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008 190424s2018 ua a|||| b||| 001 0 eng d
040 _aFUE
_erda
041 _aeng
082 0 4 _a615.19
_bA.I.D
_222
100 1 _aAbd el-moteleb,iten mamdouh fawzy.
245 1 0 _aDesign and synthesis of novel imatinib analogs as antitumor multi-target kinase inhibitors /
_citen mamdouh fawzy abd el-moteleb ; supervision khaled abouzid mohamed, khairia mohamed youssef ,nasser saad mohamed ,deena samy lasheen.
246 3 4 _aتصميم وتشييد نظائر جديدة لدواء الإيماتينيب ذات نشاط ضد السرطان كمثبطات
264 1 _c[2018]
300 _a215 pages :
_billustrations ;
_c25 cm
336 _2rdacontent
_atext
337 _2rdamedia
_aunmediated
338 _2rdacarrier
_avolume
502 _aThesis (PH.D.)- Ain Shams University. Faculty of Pharmacy. Pharmaceutical Chemistry Department,2018.
504 _aIncludes bibliographical references (p.195 - 212 ).
520 _aCancer is a life-threatening disease and a leading cause of death. Although a range of therapies based on chemotherapy, surgery, and radiotherapy are available, yet they are of limited efficacy. Moreover, current anticancer regimens are associated with significant levels of toxicity and serious adverse side-effects. Hence, many research projects have been focused on developing new chemotherapies with minimal side-effects on mammalian cells. Targeted therapies became one of the eminent principles of drug design and development nowadays to combat cancer. Imatinib (Gleevec, STI571) became one of the most popular targeted drugs which was approved by FDA for the treatment of chronic myeloid leukemia (CML) as well as various types of cancer. It was proved that imatinib had a potential role in the treatment of non-small cell lung cancer. Additionally, imatinib showed effective inhibition to all epithelial colon cancer cell lines. In fact, imatinib possess loads of proposed mechanisms to fight cancer, the foremost of which is that it acts as tyrosine kinase inhibitor especially against Bcr-Abl. Surprisingly, imatinib anti-tumor activity expressed another evolved mechanism; it had the ability to suppress CrKl phosphorylation level. Moreover, it arrested cell cycle at Go/G1 of K562 cells and dramatically activated caspase-3 together with downstream substrates PARP thus it induced apoptosis. Unfortunately, imatinib faced resistance in CML patients, due to a point mutation in the kinase domain of Bcr-Abl which leads to disruption in the binding site of imatinib on the tyrosine kinase. Consequently, extensive research had led to the production of second generation of tyrosine kinase inhibitors (TKIs) as dasatnib, nilotinib, bosutinib and ponatinib which showed less resistance and less intolerance than imatinib. Although many new potent (TKIs) are in market, imatinib still represents the front-line therapy for cancer treatment. The current study aimed to design “two series” of analogs to act as anti-tumor agents. Synthesis of the designed compounds was then accomplished and their structures were confirmed by various spectral and microanalytical data. This study involved the synthesis of the following unavailable reported intermediates: 1) 4-(4-Nitrophenyl)morpholine (2a) 2) 1-(4-Nitrophenyl)-4-phenylpiperazine (2b) 3) 2-[4-(4-Nitrophenyl)piperazin-1-yl]ethanol (2c) 4) 4-Morpholinoaniline (3a) 5) 4-(4-Phenylpiperazin-1-yl)aniline (3b) 6) 2-[4-(4-Aminophenyl)piperazin-1-yl]ethanol (3c) 7) 4-(4-Nitrophenethyl)morpholine (4a) 8) 2-(4-(4-Nitrophenethyl)piperazin-1-yl)ethanol (4c) 9) 4-(2-Morpholinoethyl)aniline (5a) 10) 2-[4-(4-Aminophenethyl)piperazin-1-yl]ethanol (5c) 11) 4-[2-(4-Nitrophenoxy)ethyl]morpholine (7) 12) 4-(2-Morpholinoethoxy)aniline (8) 13) 4-Morpholinobenzaldehyde (9a) 14) 4-(4-(2-hydroxyethyl)piperazin-1-yl)benzaldehyde (9b) 15) 4-Morpholinobenzoic acid (10a) 16) 4-(4-(2-hydroxyethyl)piperazin-1-yl)benzoic acid (10b) 17) 4-(2-Morpholinoethoxy)benzaldehyde (11a) 18) 4-(2-Morpholinoethoxy)benzoic acid (12a) 19) 4-(Chloromethyl)benzoyl chloride (17) 20) 4-(Chloromethyl)-N-(4-methyl-3-nitrophenyl)benzamide (18) 21) Ethyl 2,4-diaminofuro[2,3-d]pyrimidine-6-carboxylate (21) 22) 2,4-Diaminofuro[2,3-d]pyrimidine-6-carboxylic acid (22) Also, it comprised the following new intermediates: 1) 1-(4-Nitrophenethyl)-4-phenylpiperazine (4b) 2) 4-[2-(4-Phenylpiperazin-1-yl)ethyl]aniline (5b) 3) 4-[2-(4-Phenylpiperazin-1-yl)ethoxy]benzaldehyde (11b) 4) 4-(2-(4-Phenylpiperazin-1-yl)ethoxy)benzoic acid (12b) 5) N-(4-Methyl-3-nitrophenyl)-4-morpholinobenzamide (13a) 6) 4-[4-(2-Hydroxyethyl)piperazin-1-yl]-N-(4-methyl-3-nitrophenyl)benzamide (13b) 7) N-(3-amino-4-methylphenyl)-4-morpholinobenzamide (14a) 8) N-(3-amino-4-methylphenyl)-4-[4-(2-hydroxyethyl)piperazin-1-yl)]benzamide (14b) 9) N-(4-methyl-3-nitrophenyl)-4-(2-morpholinoethoxy)benzamide (15a) 10) N-(4-methyl-3-nitrophenyl)-4-[2-(4-phenylpiperazin-1-yl)ethoxy]benzamide (15b) 11) N-(3-amino-4-methylphenyl)-4-(2-morpholinoethoxy)benzamide (16a) 12) N-(3-amino-4-methylphenyl)-4-[2-(4-phenylpiperazin-1-yl)ethoxy]benzamide (16b) 13) N-(3-amino-4-methylphenyl)-4-[4-(2-hydroxyethyl)piperazin-1-yl)methyl]benzamide (20) 14) 3-(9H-purin-6-ylamino)-4-methylbenzoic acid (29) 15) 1-[Phenyl 2-(6-Chloro-9H-purin-9-yl)] ethan-1-one (36a) 16) 1-[(4-Methoxyphenyl)-2-(6-Chloro-9H-purin-9-yl)] ethan-1-one (36b) 17) 1-([1,1-Biphenyl]-4-yl)-2-(6-chloro-9H-purin-9-yl)ethan-1-one (36c) 18) 3-{9-[2-(Phenyl)-2-oxoethyl]-9H-purin-6-ylamino}-4-methylbenzoic acid (37a) 19) 3-{9-[2-(4-Methoxy-phenyl)-2-oxoethyl]-9H-purin-6-ylamino}-4-methylbenzoic acid (37 b) 20) 3-{9-[2-([1,1-Biphenyl]-4-yl)-2-oxoethyl)]-9H-purin-6-ylamino}-4-methylbenzoic acid (37 c) And finally, the study involved the synthesis and the characterization of the following new targeted compounds: 1) 2,4-Diamino-N-[4-(4-phenylpiperazin-1-yl)phenyl]furo[2,3-d]pyrimidine-6-carboxamide (24a) 2) 2,4-Diamino-N-{4-[4-(2-hydroxyethyl)piperazin-1-yl]phenyl}furo[2,3-d]pyrimidine-6-carboxamide (24b) 3) 2,4-Diamino-N-{4-[2-(4-phenylpiperazin-1-yl)ethyl]phenyl}furo[2,3-d]pyrimidine-6-carboxamide (25a) 4) 2,4-Diamino-N-{4-[2-(4-(2-hydroxyethyl)piperazin-1-yl)ethyl]phenyl}furo[2,3-d]pyrimidine-6-carboxamide (25b) 5) 2,4-Diamino-N-[2-methyl-4-(4-morpholinobenzamido)phenyl]furo[2,3-d]pyrimidine-6-carboxamide (26a) 6) 2,4-Diamino-N-{4-[4-(4-(2-hydroxyethyl)piperazin-1-yl)benzamido]-2-methylphenyl}furo[2,3-d]pyrimidine-6-carboxamide (26b) 7) 2,4-Diamino-N-{2-methyl-4-[4-(2-morpholinoethoxy)benzamido]phenyl}furo[2,3-d]pyrimidine-6-carboxamide (27a) 8) 