Novel fluorinated pyrazole-based heterocycles scaffold: cytotoxicity, in silico studies and molecular modelling targeting double mutant EGFR L858R/T790M as antiproliferative and apoptotic agents

• Published in: Medicinal chemistry research 2023-02, Vol.32 (2), p.369-388
• Main Authors: Fayed, Eman A., Gohar, Nirvana A., Bayoumi, Ashraf H., Ammar, Yousry A.
• Format: Article
• Language: English
• Subjects: Anticancer properties; Antineoplastic drugs; Antitumor activity; Antitumor agents; Apoptosis; Biochemistry; Biomedical and Life Sciences; Biomedicine; Bioorganic Chemistry; Caspase-3; Cell cycle; Cytotoxicity; Epidermal growth factor receptors; Hepatocellular carcinoma; Hepatocytes; Hepatoma; Hybrids; Imatinib; Inorganic Chemistry; Liver cancer; Medicinal Chemistry; Molecular modelling; Original Research; Pharmacology/Toxicology; Pyrazole; Pyrazoles; Synthesis; Toxicity; Tumor cell lines; Tumors
• ISSN: 1054-2523; 1554-8120
• DOI: 10.1007/s00044-022-03004-8

Hepatocellular carcinoma (HCC), also known as hepatoma, is the most prevalent type of primary liver cancer. It begins in the hepatocytes, the liver’s major cell type. Cancer that began in another region of the body but has spread to the liver is known as secondary cancer of life; several still unmet demands for better, less toxic therapy to treat this malignant tumor. Several novel pyrazolo[1,5- a ]pyrimidine derivatives were synthesized as part of our goal to develop promising anticancer drugs. All the synthesized hybrids have been screened for their cytotoxicity effect against three cancer cell lines which are; HepG-2, HCT-116, and MCF-7. The liver cancer cells were found to be the most sensitive to the effect of the new molecules. A subsequent set of in vitro biological evaluation studies has been conducted on the most promising derivatives to identify their effect on such a cancer type. In HepG-2 cells, four derivatives ( 8a , 8b , 10c , and 11b ) demonstrated good anticancer activity. The most efficacious compounds were 8b and 10c , which had IC 50 values of 2.36 ± 0.14 and 1.14 ± 0.063 μM, respectively, higher than the reference medication Imatinib. The latter’s putative molecular effect has been investigated further by looking at its influence on the cell cycle, EGFR, and specific apoptotic and anti-apoptotic markers in HepG-2 cells. These findings indicated that 8b and 10c could trigger apoptosis by upregulating BAX and caspase-3 and cell cycle at the Pre-G1 and G2-M stages. The compounds 8b and 10c showed high potency for EGFR with IC 50 equal to 0.098 and 0.079 μM, respectively. Compound 10c had the most effective inhibitory activity for EGFR L858R-TK with IC 50 (36.79 nM). Additionally, in silico ADMET and docking studies were done for the most active hits, representing good results. Graphical Abstract Novel Fluorinated Pyrazole-Based Heterocycles Scaffold: Cytotoxicity, In Silico Studies and Molecular Modelling Targeting Double Mutant EGFR L858R/T790M as Antiproliferative and Apoptotic Agents