title: Novel 1H-pyrrolo[2,3-b]pyridine derivative nortopsentin analogues: synthesis and antitumor activity in peritoneal mesothelioma experimental models.
abstract: In this study, we describe the synthesis of new nortopsentin analogues, 1H-pyrrolo[2,3-b]pyridine derivatives and their biological effects in experimental models of diffuse malignant peritoneal mesothelioma (DMPM), a rare and rapidly fatal disease, poorly responsive to conventional therapies. The three most active compounds, 1f (3-[2-(5-fluoro-1-methyl-1H-indol-3-yl)-1,3-thiazol-4-yl]-1H-pyrrolo[2,3-b]pyridine), 3f (3-[2-(1H-indol-3-yl)-1,3-thiazol-4-yl]-1-methyl-1H-pyrrolo[2,3-b]pyridine), and 1l (3-[2-(5-fluoro-1-methyl-1H-indol-3-yl)-1,3-thiazol-4-yl]-1-methyl-1H-pyrrolo[2,3-b] pyridine), which were shown to act as cyclin-dependent kinase 1 inhibitors, consistently reduced DMPM cell proliferation and induced a caspase-dependent apoptotic response, with a concomitant reduction of the expression of the active Thr(34)-phosphorylated form of the antiapoptotic protein survivin. Moreover, the combined treatment of DMPM cells with 3f derivative and paclitaxel produced a synergistic cytotoxic effect, which was paralleled by an enhanced apoptotic response. In the mouse model, i.p. administration of 1f, 3f, and 1l derivatives was effective, resulting in a significant tumor volume inhibition of DMPM xenografts (range, 58-75%) at well-tolerated doses, and two complete responses were observed in each treatment group.
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.forename: Marzia
authors.initials: M
authors.lastname: Pennati
authors.forename: Barbara
authors.initials: B
authors.lastname: Parrino
authors.forename: Alessia
authors.initials: A
authors.lastname: Lopergolo
authors.forename: Paola
authors.initials: P
authors.lastname: Barraja
authors.forename: Alessandra
authors.initials: A
authors.lastname: Montalbano
authors.forename: Virginia
authors.initials: V
authors.lastname: Spanò
authors.forename: Stefania
authors.initials: S
authors.lastname: Sbarra
authors.forename: Valentina
authors.initials: V
authors.lastname: Doldi
authors.forename: Michelandrea
authors.initials: M
authors.lastname: De Cesare
authors.forename: Girolamo
authors.initials: G
authors.lastname: Cirrincione
authors.forename: Patrizia
authors.initials: P
authors.lastname: Diana
authors.forename: Nadia
authors.initials: N
authors.lastname: Zaffaroni
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000494:pharmacology* / Q000627:therapeutic use; D002460:Cell Line; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D008654:Mesothelioma / Q000188:drug therapy*; D010534:Peritoneal Neoplasms / Q000188:drug therapy*; D011725:Pyridines / Q000138:chemical synthesis / Q000494:pharmacology* / Q000627:therapeutic use; D013056:Spectrophotometry, Ultraviolet
chemical_list: D000970:Antineoplastic Agents; D011725:Pyridines