الفهرس 
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Abstract
Cancer is a genetic disease characterized by two features: unregulated cell growth and tissue invasion (metastasis). It can be viewed as the result of a succession of genetic changes during which a normal cell is transformed into a malignant one. Evasion of cell death, apoptosis, is one of the essential changes in a cell that cause this malignant transformation. Hence, reduced apoptosis or its resistance plays a vital role in carcinogenesis. The Bcl-2 family of proteins regulates the mitochondrial apoptotic pathway. Disease states arise upon deregulation of the Bcl-2 family of proteins, where cell death is either promoted or evaded; one of the most common tactic cancer cells utilize to promote survival is anti-apoptotic protein overexpression. Specifically, Bcl-2 overexpression has been shown to be a major chemoresistance factor in a number of human cancers, and for this reason, Bcl-2 targeting is a pharmacologic priority in the quest to reactivate cell death for therapeutic benefit in cancer.
Several small molecule Bcl-2 inhibitors have been approved for the treatment of different types of cancer. The research objective is to design and synthesize novel inhibitors targeting Bcl-2 with promising anti-cancer activity. Building on the already known inhibitors, profound literature survey, SAR studies and molecular modeling, a series of novel benzoxazole-based and thiazole-based compounds were designed, synthesized, purified and structurally confirmed by different analytical and spectral techniques.
The study includes the synthesis of the following reported intermediates:
1- Methyl 4-hydroxy-3-nitrobenzoate (I)
2- Methyl 3-amino-4-hydroxybenzoate (II)
3- Methyl 2-aminobenzo[d]oxazole-5-carboxylate (III)
4- Ethyl 2-aminothiazole-4-carboxylate (IV)
5- 4-Chloro-3-nitrobenzoic acid (V)
6- 3-nitro-4-(phenethylamino)benzoic acid (VIa)
7- 4-(benzylamino)-3-nitrobenzoic acid (VIb)
8- 4-(3,4-dichlorophenylamino)-3-nitrobenzoic acid (VIc)
9- 4-(cyclohexylamino)-3-nitrobenzoic acid (VIe)
10- 4-(4-methylpiperazin-1-yl)-3-nitrobenzoic acid (VIg)
11- 3-nitro-4-(piperidin-1-yl)benzoic acid (VIh)
In addition to the synthesis and the characterization of the following new unreported compounds:
1- 4-(2-methyl-4-nitrophenylamino)-3-nitrobenzoic acid (VId)
2- 4-(4-benzhydrylpiperazin-1-yl)-3-nitrobenzoic acid (VIf)
3- Methyl 2-[N-(3-nitro-4-(phenethylamino)benzamido)]benzo[d]oxazole-5-carboxylate (VIIIa)
4- Methyl 2-[N-(4-benzylamino-3-nitrobenzamido)]benzo[d]oxazole-5-carboxylate (VIIIb)
5- Methyl 2-[N-(4-(3,4-dichloroanilino)-3-nitrobenzamido)]benzo[d]oxazole-5-carboxylate (VIIIc)
6-
Methyl 2-[N-(4-(2-methyl-4-nitroanilino)-3-nitrobenzamido)]benzo[d]oxazole-5-carboxylate (VIIId)
7-
Methyl 2-[N-(4-cyclohexylamino-3-nitrobenzamido)]benzo[d]oxazole-5-carboxylate (VIIIe)
8-
Methyl 2-[N-(4-(4-benzhydrylpiperazin-1-yl)-3-nitrobenzamido)]benzo[d]oxazole-5-carboxylate (VIIIf)
9-
Methyl 2-[N-(4-(4-methylpiperazin-1-yl)-3-nitrobenzamido)]benzo[d]oxazole-5-carboxylate (VIIIg)
10- Ethyl 2-[N-(3-nitro-4-(phenethylamino)benzamido)]thiazole-4-carboxylate (IXa)
11- Ethyl 2-[N-(4-benzylamino-3-nitrobenzamido)]thiazole-4-carboxylate (IXb)
12- Ethyl 2-[N-(4-(3,4-dichloroanilino)-3-nitrobenzamido)]thiazole-4-carboxylate (IXc)
13- Ethyl 2-[N-(4-(2-methyl-4-nitroanilino)-3-nitrobenzamido)]thiazole-4-carboxylate (IXd)
14- Ethyl 2-[N-(4-cyclohexylamino-3-nitrobenzamido)]thiazole-4-carboxylate (IXe)
15- Ethyl 2-[N-(4-(4-benzhydrylpiperazin-1-yl)-3-nitrobenzamido)]thiazole-4-carboxylate (IXf)
16- Ethyl 2-[N-(4-(4-methylpiperazin-1-yl)-3-nitrobenzamido)]thiazole-4-carboxylate (IXg)
17- Ethyl 2-[N-(3-nitro-4-(piperid-1-yl)benzamido)]thiazole-4-carboxylate (IXh)
18-
5-(4-benzhydrylpiperazin-1-oyl)-2-[N-(4-(3,4-dichloroanilino)-3-nitrobenzamido)]benzo[d]- oxazole (XIIc)
19-
5-(4-benzhydrylpiperazin-1-oyl)-2-[N-(4-(2-methyl-4-nitroanilino)-3-nitrobenzamido)]benzo-[d]oxazole (XIId)
20-
5-(4-benzhydrylpiperazin-1-oyl)-2-[N-(4-cyclohexylamino-3-nitrobenzamido)]benzo[d]-oxazole (XIIe)
21-
4-(4-benzhydrylpiperazin-1-oyl)-2-[N-(4-(phenethylamino)-3-nitrobenzamido)]thiazole (XIIIa)
22-
4-(4-benzhydrylpiperazin-1-oyl)-2-[N-(4-(3,4-dichloroanilino)-3-nitrobenzamido)]thiazole (XIIIc)
23-
4-(4-benzhydrylpiperazin-1-oyl)-2-[N-(4-(2-methyl-4-nitroanilino)-3-nitrobenzamido)]-thiazole (XIIId)
24-
4-(4-benzhydrylpiperazin-1-oyl)-2-[N-(4-cyclohexylamino-3 nitrobenzamido)]thiazole (XIIIe)
The newly synthesized compounds were evaluated in vitro through testing both Bcl-2 enzyme inhibition activity and anti-proliferative activity against NCI 60-cell line panel. And for better elucidation of their effectiveness as anti-cancer agents, three representative compounds (VIIIg, XIIe, XIIId) were subjected to cell cycle analysis and caspase-3 expression level on HCT-116 human cell lines.
Finally, molecular docking was performed in an attempt to explain the biological evaluation results and investigate the binding mode of the synthesized compounds.