Thesis (Ph.D.) - Cairo University - Faculty of Pharmacy - Department of Pharmaceutical Chemistry

Quinazoline and pyrrolotriazine are interesting bioactive scaffolds that elicit a wide range of biological activities including anticancer activity. According to WHO Global Cancer Country Profiles, breast and liver cancers are the most prevalent cancers worldwide. Herein, we highlighted on the anticancer activity of the quinazoline and pyrrolotriazine nuclei as protein tyrosine kinase inhibitors. HER-2 and VEGFR2 kinases as well-established targets for breast cancer (BC) and liver cancer (HCC) therapy, respectively, are associated with aggressive clinical outcomes.Thus, the present investigation deals with design and synthesis of a new series of twenty seven quinazoline derivatives (72a-c, 77a-l, 79a-d and 87a-h) and twenty pyrrolotriazine derivatives (102a-j, 103a-e and 107a-e), as lapatinib and sorafenib congeners, respectively, aiming to identify new alternative drug candidates for treatment of breast and liver cancers.The newly synthesized compounds were screened for their enzyme inhibitory and anticancer activities.The results revealed that, the developed quinazoline derivatives demonstrated potent HER-2 inhibitions (IC₅₀: 5.4{u2212}12 nM) compared to lapatinib (IC50: 95.5 nM), significant selective and potent antiproliferative activities ({u223C}20-fold) against HER-2+ (AU565, BT474) compared to HER-2({u2212})cells. Favorably, the quinazoline derivative(79d)exhibited potent in vivo tumor regression against the BT474 xenograft model with high metabolic stability and low intrinsic clearance (T1/2 > 145 min and CLint(mic) < 9.6 mL/min/kg)

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