الفهرس 
Design, synthesis and anticancer activity of some new quinazoline derivatives targeting tyrosine kinase
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Abstract
Study involves design and synthesis of five series of 6-bromo2-(pyridin-3-yl)-4-substituted quinazolines Xa-l, XIa-e, XIIa-c, XIIIa-f and XIVae. Candidates Xa-l and XIa-e were evaluated for their EGFR and HER2 inhibitory
activity compared to Lapatinib. Compounds Xb, Xd, Xf, XIb and XIc were further
screened for their in vitro cytotoxicity against two human breast cancer cell lines:
AU-565 and MDA-MB-231 in addition to normal breast cell line MCF10A.
Compound Xd revealed a remarkable cytotoxic efficacy against AU-565 cell line
(IC50 = 1.54 μM) relative to Lapatinib (IC50 = 0.48 μM), whereas compounds Xd
and XIc showed a superior cytotoxicity towards MDA-MB-231 (IC50 = 2.67 and
1.75 μM, respectively) in comparison to Lapatinib (IC50 = 9.29 μM). Moreover,
compounds XIIa-c, XIIIa-f and XIVa-e were tested for their VEGFR-2 inhibitory
activity compared to Sorafenib. Compounds XIIa, XIIIc and XIIIe exhibited
remarkable inhibition (IC50 = 79.80, 50.22 and 78.02 nM, respectively) relative to
Sorafenib (IC50 = 51.87 nM). In vitro cytotoxicity of these compounds against
HepG2, HCT-116 and normal cell (WISH) revealed a superior cytotoxicity against
HepG2, HCT-116 especially XIIa (IC50 = 17.51 and 5.56 μM, respectively) and
XIIIc (IC50 = 10.40 and 3.37 μM, respectively) compared to Sorafenib (IC50 =
19.33 and 6.82 μM, respectively). Compounds Xd, XIc and XIIIc were subjected
to cell cycle analysis and apoptotic assay. Molecular docking and ADME
prediction studies were fulfilled to illustrate the interaction of the potent derivatives
with the hot spots of the active site of EGFR, HER2 and VEGFR-2 along with
prediction of their pharmacokinetic and physicochemical properties.