Pharmaceutical Sciences and Natural Products - Research Publications

Permanent URI for this collectionhttps://kr.cup.edu.in/handle/32116/56

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Dual inhibitors of epidermal growth factor receptor and topoisomerase IIa derived from a quinoline scaffold
(Royal Society of Chemistry, 2016) Chauhan, Monika; Joshi, Gaurav; Kler, Harveen; Kashyap, Archana; Amrutkar, Suyog M.; Sharma, Praveen; Bhilare, Kiran D.; Banerjee, Uttam C.; Singh, Sandeep; Kumar, Raj
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 II? 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. ? 2018 The Royal Society of Chemistry.
Synthesis and biological evaluation of new 2, 5- dimethylthiophene/furan based N-acetyl pyrazolines as selective topoisomerase II inhibitors
(Royal Society of Chemistry, 2016) Darpan; Joshi, Gaurav; Amrutkar, Suyog M.; Baviskar, Ashish T.; Kler, Harveen; Singh, Sandeep; Banerjee, Uttam C.; Kumar, Raj
Based on the reported pharmacophores as topoiomerase inhibitors, 2,5 dimethylthiophen/furan based N-acetyl pyrazolines were designed and envisaged as topoisomerase inhibitors. The target compounds were synthesized and tested in vitro against human topoisomerases in decatenation, relaxation, cleavage complex and DNA intercalation assay. Out of 29 compounds, three (10, 11 and 29) showed potent and selective toposiomerse II inhibitory activity with no intercalation with DNA. Further, molecular docking studies also endorsed them as ATP dependent topoisomerase II catalytic inhibitors. These compounds exerted potential anticancer effects on breast, colon, lung and prostate cancer cell lines at low micromolar level as compared to etoposide and low toxicity to normal cells. Apart from the topoisomerase II inhibition, these compounds also induced the reactive oxygen species (ROS) level in cancer cells. The cell cycle analyses showed their apoptotic effect at G1 phase.