparable to erlotinib. Furthermore, representative compounds inhibited the human topoisomerase IIa selectively and catalytically, did not intercalate with DNA, increased intracellular ROS concentration (except 3m) and altered the mitochondrial membrane potential of the cancer cells. Cell cycle analysis and annexin-V staining in a lung cancer cell line showed that the compounds delayed cell cycle progression by inducing cell cycle arrest and subsequent apoptosis at the G1 phase. The facts were further corroborated through molecular modeling studies.

• 出版日期2016