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• W4221010930 endingPage "105740" @default.
• W4221010930 startingPage "105740" @default.
• W4221010930 abstract "Brain tumors are stubborn cancers with poor prognosis and disappointing survival rates. Targeted cancer therapeutics with higher efficacy and lower resistance are highly demanded. An efficient one-pot synthesis of polyfunctionalized phthalazines derivatives was developed by reacting ethyl 1-aryl-5-cyano-1,6-dihydro-4-methyl-6-oxo-3-pyridazine-carboxylates with cinnamonitrile derivatives and the cycloaddition reaction of thieno[3,4-d]pyridazines with activated double or triple bond systems under controlled microwave heating with high yields. The resultant synthesized phthalazines (5a-e, 9 and 13) were tested for their in vitro anti-cancer activities by using in vitro one dose assay at National Cancer institute, USA. Only phthalazine (5b) showed broad spectrum anti-tumor activity against most tested cancer cell lines from all subpanels with mean % GI = 22.61. Interestingly, all tested compounds showed varying growth inhibitory activity against a particular cell line, CNS SNB-75 cell line, but (5b) exhibited the highest growth inhibitory activity against CNS-SNB-75 cell line with (GI% = 108.81) and (IC50 = 3.703 ± 0.2) compared to erlotinib; (IC50 = 12.5 ± 0.68). It caused Pre-G1 apoptosis and growth arrest at S phase. It also increased percentage of the total apoptotic cells in CNS-SNB-75 cell line (39.26%) compared to control cells (2.17%) in the annexin V-FITC experiment. It revealed pronounced EGFR inhibitory activity (IC50 = 47.27 ± 2.41 ng/mL) compared to erlotinib (IC50 = 30.7 ± 1.56 ng/mL). It also inhibited the different PI3K isoforms α, β, γ and δ (with IC50 of 4.39, 13.6, 12.5 and 3.11 μg/mL, respectively compared to LY294002 (with IC50 of 12.7, 8.57, 6.89 and 5.7 μg/mL, respectively). It also caused significant lower protein expression levels of pPI3K, AKT, pAKT and Bcl2 and higher protein expression levels of BAX, Casp3 and Casp9 when compared to untreated cells. Conclusion: Phthalazine (5b) may be an effective, convenient and safe anti-cancer agent acting via proapoptotic and dual EGFR and PI3K kinase inhibitory actions in CNS SNB-75 cell line." @default.
• W4221010930 created "2022-04-03" @default.
• W4221010930 creator A5006800696 @default.
• W4221010930 creator A5016532000 @default.
• W4221010930 creator A5020082155 @default.
• W4221010930 creator A5055971813 @default.
• W4221010930 creator A5069290084 @default.
• W4221010930 creator A5080456047 @default.
• W4221010930 date "2022-05-01" @default.
• W4221010930 modified "2023-09-25" @default.
• W4221010930 title "Controlled microwave-assisted reactions: A facile synthesis of polyfunctionally substituted phthalazines as dual EGFR and PI3K inhibitors in CNS SNB-75 cell line" @default.
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