الفهرس 
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Abstract
Cancer is considered a major health problem that requires urgent development of effective and safe medications. Cancer is the second major cause of death in the United States and worldwide exceeded only with cardiovascular disorders. Most of the current anticancer agents depend on the high rate of division and massive metabolism of cancerous cells. On the other hand, targeting anticancer therapy is directed towards some over- expressed molecular targets (enzymes and receptors) in cancer cells that are responsible for their mutations and cancerous nature. Epidermal growth factor receptor (EGFR) tyrosine kinase is one of these targets that is highly expressed in many kinds of cancers and responsible for poor prognosis of cancer patients.
In this study, scaffold hopping approach was utilized for the discovery of new ring system with new biological activity as an alternative for the quinazoline. Based on the crystal structure of Gefitininb and Erlotininb bounded to EGFR tyrosine kinase, compounds with benzo[d]isothiazole 1,1-dioxide core were designed as surrogates of quinazoline core of these drugs. In addition isoindolinone scaffold as bioisostere of benzo[d]isothiazole 1,1-dioxide was adopted to test the effect of this bioisosteric replacement. This new scaffold was adopted for the development of novel tyrosine kinase inhibitors of both type 1 and type 2 targeting EGFR and VEGFR-2 tyrosine kinases.
Synthesis of the designed benzo[d]isothiazole 1,1-dioxide compounds was accomplished and their structures were confirmed by various spectral and micro analytical data.
This study involves the synthesis of the following unavailable reported intermediates:
1. 2-Methyl-4-nitrobenzenesulfonamide (II)
2. 5-Nitrosaccharine (5-nitrobenzo[d]isothiazole 1,1-dioxide)(III)
3. 3-Chloro-5-nitrobenzo[d]isothiazole 1,1-dioxide (IV)
4. 3-Chlorobenzo[d]isothiazole 1,1-dioxide (3-chloropseudosaccharine)(X)
5. 3-(4-Nitrophenoxy)benzo[d]isothiazole 1,1-dioxide(XI)
6. 4-Nitrobenzoyl chloride (XIV)
7. 4-Nitrobenzoyl azide (XV)
Abstract
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8. 1-(4-Nitrophenyl)-3-phenylurea (XVIa)
9. 1-(4-Methoxyphenyl)-3-(4-nitrophenyl)urea (XVIb)
10. 1-(3-Bromophenyl)-3-(4-nitrophenyl)urea (XVIc)
11. 1-(2,4-Dichlorophenyl)-3-(4-nitrophenyl) urea (XVId)
12. 1-(4-Aminophenyl)-3-phenylurea (XVIIa)
13. 1-(4-Aminophenyl)-3-(4-methoxyphenyl)urea (XVIIb)
14. 4-Nitro-N-(m-tolyl)benzamide (XIXa)
15. N-(2-Chlorophenyl)-4-nitrobenzamide (XIXb)
16. N-(4-Methoxyphenyl)-4-nitrobenzamide (XIXc)
17. 4-Amino-N-(m-tolyl)benzamide (XXa)
18. 4-Amino-N-(2-chlorophenyl)benzamide (XXb)
19. 4-Amino-N-(4-methoxyphenyl)benzamide (XXc)
Also, it comprises the following new intermediates:
1. 5-Nitro-3-(p-tolylamino)benzo[d]isothiazole 1,1-dioxide(Va)
2. 3-[(3-Bromophenyl) amino]-5-nitrobenzo[d]isothiazole 1,1-dioxide (Vb)
3. 3-[(4-Chlorophenyl)amino]-5-nitrobenzo[d]isothiazole 1,1-dioxide (Vc)
4. 3-[(2,4-Dichlorophenyl)amino]-5-nitrobenzo[d]isothiazole 1,1-dioxide (Vd)
5. 3-(4-Aminophenoxy)benzo[d]isothiazole 1,1-dioxide(XII)
