الفهرس 
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Abstract
Pharmacologic inhibition of the oncogenic protein kinases using small molecules is a promising strategy to combat several human malignancies. CDK1 is an example of such a valuable target for the management of pancreatic ductal adenocarcinomas (PDAC); its overexpression in PDAC positively correlates with the size, histological grade and tumor aggressiveness. Here we report the identification of novel series of 1-piperazinyl-4-benzylphthalazine derivatives (VIIIa-g, Xa-i and XIIa-d) as promising anticancer agents with CDK1 inhibitory activity. The anti-proliferative activity of these agents was first screened on a panel of 11 cell lines representing 5 cancers (pancreas, melanoma, leukemia, colon and breast), and then confirmed on two CDK1-overexpressing PDAC cell lines (MDA-PATC53 and PL45 cells). Phthalazines VIIIg, Xd and Xh displayed potent activity against MDA-PATC53 (IC50 = 0.51, 0.88 and 0.73 μM, respectively) and PL45 (IC50 = 0.74, 1.14 and 1.00 μM, respectively) cell lines. Furthermore, compounds VIIIg, Xd and Xh exhibited potent and selective inhibitory activity toward CDK1 with IC50 spanning in the range 36.80 – 44.52 nM, whereas they exerted weak inhibitory effect on CDK2, CDK5, AXL, PTK2B, FGFR, JAK1, IGF1R and BRAF kinases. compounds for designing further selective CDK1 inhibitors. Therefore, the focus of this research is the synthesis of 20 phthalazine derivatives and their biological evaluation as CDK against various isoforms. The newly synthesized compounds were verified through elemental analysis and spectral data (IR, 1H NMR, 13C NMR and MS). Additionally, Molecular docking studies were applied to reveal the binding mode of the synthesized compounds with the different amino acids present in the active site of CDK1 enzyme.
The thesis includes a list of (124) references, (6) tables, (27) figures, and ends with an Arabic summary.