2,4-Diamino-N-{2-methyl-4-[4-(2-(4-phenylpiperazin-1-yl)ethoxy)benzamido]phenyl}furo[2,3-d]pyrimidine-6-carboxamide (27b) 9) 2,4-Diamino-N-{4-[4-((4-(2-hydroxyethyl)piperazin-1-yl)methyl)benzamido]-2-methylphenyl}furo[2,3-d]pyrimidine-6-carboxamide (28) 10) 3-(9H-purin-6-ylamino)-4-methyl-N-(4-morpholinophenyl)benzamide (31a) 11) 3-(9H-purin-6-ylamino)-N-{4-[4-(2-hydroxyethyl)piperazin-1-yl]phenyl}-4-methylbenzamide (31b) 12) 3-(9H-purin-6-ylamino)-4-methyl-N-[4-(2-morpholinoethyl)phenyl]benzamide (32a) 13) 3-(9H-purin-6-ylamino)-4-methyl-N-{4-[2-(4-phenylpiperazin-1-yl)ethyl]phenyl}benzamide (32b) 14) 3-(9H-purin-6-ylamino)-N-{4-[2-(4-(2-hydroxyethyl)piperazin-1-yl)ethyl]phenyl}-4-methylbenzamide (32c) 15) 3-(9H-purin-6-ylamino)-N-{4-[2-(4-(2-chloroethyl)piperazin-1-yl)ethyl]phenyl}-4-methylbenzamide (33) 16) 3-(9H-purin-6-ylamino)-4-methyl-N-[4-(2-morpholinoethoxy)phenyl]benzamide (34) 17) 3-{9-[2-(Phenyl)-2-oxoethyl]-9H-purin-6-ylamino}-N-(4-morpholinophenyl)-4-methyl-1-benzamide (39a) 18) 3-{9-[2-(Phenyl)-2-oxoethyl]-9H-purin-6-ylamino}-N-[4-(4-hydroxyethyl-piperazine)phenyl]-4-methyl-1-benzamide (39b) 19) 3-{9-[2-([1,1 Biphenyl]-4-yl)-2-oxoethyl)]-9H-purin-6-ylamino}-N-[4-(4-phenylpiperazin -1-yl)phenyl]-4-methyl-1-benzamide (40) 20) 3-{9-[2-(1-(4-Methoxy)phenyl)-2-oxoethyl)]-9H-purin-6-ylamino}-N-{4-[2-(4-phenylpiperazin-1-yl)ethyl]phenyl}-4-methyl-1-benzamide (41) 21) 3-{9-[2-(1-(4-methoxy)phenyl)-2-oxoethyl]-9H-purin-6-ylamino}-N-[4-(2-morpholinoethoxy)phenyl]-4-methyl-1-benzamide (42) In search for the mechanism of action of the newly synthesized compounds various bioassay studies were performed. Anti-tumor activity of the newly synthesized compounds was achieved through in vitro kinase inhibitory assay against Bcr-Abl and Ck-1 performed at BPS Bioscience at 10 µM concentration. The compounds didn’t show potency against those enzymes and hence field alignment study was performed to unleash the reasons. In addition, anti-proliferative evaluation was carried out against both (A549) non-small lung and (Caco) colon cancer cell lines. The compounds showed moderate to high antitumor activity displaying IC50 = 0.14-5.07 µM on both cell lines. Furtherly, three of the most active agents; (24a, 31b and 39a) were subjected to flow cytometry cell cycle and caspase-3 colorimetric assays. Finally, a comprehensive molecular modeling studies including molecular docking, ADMET and 3D-QSAR based pharmacophore studies were also performed to narrate the antitumor activity of the synthesized compounds with the essential chemical features within their structures.
546 _atext in english ,abstract in arabic and english .
650 0 0 _aDrug development
_xAbbreviations
650 0 0 _aDrug development
_xAcronyms
650 0 0 _aPharmaceutical industry
_xAbbreviations
650 0 0 _aPharmaceutical industry
_xAcronyms
650 0 0 _aDrug Design
_xAbbreviations
650 0 0 _aDrug Design
_xHandbooks
650 0 0 _aDrug Industry
_xAbbreviations
650 0 0 _aDrug Industry
_xHandbooks
650 0 0 _aPharmaceutical Preparations
_xHandbooks
650 0 0 _aPharmaceutical Preparations
_xAbbreviations
700 1 _amohamed,khaled abouzid,
_esupervisor.
700 1 _aYoussef, Khairia Mohamed,
_esupervisor.
700 1 _aMohamed, Nasser Saad,
_esupervisor.
700 1 _aLasheen, Deena Samy.
_esupervisor.
942 _2ddc
_cTHESIS