title: Preclinical Activity of New [1,2]Oxazolo[5,4-e]isoindole Derivatives in Diffuse Malignant Peritoneal Mesothelioma.
abstract: A series of 22 derivatives of the [1,2]oxazolo[5,4-e]isoindole system were synthesized through an efficient and versatile procedure that involves the annelation of the [1,2]oxazole moiety to the isoindole ring, producing derivatives with a wide substitution pattern. The structure-activity relationship indicates that the N-4-methoxybenzyl group appears crucial for potent activity. In addition, the presence of a 6-phenyl moiety is important and the best activity is reached with a 3,4,5-trimethoxy substituent. The most active compound, bearing both the structural features, was able to inhibit tumor cell proliferation at nanomolar concentrations when tested against the full NCI human tumor cell line panel. Interestingly, this compound was effective in reducing in vitro and in vivo cell growth, impairing cell cycle progression and inducing apoptosis, as a consequence of the inhibition of tubulin polymerization, in experimental models of diffuse malignant peritoneal mesothelioma (DMPM), a rapidly lethal disease, poorly responsive to conventional therapeutic strategies.
authors.affiliation: Dipartimento di Scienze e Tecnologie Biologiche Chimiche e Farmaceutiche (STEBICEF), Università degli Studi di Palermo , Via Archirafi 32, 90123 Palermo, Italy.
authors.forename: Virginia
authors.initials: V
authors.lastname: Spanò
authors.affiliation: Molecular Pharmacology Unit, Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale Tumori , Via Amadeo 42, 20133 Milano, Italy.
authors.forename: Marzia
authors.initials: M
authors.lastname: Pennati
authors.affiliation: Dipartimento di Scienze e Tecnologie Biologiche Chimiche e Farmaceutiche (STEBICEF), Università degli Studi 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 (STEBICEF), Università degli Studi 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 (STEBICEF), Università degli Studi 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 (STEBICEF), Università degli Studi di Palermo , Via Archirafi 32, 90123 Palermo, Italy.
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Cilibrasi
authors.affiliation: Molecular Pharmacology Unit, Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale Tumori , Via Amadeo 42, 20133 Milano, Italy.
authors.forename: Valentina
authors.initials: V
authors.lastname: Zuco
authors.affiliation: Molecular Pharmacology Unit, Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale Tumori , Via Amadeo 42, 20133 Milano, Italy.
authors.forename: Alessia
authors.initials: A
authors.lastname: Lopergolo
authors.affiliation: Molecular Pharmacology Unit, Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale Tumori , Via Amadeo 42, 20133 Milano, Italy.
authors.forename: Denis
authors.initials: D
authors.lastname: Cominetti
authors.affiliation: Dipartimento di Scienze e Tecnologie Biologiche Chimiche e Farmaceutiche (STEBICEF), Università degli Studi di Palermo , Via Archirafi 32, 90123 Palermo, Italy.
authors.forename: Patrizia
authors.initials: P
authors.lastname: Diana
authors.affiliation: Dipartimento di Scienze e Tecnologie Biologiche Chimiche e Farmaceutiche (STEBICEF), Università degli Studi 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 (STEBICEF), Università degli Studi di Palermo , Via Archirafi 32, 90123 Palermo, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Barraja
authors.affiliation: Molecular Pharmacology Unit, Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale Tumori , Via Amadeo 42, 20133 Milano, Italy.
authors.forename: Nadia
authors.initials: N
authors.lastname: Zaffaroni
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; 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*; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000473:pathology; D008654:Mesothelioma / Q000188:drug therapy* / Q000473:pathology; D000086002:Mesothelioma, Malignant; D051379:Mice; D008819:Mice, Nude; D015394:Molecular Structure; D009374:Neoplasms, Experimental / Q000188:drug therapy / Q000473:pathology; D010534:Peritoneal Neoplasms / Q000188:drug therapy* / Q000473:pathology; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D054833:Isoindoles