title: Induction of intrinsic apoptosis pathway in colon cancer HCT-116 cells by novel 2-substituted-5,6,7,8-tetrahydronaphthalene derivatives.
abstract: 2-Acetyl tetralin (1) reacted with N,N-dimethylformamide dimethylacetal (DMF-DMA) to afford the enaminone 3. The reaction of 3 with piperidine and morpholine afforded the trans enaminone 5a,b, respectively. Compound 3 was treated with primary aromatic amines to give secondary enaminones 6a-e. The enaminone 3 reacted with acetylglycine and hippuric acid to yield pyranones 10a, b, respectively. The reaction of enaminone 3 with 1,4-benzoquinone and 1,4-naphthoquinone gave benzofuranyl tetralin derivatives 14a,b, respectively. Also, when 3 reacted with 5-amino-3-phenyl-1H-pyrazole 15a and 5-amino-1,2,3-triazole 15b, it afforded the new pyrazolo[1,5-a]pyrimidine 17a and 1,2,3-triazolo[1,5-a]pyrimidine 17b, respectively. While the reaction of 3 with pyrimidines 18a, b resulted in the formation of pyrido[2,3-d]pyrimidine derivatives 20a, b, respectively. Investigations of the cytotoxic effect of those compounds against different human cell lines indicated that some compounds showed high selective cytotoxicity against colon cancer HCT-116 cells. Some of these compounds led to DNA damaging and fragmentation that was associated with the induction of apoptosis via mitochondrial pathway. This pathway is initiated by the impairment of mitochondrial transmembrane potential (Δψm) and in response to that the mitochondria released cytochrome c increased, that in turn activated caspase-9 and caspase-3 and induced apoptosis. Compounds 17b and 20b were promising anti-cancer agents that induced intrinsic apoptosis pathway in colon cancer cells.
authors.affiliation: Cancer Biology Laboratory, Center of Excellence for Advanced Sciences, National Research Center, Dokki, 12622 Cairo, Egypt. Electronic address: aeldeen7@yahoo.com.
authors.forename: Amira M
authors.initials: AM
authors.lastname: Gamal-Eldeen
authors.affiliation: Applied Organic Chemistry Department, National Research Centre, Dokki, Cairo, Egypt. Electronic address: drnehalhamdy63@hotmail.com.
authors.forename: Nehal A
authors.initials: NA
authors.lastname: Hamdy
authors.affiliation: Applied Organic Chemistry Department, National Research Centre, Dokki, Cairo, Egypt; Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh 11451, Saudi Arabia.
authors.forename: Hatem A
authors.initials: HA
authors.lastname: Abdel-Aziz
authors.affiliation: Zoology Department, Faculty of Science, Ain Shams University, Cairo, Egypt.
authors.forename: Enas A
authors.initials: EA
authors.lastname: El-Hussieny
authors.affiliation: Applied Organic Chemistry Department, National Research Centre, Dokki, Cairo, Egypt.
authors.forename: Issa M I
authors.initials: IM
authors.lastname: Fakhr
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects; D003110:Colonic Neoplasms / Q000473:pathology*; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D045325:HCT116 Cells; D006801:Humans; D061986:MCF-7 Cells; D008958:Models, Molecular; D015394:Molecular Structure; D011720:Pyrazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D011725:Pyridines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D011744:Pyrimidinones / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
chemical_list: C000593390:2-phenyl-7-(5,6,7,8-tetrahydronaphthalen-2-yl)pyrazolo(1,5-a)pyrimidine; C000593391:5-(5,6,7,8-tetrahydronaphthalen-2-yl)-2-thioxo-2,3-dihydropyrido(2,3-d)pyrimidin-4(1H)-one; D000970:Antineoplastic Agents; D011720:Pyrazoles; D011725:Pyridines; D011743:Pyrimidines; D011744:Pyrimidinones
keywords: 1,2,3-Triazolo[1,5-a]pyrimidine; 2-Acetyl tetralin; Apoptosis; Enaminone; Mitochondrial membrane potential; Pyranone; Pyrazolo[1,5-a]pyrimidine; Pyrido[2,3-d]pyrimidine