000 08521nam a2200265 i 4500
008 210404s2020 ua a|||| bm|| 00| 0 eng d
040 _aEG-NcFUE
_erda
082 0 4 _222
_a615.7
_bE.D.D
100 1 _aEl-Ansary, Dina Yousry Mohamed Kamel
_eauthor
245 1 0 _aDesign, synthesis and antitumor activity of some novel pyrazoline derivatives /
_cThesis presented by Dina Yousry Mohamed Kamel El-Ansary; Under the supervision of Ass. Prof. Dr. Riham François George, Prof. Dr. Manal Mostafa Hassan Kandeel, Dr. Ahmed Mahmoud Mahmoud El Kerdawy.
246 1 5 _aتصميم وتشييد بعض مشتقات البيرازولين الجديدة ذات الفاعلية المضادة للاورام
300 _avii, 84 pages :
_billustrations ;
_c25 cm.
500 _a supervision of Ass. Prof. Dr. Riham François George, Prof. Dr. Manal Mostafa Hassan Kandeel, Dr. Ahmed Mahmoud Mahmoud El Kerdawy.
502 _aThesis (M.Sc)-Cairo university, Faculty of pharmacy, 2020.
504 _aIncludes bibliographical references.
520 3 _a Cancer is the second cause of death after cardiac diseases worldwide. It is continuing to act as the main health problem in both developing and developed countries. Therefore, there is an incessant need to search for new anticancer agents that inhibit new targets leading to more effectiveness and less side effects compared to the conventional chemotherapy. Literature review showed that pyrazoline derivatives display a therapeutic activity as anticancer agents against breast, colon, lung, liver, cervical cancer by different mechanisms of action through acting on variable targets. Accordingly, the present study is concerned with the synthesis of some 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 (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) -1-(4-Chlorophenyl)-5-phenylpenta-2,4-dien-1-one (Vb) and (2E,4E)-1-(4- Methoxyphenyl)-5-phenylpenta-2,4-dien-1-one (Vc). The newly synthesized compounds were evaluated for their in vitro cytotoxicity against human breast cancer cell line (MCF-7) in addition to normal fibroblast cell (WI38) using staurosporine and erlotinib as reference standards. Compounds eliciting superior anticancer activity were screened for their EGFR inhibitory activity and were compared to erlotinib. Moreover, Molecular docking simulations were performed on compounds revealing significant EGFR inhibitory activity to investigate their binding mode in the active site of the enzyme. The thesis consists of the following parts: 1. Introduction This part includes a brief introduction on cancer and the different anticancer agents based on their mode of action. Also, it presents a literature review concerning the different biological activities of pyrazoline containing compounds. 2. Aim of the work This part explains the chemical and the pharmacological basis upon which the synthesis of our target compounds was designed aiming to obtain new anticancer hits acting as EGFR inhibitors. v 3. Theoretical Discussion This part includes the synthetic pathways for the synthesis of the target compounds using 3 Schemes. Also, it deals with the discussion of various experimental methods and conditions of the reactions adopted for the synthesis of six intermediate compounds and twenty-nine final compounds as well as a summarized data concerning the analytical methods for the verification of the obtained compounds structures. 4. Experimental This part deals with the practical procedures for the synthesis of the intermediates and the final compounds. Moreover, their physical property, elemental analyses and spectral data are presented. Known Intermediates: (6 compounds) 1- (1E,4E)-1,5-Diphenylpenta-1,4-dien-3-one (Ia) 2- (1E,4E)-1,5-Bis(4-chlorophenyl)penta-1,4-dien-3-one (Ib) 3- (1E,4E)-1,5-Bis(4-methoxyphenyl)penta-1,4-dien-3-one (Ic) 4- (2E,4E)-1,5-Diphenylpenta-2,4-dien-1-one (Va) 5- (2E,4E)-1-(4-Chlorophenyl)-5-phenylpenta-2,4-dien-1-one (Vb) 6- (2E,4E)-1-(4-Methoxyphenyl)-5-phenylpenta-2,4-dien-1- one (Vc) Known final compounds: (14 compounds) 1- (E)-1-(5-Phenyl-3-styryl-4,5-dihydro-1H-pyrazol-1-yl)ethan-1-one (IIa) 