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Rational Design Explore Trifluoromethyl Placement on 6, 7-Disubstituted-7h-Purine Scaffold Potentially Induces Apoptosis Through Dual Inhibition of EGFR/HER2 in Breast Cancers Irrespective of Lapatinib Resistance

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Document pages: 45 pages

Abstract: A new series of 6, 7 disubstituted-7H-purine derivatives (10a-u) were synthesized and evaluated for their anticancer activity. Using simple and efficient methodologies, 21 compounds were prepared and characterized. We screened the compounds in-vitro to derive conclusions about their kinase inhibition against a panel of seven kinases including EGFR family, VEGFR, PDGFRα, and PDFGRβ. Five compounds 10d, 10e, 10i, 10m , and 10r from three synthetic series, identified as potent EGFR family kinase inhibitors. Compound 10r (Trifluoromethyl substituted) displayed potent dual inhibition of EGFR HER2 with a kinase inhibition (IC 50 ) of 0.017 ± 0.003 0.014 ± 0.002 µM. Cell cytotoxicity of all molecules was evaluated against a panel of breast cancer cells having a heterogeneous expression of EGFR and HER2. In-vitro cytotoxic results revealed that compounds 10i, and 10r significantly altered the growth which finally leads to potential anti-proliferation in selected cancer cells except for MCF-7 when compared with Lapatinib. Following kinase inhibition results, 10r showed the lowest growth inhibition IC 50 against all breast cancer cells ranging from 0.098 to 0.136 µM except MCF-7 cells. Based on potential cytotoxic studies compounds 10i and 10r were successfully evaluated against Lapatinib resistant lines BT-474 L and SK-BR3 L and showed promising IC 50 ranging from 0.096 to 0.125 µM. Further apoptotic evaluation of 10r showed the highest percentage of cells including both sensitive and resistant BT-474, and SK-BR3 cells driven into accelerated death phase which indicated the strength of newly designed molecular series towards cytotoxic and apoptotic behavior. Molecular docking studies revealed that 10r successfully binds to both EGFR and HER2 with ‘H’ and pi bond involved interactions which brings irreversible dual inhibition of kinases. Our study suggests that substitution on 6, 7 positions, in the purine core would generate potential anti-cancer agents including combating the ability of Lapatinib resistance.

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