title: Synthesis of 4(3H)quinazolinimines with selective cytotoxic effect on human acute promyelocytic leukemia cells.
abstract: We synthesized a new family of six 4(3H)quinazolinimines based on the reaction between (E)-N-(2-cyanophenyl)benzimidoyl chloride and substituted anilines reaching the formation of their corresponding C2, N3-substituted quinazoliniminium chlorides. This method provides novel, direct and flexible access to diverse substituted 4(3H)quinazolinimines. New compounds obtained following the proposed synthesis were fully characterized and, including the thirteen 4(3H)quinazolinimines synthesized by this method and previously reported by us, were used to study its cytotoxic effect on neoplastic cell lines. The mechanism involved in cell toxicity was also studied. Results showed that these compounds were highly cytotoxic, in particular on Human Promyelocytic Leukemia cells (HL60) and Chronic Myelogenous Leukemia cells (K562) when compared with conventional antineoplastic drugs such as etoposide and cisplatin. The mechanism associated to cytotoxic effect was mainly apoptosis, which not was decreased by antioxidant addition, thereby suggesting that the compounds exert apoptotic death through a mechanism unrelated with oxidative stress.
authors.affiliation: Departamento de Química Inorgánica, Facultad de Química, Pontificia Universidad Católica de Chile, Casilla 306, Santiago 22, Chile.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Becerra
authors.affiliation: Departamento de Química Inorgánica, Facultad de Química, Pontificia Universidad Católica de Chile, Casilla 306, Santiago 22, Chile.
authors.forename: Celso
authors.initials: C
authors.lastname: Quintero
authors.affiliation: Departamento de Química Inorgánica, Facultad de Química, Pontificia Universidad Católica de Chile, Casilla 306, Santiago 22, Chile.
authors.forename: Valeria
authors.initials: V
authors.lastname: Morales
authors.affiliation: Departamento de Química Inorgánica, Facultad de Química, Pontificia Universidad Católica de Chile, Casilla 306, Santiago 22, Chile.
authors.forename: Mauricio
authors.initials: M
authors.lastname: Valderrama
authors.affiliation: Departamento de Farmacia, Facultad de Química, Pontificia Universidad Católica de Chile, Casilla 306, Santiago 22, Chile.
authors.forename: Adam
authors.initials: A
authors.lastname: Aguirre
authors.affiliation: Departamento de Farmacia, Facultad de Química, Pontificia Universidad Católica de Chile, Casilla 306, Santiago 22, Chile. Electronic address: mfaundeza@uc.cl.
authors.forename: Mario A
authors.initials: MA
authors.lastname: Faúndez
authors.affiliation: Departamento de Química Inorgánica, Facultad de Química, Pontificia Universidad Católica de Chile, Casilla 306, Santiago 22, Chile. Electronic address: rrojasg@uc.cl.
authors.forename: Rene S
authors.initials: RS
authors.lastname: Rojas
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000633:toxicity; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D004354:Drug Screening Assays, Antitumor; D018922:HL-60 Cells; D006801:Humans; D015473:Leukemia, Promyelocytic, Acute / Q000378:metabolism / Q000473:pathology; D018384:Oxidative Stress / Q000187:drug effects; D052999:Quinazolinones / Q000138:chemical synthesis / Q000737:chemistry* / Q000633:toxicity; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D052999:Quinazolinones; C000614528:quinazolinimine
keywords: (E)-N-(2-Cyanophenyl)benzimidoyl chloride; 4(3H)Quinazolinimines; Cell death mechanism; Cytotoxic activity; Leukemia cells