2- (E)-1-[5-(4-Chlorophenyl)-3-(4-chlorostyryl)-4,5-dihydro-1Hpyrazol-1-yl]ethan-1-one (IIb) 3- (E)-1-[5-(4-Methoxyphenyl)-3-(4-methoxystyryl)-4,5-dihydro-1Hpyrazol-1-yl]ethan-1-one (IIc) 4- (E)-5-Phenyl-3-styryl-4,5-dihydro-1H-pyrazole-1-carboxamide (IIIa) 5- (E)-1,5-Diphenyl-3-styryl-4,5-dihydro-1H-pyrazole (IVa) 6- (E)-5-(4-Chlorophenyl)-3-(4-chlorostyryl)-1-phenyl-4,5-dihydro-1Hpyrazole (IVb) 7- (E)-5-(4-Methoxyphenyl)-3-(4-methoxystyryl)-1-phenyl-4,5-dihydro1H-pyrazole (IVc) 8- (E)-1-(4-Methoxyphenyl)-5-phenyl-3-styryl-4,5-dihydro-1H-pyrazole (IVd) 9- (E)-1,5-Bis(4-methoxyphenyl)-3-(4-methoxystyryl)-4,5-dihydro-1Hpyrazole (IVf) 10- (E)-1-(3-Phenyl-5-styryl-4,5-dihydro-1H-pyrazol-1-yl)ethan-1-one (VIa) vi 11- (E)-1-[3-(4-Chlorophenyl)-5-styryl-4,5-dihydro-1H-pyrazol-1- yl]ethan-1-one (VIb) 12- (E)-1-[3-(4-Methoxyphenyl)-5-styryl-4,5-dihydro-1H-pyrazol-1- yl]ethan-1-one (VIc) 13- (E)-1,3-Diphenyl-5-styryl-4,5-dihydro-1H-pyrazole (VIIIa) 14- (E)-3-(4-Methoxyphenyl)-1-phenyl-5-styryl-4,5-dihydro-1Hpyrazole (VIIIc) New final compounds: (15 compounds) 1- (E)-5-(4-Chlorophenyl)-3-(4-chlorostyryl)-4,5-dihydro-1H-pyrazole1-carboxamide (IIIb) 2- (E)-5-(4-Methoxyphenyl)-3-(4-methoxystyryl)-4,5-dihydro-1Hpyrazole-1-carboxamide (IIIc) 3- (E)-5-(4-Chlorophenyl)-3-(4-chlorostyryl)-1-(4-methoxyphenyl)-4,5- dihydro-1H-pyrazole (IVe) 4- (E)-3-Phenyl-5-styryl-4,5-dihydro-1H-pyrazole-1-carboxamide (VIIa) 5- (E)-3-(4-Chlorophenyl)-5-styryl-4,5-dihydro-1H-pyrazole-1- carboxamide (VIIb) 6- (E)-3-(4-Methoxyphenyl)-5-styryl-4,5-dihydro-1H-pyrazole-1- carboxamide (VIIc) 7- (E)-3-Phenyl-5-styryl-4,5-dihydro-1H-pyrazole-1-carbothioamide (VIId) 8- (E)-3-(4-Chlorophenyl)-5-styryl-4,5-dihydro-1H-pyrazole-1- carbothioamide (VIIe) 9- (E)-3-(4-Methoxyphenyl)-5-styryl-4,5-dihydro-1H-pyrazole-1- carbothioamide (VIIf) 10- (E)-3-(4-Chlorophenyl)-1-phenyl-5-styryl-4,5-dihydro-1H-pyrazole (VIIIb) 11- (E)-1-(4-Methoxyphenyl)-3-phenyl-5-styryl-4,5-dihydro-1H-pyrazole (VIIId) 12- (E)-1-[(2E,4E)-1-(4-Chlorophenyl)-5-phenylpenta-2,4-dien-1- ylidene)-2-(4-methoxyphenyl]hydrazine (VIIIe) 13- (E)-1-(4-Methoxyphenyl)-2-[(2E,4E)-1-(4-methoxyphenyl)-5- phenylpenta-2,4-dien-1-ylidene]hydrazine (VIIIf) 14- N'-[(1E,4E)-1,5-Diphenylpenta-1,4-dien-3-ylidene]benzohydrazide (IXa) 15- N'-[(1E,4E)-1,5-Bis(4-chlorophenyl)penta-1,4-dien-3- ylidene]benzohydrazide (IXb) vii 5. Biological evaluation This part includes the cytotoxic activity of the prepared compounds against MCF-7 (breast cancer) cell line in addition to normal fibroblast cell line (WI38) using staurosporine and erlotinib as reference standards. The results revealed that the synthesized compounds showed a significant anticancer activity (IC50= 3.79 - 10.59 µM) compared to staurosporine (IC50= 10.61 µM). Furthermore, five of the tested compounds elicited superior cytotoxic activity were evaluated for their EGFR inhibitory activity using erlotinib as a reference drug. The results indicated that compounds IIIc, VIc, VIId and VIIId exhibited significant EGFR inhibitory activity at sub-micromolar level (IC50= 0.33, 0.46, 0.33 and 0.343 µM), respectively, compared to erlotinib (IC50= 0.23 µM). 6. Molecular docking: This part involves the results of molecular docking of compounds IIIc, VIc, VIId, VIIIb and VIIId that were tested for EGFR inhibitory activity in order to validate the obtained results and study their binding mode to the active site of the enzyme in comparison to erlotinib as a reference standard. 7. References: This part includes 118 references covering the period from 1946 to 2019. 8. Arabic summary
546 _aText in English, abstracts in English and Arabic.
650 4 _aSynthesis
650 4 _aPyrazoline
700 1 _aGeorge, Riham François.
_esupervisor
700 1 _aKandeel, Manal Mostafa Hassan.
_esupervisor
700 1 _aEl Kerdawy, Ahmed Mahmoud Mahmoud.
_esupervisor
856 4 0 _3DSpace electronic resource
_uhttp://repository.fue.edu.eg/xmlui/handle/123456789/5781
942 _cTHESIS
_2ddc
999 _c12954
_d12954