title: Synthesis and In Vitro Cytotoxic Properties of Polycarbo-Substituted 4-(Arylamino)quinazolines.
abstract: Herein, we describe the synthesis of novel unsymmetrical polycarbo-substituted 4-anilinoquinazolines derived from the 2-aryl-6-bromo-8-iodoquinazolines via one-pot three-step reaction sequences involving initial amination and subsequent double cross-coupling (bis-Suzuki, Sonogashira/Stille or Sonogashira/Suzuki-Miyaura) reactions with different cross coupling partners for the two carbon-carbon bond formation steps. The 4-anilinoquinazolines were evaluated for potential cytotoxicity against three cancer cell lines, namely, human breast adenocarcinoma (MCF-7) cells, human cervical cancer (HeLa) and human lung cancer (A549) cells. The most active compounds,2b,2c,3c,4a,4cand5a, were found to be more selective against the MCF-7 and HeLa cell lines than the human lung carcinoma (A549) cells. We selected compounds2c,3cand7aas representatives for further evaluation for potential to induce apoptosis and/or necrotic properties in the three cancer cell lines. Compound2cinduced apoptosis of MCF-7 cells through cell membrane alteration. Treatment of Hela and A549 cell lines with compounds3cand7a, respectively, led to caspase-3 activation in both cell lines. Compound3c, on the other hand, caused more necrosis than apoptosis induction in the membrane alteration assay.
authors.affiliation: Department of Chemistry, College of Science, Engineering and Technology, University of South Africa, Private Bag X06, Florida 1710, South Africa. tkamdeh@unisa.ac.za.
authors.forename: Hugues Kamdem
authors.initials: HK
authors.lastname: Paumo
authors.affiliation: Department of Life and Consumer Sciences, College of Agriculture and Environmental Sciences, University of South Africa, Private Bag X06, Florida 1710, South Africa. makhat@unisa.ac.za.
authors.forename: Tshepiso Jan
authors.initials: TJ
authors.lastname: Makhafola
authors.affiliation: Department of Chemistry, College of Science, Engineering and Technology, University of South Africa, Private Bag X06, Florida 1710, South Africa. mphahmj@unisa.ac.za.
authors.forename: Malose Jack
authors.initials: MJ
authors.lastname: Mphahlele
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D017209:Apoptosis; D053148:Caspase 3 / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006367:HeLa Cells; D006801:Humans; D007093:Imidazoles / Q000138:chemical synthesis* / Q000494:pharmacology; D061986:MCF-7 Cells; D011799:Quinazolines / Q000138:chemical synthesis* / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D007093:Imidazoles; D011799:Quinazolines; C505407:CASP3 protein, human; D053148:Caspase 3
keywords: 2-aryl-6-bromo-4-chloro-8-iodoquinazolines; amination; apoptosis; cross-coupling; cytotoxicity; polycarbo-substituted 4-anilinoquinazolines