6. 1-(4-Aminophenyl)-3-(3-bromophenyl)urea (XVIIc)
7. 1-(4-Aminophenyl)-3-(2,4-dichlorophenyl)urea (XVIIe)
Moreover, these new target compounds were synthesized:
1. 4-{[1,1-Dioxido-3-(p-tolylamino)benzo[d]isothiazol-5-yl]amino}-4-oxobutanoic acid (VIIa)
2. 4-{[3-((3-Bromophenyl)amino)-1,1-dioxidobenzo[d]isothiazol-5-yl]amino}-4-oxobutanoic acid (VIIb)
3. Diethyl 2-{[(3-[(4-chlorophenyl)amino]-1,1-dioxidobenzo[d]isothiazol-5-yl)amino] methylene}malonate (VIIIa)
4. Diethyl 2-{[(3-[(3-bromophenyl)amino]-1,1-dioxidobenzo[d]isothiazol-5-yl)amino] methylene}malonate (VIIIb)
5. 1-{3-[(2,4-Dichlorophenyl)amino]-1,1-dioxidobenzo[d]isothiazol-5-yl}-3-phenylurea (IXa)
6. 1-(4-Chlorophenyl)-3-{3-[(2,4-dichlorophenyl)amino]-1,1-dioxidobenzo[d]isothiazol-5-yl}urea (IXb)
7. 1-{4-[(1,1-Dioxidobenzo[d]isothiazol-3-yl)oxy]phenyl}-3-phenylurea (XIIIa)
8. 1-(2-Chlorophenyl)-3-{4-[(1,1-dioxidobenzo[d]isothiazol-3-yl)oxy]phenyl}urea (XIIIb)
9. 1-(4-Chlorophenyl)-3-{4-[(1,1-dioxidobenzo[d]isothiazol-3-yl)oxy]phenylurea (XIIIc)
10. 1-(4-Bromophenyl)-3-{4-[(1,1-dioxidobenzo[d]isothiazol-3-yl)oxy]phenyl}urea (XIIId)
11. 1-{4-[(1,1-Dioxidobenzo[d]isothiazol-3-yl)amino]phenyl}-3-phenylurea (XVIIIa)
12. 1-{4-[(1,1-Dioxidobenzo[d]isothiazol-3-yl)amino]phenyl}-3-(4-methoxyphenyl)urea (XVIIIb)
13. 1-(3-Bromophenyl)-3-{4-[(1,1-dioxidobenzo[d]isothiazol-3-yl)amino]phenyl}urea (XVIIIc)
14. 4-[(1,1-Dioxidobenzo[d]isothiazol-3-yl)amino]-N-(m-tolyl)benzamide (XXI a):
15. N-(2-chlorophenyl)-4-[(1,1-dioxidobenzo[d]isothiazol-3-yl)amino]benzamide (XXIb)
16. 4-[(1,1-Dioxidobenzo[d]isothiazol-3-yl)amino]-N-(4-methoxyphenyl)benzamide (XXIc)
17. 1-(2,4-Dichlorophenyl)-3-{4-[(1-oxo-1H-isoindol-3-yl)amino]phenyl}urea (XXIII)
18. 4-[(1-Oxo-1H-isoindol-3-yl)amino]-N-(m-tolyl)benzamide (XIV)
Furthermore, the biological activity of compounds (VIIa, IXb, XIIIa, XIIIb, XVIIIa, XVIIIb, XVIIIc, XXIb, XXIc and XXIII) was evaluated at two levels; molecular and cellular. The anticancer activity of the synthesized compounds was evaluated at the national cancer institute (NCI), Maryland, USA. They were challenged against 60 cancer cell lines at 10 μM. Compound IXb showed promising activity against a wide range of cancer cell lines and subsequently selected for five dose anticancer assay by NCI which revealed GI50 against the 60 cell line at the range between 2 to 20 μM.
The enzymatic activity of the synthesized compounds was assessed against EGFR and VEGFR tyrosine kinases. Their enzymatic activity ranged from moderate to weak inhibition which couldn’t explain the potent antiproliferative activity of compound IXb. Therefore, IXb was further tested against other related tyrosine kinases where it showed promising activity against Src tyrosine kinase with 58% inhibition at 10 μM. Since, Src tyrosine kinase is a non receptor tyrosine kinase enzyme that is highly correlated with the development of many types of cancers. Therefore, this could explain the prominent anticancer activity.
Detailed Molecular docking using GOLD software was performed for the three tyrosine kinases in order to study the binding mode of the synthesized compounds.