title: Aza-isoindolo and isoindolo-azaquinoxaline derivatives with antiproliferative activity.
abstract: Three new ring systems, pyrido[2',3':3,4]pyrrolo[1,2-a]quinoxalines, pyrido[3',2':3,4]pyrrolo[1,2-a]quinoxalines and pyrido[2',3':5,6]pyrazino[2,1-a]isoindoles, were synthesized through an aza-substitution on the already active isoindolo-quinoxaline system and in particular in the position 7 or 4 of the isoindole moiety and in position 5 of the quinoxaline portion. All new compounds were screened by the National Cancer Institute (Bethesda, MD) against a panel of 60 human tumor cell lines. Biological results of the most active derivatives, with pGI50 values between 7.09 and 7.27, confirmed the importance of the presence of methoxy substituents for biological activity. The anti-proliferative effect of selected quinoxalines was associated with apoptosis of the cells and arrest in G2/M phase of the cell cycle. DNA binding properties of the compounds was also assessed to investigate the possible mechanism of action.
authors.affiliation: Dipartimento di Scienze e Tecnologie Biologiche Chimiche e Farmaceutiche, Università di Palermo, Via Archirafi 32, 90123 Palermo, Italy.
authors.forename: Barbara
authors.initials: B
authors.lastname: Parrino
authors.affiliation: Dipartimento di Scienze e Tecnologie Biologiche Chimiche e Farmaceutiche, Università di Palermo, Via Archirafi 32, 90123 Palermo, Italy.
authors.forename: Anna
authors.initials: A
authors.lastname: Carbone
authors.affiliation: Dipartimento di Scienze e Tecnologie Biologiche Chimiche e Farmaceutiche, Università di Palermo, Via Archirafi 32, 90123 Palermo, Italy.
authors.forename: Virginia
authors.initials: V
authors.lastname: Spanò
authors.affiliation: Dipartimento di Scienze e Tecnologie Biologiche Chimiche e Farmaceutiche, Università di Palermo, Via Archirafi 32, 90123 Palermo, Italy.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Montalbano
authors.affiliation: Dipartimento di Scienze e Tecnologie Biologiche Chimiche e Farmaceutiche, Università di Palermo, Via Archirafi 32, 90123 Palermo, Italy.
authors.forename: Daniele
authors.initials: D
authors.lastname: Giallombardo
authors.affiliation: Dipartimento di Scienze e Tecnologie Biologiche Chimiche e Farmaceutiche, Università di Palermo, Via Archirafi 32, 90123 Palermo, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Barraja
authors.affiliation: Dipartimento di Scienze e Tecnologie Biologiche Chimiche e Farmaceutiche, Università di Palermo, Via Archirafi 32, 90123 Palermo, Italy.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Attanzio
authors.affiliation: Dipartimento di Scienze e Tecnologie Biologiche Chimiche e Farmaceutiche, Università di Palermo, Via Archirafi 32, 90123 Palermo, Italy.
authors.forename: Luisa
authors.initials: L
authors.lastname: Tesoriere
authors.affiliation: Dipartimento di Scienze del Farmaco, Università di Padova, Via Marzolo 5, 35131 Padova, Italy.
authors.forename: Claudia
authors.initials: C
authors.lastname: Sissi
authors.affiliation: Dipartimento di Scienze del Farmaco, Università di Padova, Via Marzolo 5, 35131 Padova, Italy.
authors.forename: Manlio
authors.initials: M
authors.lastname: Palumbo
authors.affiliation: Dipartimento di Scienze e Tecnologie Biologiche Chimiche e Farmaceutiche, Università di Palermo, Via Archirafi 32, 90123 Palermo, Italy.
authors.forename: Girolamo
authors.initials: G
authors.lastname: Cirrincione
authors.affiliation: Dipartimento di Scienze e Tecnologie Biologiche Chimiche e Farmaceutiche, Università di Palermo, Via Archirafi 32, 90123 Palermo, Italy. Electronic address: patrizia.diana@unipa.it.
authors.forename: Patrizia
authors.initials: P
authors.lastname: Diana
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001372:Aza Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D054833:Isoindoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D015394:Molecular Structure; D011810:Quinoxalines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D001372:Aza Compounds; D054833:Isoindoles; D011810:Quinoxalines
keywords: Antiproliferative activity; Apoptosis; Azaisoindolo-quinoxalines; DNA interaction; Isoindolo-azaquinoxalines; Quinoxalines