title: Pyrazino[1,2-b]isoquinolines: synthesis and study of their cytostatic and cytotoxic properties.
abstract: The in vitro antitumor potential of novel pyrazino[1,2-b]-isoquinoline-4-ones that contain a half portion of significant natural products was explored in three cancer cell lines: MDA-MB 231 human breast carcinoma, A-549 human lung carcinoma, and HT-29 human colon carcinoma. In general, these compounds show mid to low muM GI(50)s, but LC(50)s over 100 microM with the exceptions of compounds 3b and 31 that are moderately toxic in all cell lines, while compound 4a is highly toxic and selective for HT-29 cells with LC(50) values in the high nanomolar range. Experiments directed to elucidate possible mechanisms of action with compounds 3a, 29, and 31 showed that compound 3a is able to efficiently induce apoptosis triggered directly from the G2/M phase of cell cycle, while compounds 29 and 31 are potentially cytostatic agents that induce the G1/S arrest of cell cycle. All three compounds do not act through DNA damage, since they do not activate this signaling at the level of sensors, transducers, and executers. Furthermore, the apoptosis induction of 3a is not mediated by activation of pro-apoptotic kinases JNK and p38 or by activation of AKT.
authors.affiliation: Departamento de Química Orgánica y Farmacéutica, Facultad de Farmacia, Universidad Complutense, Plaza Ramón y Cajal s/n, 28040 Madrid, Spain.
authors.forename: Irene
authors.initials: I
authors.lastname: Ortín
authors.forename: Juan Francisco
authors.initials: JF
authors.lastname: González
authors.forename: Elena de la
authors.initials: Ede L
authors.lastname: Cuesta
authors.forename: Cristina
authors.initials: C
authors.lastname: Manguan-García
authors.forename: Rosario
authors.initials: R
authors.lastname: Perona
authors.forename: Carmen
authors.initials: C
authors.lastname: Avendaño
mesh_terms: D000230:Adenocarcinoma / Q000378:metabolism / Q000473:pathology; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D002453:Cell Cycle / Q000187:drug effects* / Q000502:physiology; D002455:Cell Division; D045744:Cell Line, Tumor; D054697:Cytostatic Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D004249:DNA Damage / Q000187:drug effects* / Q000502:physiology; D016193:G1 Phase; D016195:G2 Phase; D019073:HT29 Cells; D006801:Humans; D020128:Inhibitory Concentration 50; D007546:Isoquinolines / Q000138:chemical synthesis / Q000494:pharmacology*; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D008175:Lung Neoplasms / Q000378:metabolism / Q000473:pathology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011719:Pyrazines / Q000138:chemical synthesis / Q000494:pharmacology*; D016196:S Phase; D013329:Structure-Activity Relationship; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D054697:Cytostatic Agents; D007546:Isoquinolines; D011719:Pyrazines; D051057:Proto-Oncogene Proteins c-akt; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases