PMID- 32718297 OWN - NLM STAT- MEDLINE DCOM- 20210615 LR - 20210714 IS - 1875-5992 (Electronic) IS - 1871-5206 (Linking) VI - 21 IP - 1 DP - 2021 TI - Design, Synthesis, Molecular Docking, and Anticancer Evaluation of Pyrazole Linked Pyrazoline Derivatives with Carbothioamide Tail as EGFR Kinase Inhibitors. PG - 42-60 LID - 10.2174/1871520620666200727093613 [doi] AB - BACKGROUND: The Epidermal Growth Factor Receptor (known as EGFR) induces cell differentiation and proliferation upon activation through the binding of its ligands. Since EGFR is thought to be involved in the development of cancer, the identification of new target inhibitors is the most viable approach, which recently gained momentum as a potential anticancer therapy. OBJECTIVE: To assess various pyrazole linked pyrazoline derivatives with carbothioamide for EGFR kinase inhibitory as well as anti-proliferative activity against human cancer cell lines viz. A549 (non-small cell lung tumor), MCF-7 (breast cancer cell line), SiHa (cancerous tissues of the cervix uteri), and HCT-116 (colon cancer cell line). METHODS: In vitro EGFR kinase assay, in vitro MTT assay, Lactate dehydrogenase release, nuclear staining (DAPI), and flow cytometry cell analysis. RESULTS: Compounds 6h and 6j inhibited EGFR kinase at concentrations of 1.66muM and 1.9muM, respectively. Furthermore, compounds 6h and 6j showed the most potent anti-proliferative results against the A549 KRAS mutation cell line (IC50 = 9.3 & 10.2muM). Through DAPI staining and phase contrast microscopy, it was established that compounds 6h and 6j also induced apoptotic activity in A549 cells. This activity was further confirmed by FACS using Annexin-V-FITC and Propidium Iodide (PI) labeling. Molecular docking studies performed on 6h and 6j suggested that the compounds can bind to the hinge region of ATP binding site of EGFR tyrosine kinase in a similar pose as that of the standard drug gefitinib. CONCLUSION: The potential anticancer activity of compounds 6h and 6j was confirmed and need further exploration in cancer cell lines of different tissue origin and signaling pathways, as well as in animal models of cancer development. CI - Copyright(c) Bentham Science Publishers; For any queries, please email at epub@benthamscience.net. FAU - Nawaz, Farah AU - Nawaz F AD - Medicinal Chemistry and Molecular Modelling Lab, Department of Pharmaceutical Chemistry, School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi-110062, India. FAU - Alam, Ozair AU - Alam O AD - Medicinal Chemistry and Molecular Modelling Lab, Department of Pharmaceutical Chemistry, School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi-110062, India. FAU - Perwez, Ahmad AU - Perwez A AD - Genome Biology Lab, Department of Biosciences, Jamia Millia Islamia, New Delhi, 110025, India. FAU - Rizvi, Moshahid A AU - Rizvi MA AD - Genome Biology Lab, Department of Biosciences, Jamia Millia Islamia, New Delhi, 110025, India. FAU - Naim, Mohd Javed AU - Naim MJ AD - Medicinal Chemistry and Molecular Modelling Lab, Department of Pharmaceutical Chemistry, School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi-110062, India. FAU - Siddiqui, Nadeem AU - Siddiqui N AD - Medicinal Chemistry and Molecular Modelling Lab, Department of Pharmaceutical Chemistry, School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi-110062, India. FAU - Firdaus, Jannat Ul AU - Firdaus JU AD - Medicinal Chemistry and Molecular Modelling Lab, Department of Pharmaceutical Chemistry, School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi-110062, India. FAU - Rahman, Shakilur AU - Rahman S AD - Genome Biology Lab, Department of Biosciences, Jamia Millia Islamia, New Delhi, 110025, India. FAU - Jha, Mukund AU - Jha M AD - Medicinal Chemistry and Molecular Modelling Lab, Department of Pharmaceutical Chemistry, School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi-110062, India. FAU - Sheikh, Aadil A AU - Sheikh AA AD - Medicinal Chemistry and Molecular Modelling Lab, Department of Pharmaceutical Chemistry, School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi-110062, India. LA - eng GR - SB/FT/LS-203-2012/DST/SERB/ PT - Journal Article PT - Research Support, Non-U.S. Gov't PL - Netherlands TA - Anticancer Agents Med Chem JT - Anti-cancer agents in medicinal chemistry JID - 101265649 RN - 0 (Antineoplastic Agents) RN - 0 (Biomarkers, Tumor) RN - 0 (Protein Kinase Inhibitors) RN - 0 (Pyrazoles) RN - 0 (Thioamides) RN - EC 2.7.10.1 (EGFR protein, human) RN - EC 2.7.10.1 (ErbB Receptors) RN - S65743JHBS (Gefitinib) SB - IM MH - Antineoplastic Agents/*chemical synthesis/*pharmacology MH - Apoptosis/drug effects MH - Biomarkers, Tumor/metabolism MH - Cell Line, Tumor MH - Cell Proliferation/drug effects MH - Drug Screening Assays, Antitumor MH - ErbB Receptors/antagonists & inhibitors MH - Gefitinib/pharmacology/standards MH - Humans MH - Molecular Conformation MH - Molecular Docking Simulation MH - Molecular Targeted Therapy MH - Protein Binding MH - Protein Kinase Inhibitors/*chemical synthesis/*pharmacology MH - Pyrazoles/*chemical synthesis/pharmacology MH - Structure-Activity Relationship MH - Thioamides/*chemistry OTO - NOTNLM OT - Anticancer OT - EGFR kinase OT - apoptosis OT - carbothioamide OT - molecular docking studies OT - pyrazoline EDAT- 2020/07/29 06:00 MHDA- 2021/06/16 06:00 CRDT- 2020/07/29 06:00 PHST- 2019/11/16 00:00 [received] PHST- 2020/04/25 00:00 [revised] PHST- 2020/05/13 00:00 [accepted] PHST- 2020/07/29 06:00 [pubmed] PHST- 2021/06/16 06:00 [medline] PHST- 2020/07/29 06:00 [entrez] AID - ACAMC-EPUB-108479 [pii] AID - 10.2174/1871520620666200727093613 [doi] PST - ppublish SO - Anticancer Agents Med Chem. 2021;21(1):42-60. doi: 10.2174/1871520620666200727093613.