الفهرس | Only 14 pages are availabe for public view |
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. |