| Summary, etc |
Cancer is the second cause of death after cardiac diseases worldwide. It is<br/>continuing to act as the main health problem in both developing and developed<br/>countries. Therefore, there is an incessant need to search for new anticancer<br/>agents that inhibit new targets leading to more effectiveness and less side<br/>effects compared to the conventional chemotherapy.<br/> Literature review showed that pyrazoline derivatives display a therapeutic<br/>activity as anticancer agents against breast, colon, lung, liver, cervical cancer<br/>by different mechanisms of action through acting on variable targets.<br/> Accordingly, the present study is concerned with the synthesis of some<br/>derivatives belonging to the 1,3,5-trisubstituted pyrazolines IIa-c, IIIa-c, IVaf, VIa-c, VIIa-f, VIIIa-f, IXa,b. This is achieved via the intermediates<br/>(1E,4E)-1,5-Diphenylpenta-1,4-dien-3-one (Ia), (1E,4E)-1,5-Bis(4-chlorophenyl) penta-1,4-dien-3-one (Ib), (1E,4E)-1,5-Bis(4-methoxyphenyl)penta1,4-dien-3-one (Ic), (2E,4E)-1,5-Diphenylpenta-2,4-dien-1-one (Va), (2E,4E)<br/>-1-(4-Chlorophenyl)-5-phenylpenta-2,4-dien-1-one (Vb) and (2E,4E)-1-(4-<br/>Methoxyphenyl)-5-phenylpenta-2,4-dien-1-one (Vc).<br/> The newly synthesized compounds were evaluated for their in vitro<br/>cytotoxicity against human breast cancer cell line (MCF-7) in addition to<br/>normal fibroblast cell (WI38) using staurosporine and erlotinib as reference<br/>standards. Compounds eliciting superior anticancer activity were screened for<br/>their EGFR inhibitory activity and were compared to erlotinib. Moreover,<br/>Molecular docking simulations were performed on compounds revealing<br/>significant EGFR inhibitory activity to investigate their binding mode in the<br/>active site of the enzyme.<br/>The thesis consists of the following parts:<br/>1. Introduction<br/> This part includes a brief introduction on cancer and the different<br/>anticancer agents based on their mode of action. Also, it presents a literature<br/>review concerning the different biological activities of pyrazoline containing<br/>compounds.<br/>2. Aim of the work<br/> This part explains the chemical and the pharmacological basis upon which<br/>the synthesis of our target compounds was designed aiming to obtain new<br/>anticancer hits acting as EGFR inhibitors.<br/>v<br/>3. Theoretical Discussion<br/> This part includes the synthetic pathways for the synthesis of the target<br/>compounds using 3 Schemes. Also, it deals with the discussion of various<br/>experimental methods and conditions of the reactions adopted for the synthesis<br/>of six intermediate compounds and twenty-nine final compounds as well as a<br/>summarized data concerning the analytical methods for the verification of the<br/>obtained compounds structures.<br/>4. Experimental<br/> This part deals with the practical procedures for the synthesis of the<br/>intermediates and the final compounds. Moreover, their physical property,<br/>elemental analyses and spectral data are presented.<br/>Known Intermediates: (6 compounds)<br/>1- (1E,4E)-1,5-Diphenylpenta-1,4-dien-3-one (Ia)<br/>2- (1E,4E)-1,5-Bis(4-chlorophenyl)penta-1,4-dien-3-one (Ib)<br/>3- (1E,4E)-1,5-Bis(4-methoxyphenyl)penta-1,4-dien-3-one (Ic)<br/>4- (2E,4E)-1,5-Diphenylpenta-2,4-dien-1-one (Va)<br/>5- (2E,4E)-1-(4-Chlorophenyl)-5-phenylpenta-2,4-dien-1-one (Vb)<br/>6- (2E,4E)-1-(4-Methoxyphenyl)-5-phenylpenta-2,4-dien-1- one (Vc)<br/>Known final compounds: (14 compounds)<br/>1- (E)-1-(5-Phenyl-3-styryl-4,5-dihydro-1H-pyrazol-1-yl)ethan-1-one<br/>(IIa)<br/>2- (E)-1-[5-(4-Chlorophenyl)-3-(4-chlorostyryl)-4,5-dihydro-1Hpyrazol-1-yl]ethan-1-one (IIb)<br/>3- (E)-1-[5-(4-Methoxyphenyl)-3-(4-methoxystyryl)-4,5-dihydro-1Hpyrazol-1-yl]ethan-1-one (IIc)<br/>4- (E)-5-Phenyl-3-styryl-4,5-dihydro-1H-pyrazole-1-carboxamide (IIIa)<br/>5- (E)-1,5-Diphenyl-3-styryl-4,5-dihydro-1H-pyrazole (IVa)<br/>6- (E)-5-(4-Chlorophenyl)-3-(4-chlorostyryl)-1-phenyl-4,5-dihydro-1Hpyrazole (IVb)<br/>7- (E)-5-(4-Methoxyphenyl)-3-(4-methoxystyryl)-1-phenyl-4,5-dihydro1H-pyrazole (IVc)<br/>8- (E)-1-(4-Methoxyphenyl)-5-phenyl-3-styryl-4,5-dihydro-1H-pyrazole<br/>(IVd)<br/>9- (E)-1,5-Bis(4-methoxyphenyl)-3-(4-methoxystyryl)-4,5-dihydro-1Hpyrazole (IVf)<br/>10- (E)-1-(3-Phenyl-5-styryl-4,5-dihydro-1H-pyrazol-1-yl)ethan-1-one<br/>(VIa)<br/>vi<br/>11- (E)-1-[3-(4-Chlorophenyl)-5-styryl-4,5-dihydro-1H-pyrazol-1-<br/>yl]ethan-1-one (VIb)<br/>12- (E)-1-[3-(4-Methoxyphenyl)-5-styryl-4,5-dihydro-1H-pyrazol-1-<br/>yl]ethan-1-one (VIc)<br/>13- (E)-1,3-Diphenyl-5-styryl-4,5-dihydro-1H-pyrazole (VIIIa)<br/>14- (E)-3-(4-Methoxyphenyl)-1-phenyl-5-styryl-4,5-dihydro-1Hpyrazole (VIIIc)<br/>New final compounds: (15 compounds)<br/>1- (E)-5-(4-Chlorophenyl)-3-(4-chlorostyryl)-4,5-dihydro-1H-pyrazole1-carboxamide (IIIb)<br/>2- (E)-5-(4-Methoxyphenyl)-3-(4-methoxystyryl)-4,5-dihydro-1Hpyrazole-1-carboxamide (IIIc)<br/>3- (E)-5-(4-Chlorophenyl)-3-(4-chlorostyryl)-1-(4-methoxyphenyl)-4,5-<br/>dihydro-1H-pyrazole (IVe)<br/>4- (E)-3-Phenyl-5-styryl-4,5-dihydro-1H-pyrazole-1-carboxamide<br/>(VIIa)<br/>5- (E)-3-(4-Chlorophenyl)-5-styryl-4,5-dihydro-1H-pyrazole-1-<br/>carboxamide (VIIb)<br/>6- (E)-3-(4-Methoxyphenyl)-5-styryl-4,5-dihydro-1H-pyrazole-1-<br/>carboxamide (VIIc)<br/>7- (E)-3-Phenyl-5-styryl-4,5-dihydro-1H-pyrazole-1-carbothioamide<br/>(VIId)<br/>8- (E)-3-(4-Chlorophenyl)-5-styryl-4,5-dihydro-1H-pyrazole-1-<br/>carbothioamide (VIIe)<br/>9- (E)-3-(4-Methoxyphenyl)-5-styryl-4,5-dihydro-1H-pyrazole-1-<br/>carbothioamide (VIIf)<br/>10- (E)-3-(4-Chlorophenyl)-1-phenyl-5-styryl-4,5-dihydro-1H-pyrazole<br/>(VIIIb)<br/>11- (E)-1-(4-Methoxyphenyl)-3-phenyl-5-styryl-4,5-dihydro-1H-pyrazole<br/>(VIIId)<br/>12- (E)-1-[(2E,4E)-1-(4-Chlorophenyl)-5-phenylpenta-2,4-dien-1-<br/>ylidene)-2-(4-methoxyphenyl]hydrazine (VIIIe)<br/>13- (E)-1-(4-Methoxyphenyl)-2-[(2E,4E)-1-(4-methoxyphenyl)-5-<br/>phenylpenta-2,4-dien-1-ylidene]hydrazine (VIIIf)<br/>14- N'-[(1E,4E)-1,5-Diphenylpenta-1,4-dien-3-ylidene]benzohydrazide<br/>(IXa)<br/>15- N'-[(1E,4E)-1,5-Bis(4-chlorophenyl)penta-1,4-dien-3-<br/>ylidene]benzohydrazide (IXb)<br/>vii<br/>5. Biological evaluation<br/> This part includes the cytotoxic activity of the prepared compounds against<br/>MCF-7 (breast cancer) cell line in addition to normal fibroblast cell line<br/>(WI38) using staurosporine and erlotinib as reference standards. The results<br/>revealed that the synthesized compounds showed a significant anticancer<br/>activity (IC50= 3.79 - 10.59 µM) compared to staurosporine (IC50= 10.61 µM).<br/>Furthermore, five of the tested compounds elicited superior cytotoxic activity<br/>were evaluated for their EGFR inhibitory activity using erlotinib as a reference<br/>drug. The results indicated that compounds IIIc, VIc, VIId and VIIId<br/>exhibited significant EGFR inhibitory activity at sub-micromolar level (IC50=<br/>0.33, 0.46, 0.33 and 0.343 µM), respectively, compared to erlotinib (IC50= 0.23<br/>µM).<br/>6. Molecular docking:<br/> This part involves the results of molecular docking of compounds IIIc,<br/>VIc, VIId, VIIIb and VIIId that were tested for EGFR inhibitory activity in<br/>order to validate the obtained results and study their binding mode to the active<br/>site of the enzyme in comparison to erlotinib as a reference standard.<br/>7. References:<br/> This part includes 118 references covering the period from 1946 to 2019.<br/>8. Arabic summary |