title: Synthesis and antiproliferative activity of 3-(2-chloroethyl)-5-methyl-6-phenyl-8-(trifluoromethyl)-5,6-dihydropyrazolo[3,4-f][1,2,3,5]tetrazepin-4-(3H)-one.
abstract: Based on the encouraging results found for 3,5-dimethyl-6-phenyl-8-(trifluoromethyl)-5,6-dihydropyrazolo[3,4-f][1,2,3,5]tetrazepin-4-(3H)-one 7 previously tested by us, as well as the consideration that heterocycle fused tetrazepinones bearing the 2-chloroethyl substituent show a better cytotoxic profile than temozolomide and mitozolomide against human cancer cell lines which express the DNA repair protein O6-methylguanine-DNA methyltransferase (MGMT), in this paper we report the multistep synthesis and the biological study of 3-(2-chloroethyl)-5-methyl-6-phenyl-8-(trifluoromethyl)-5,6-dihydropyrazolo[3,4-f][1,2,3,5]tetrazepin-4-(3H)-one 10. Like compound 7, it was active on P-glycoprotein expressing cells (MDR) HL60 and on K562 cell line that are resistant to apoptosis induced by different stimuli, showing GI50 values of 14 and 18 μM respectively. As an antiproliferative agent against the above cells compound 10 was about 2.2 times more active than compound 7. Compound 10 was also tested against WiDR cells which are overexpressing the DNA repair protein MGMT, showing a GI50 value of 2.3 μM. Finally, concerning the effect on cell cycle we observed an evident difference between compounds 7 and 10. In fact, compound 7 induces a block of cell cycle in G0-G1, therefore acting as phase-specific drug, in contrast, compound 10 is a not phase-specific agent. Both the compounds are able to increase the apoptotic sub G0-G1 peak of cell cycle.
authors: Dipartimento di Scienze e Tecnologie Biologiche, Chimiche e Farmaceutiche, Università degli Studi di Palermo, Via Archirafi 32, 90123 Palermo, Italy.
authors: Benedetta
authors: B
authors: Maggio
authors: Dipartimento di Scienze e Tecnologie Biologiche, Chimiche e Farmaceutiche, Università degli Studi di Palermo, Via Archirafi 32, 90123 Palermo, Italy. Electronic address: mariavaleria.raimondi@unipa.it.
authors: Maria Valeria
authors: MV
authors: Raimondi
authors: Dipartimento di Scienze e Tecnologie Biologiche, Chimiche e Farmaceutiche, Università degli Studi di Palermo, Via Archirafi 32, 90123 Palermo, Italy. Electronic address: demetrio.raffa@unipa.it.
authors: Demetrio
authors: D
authors: Raffa
authors: Dipartimento di Scienze e Tecnologie Biologiche, Chimiche e Farmaceutiche, Università degli Studi di Palermo, Via Archirafi 32, 90123 Palermo, Italy.
authors: Fabiana
authors: F
authors: Plescia
authors: Dipartimento di Scienze e Tecnologie Biologiche, Chimiche e Farmaceutiche, Università degli Studi di Palermo, Via Archirafi 32, 90123 Palermo, Italy.
authors: Stella
authors: S
authors: Cascioferro
authors: Dipartimento di Scienze e Tecnologie Biologiche, Chimiche e Farmaceutiche, Università degli Studi di Palermo, Via Archirafi 32, 90123 Palermo, Italy.
authors: Gabriella
authors: G
authors: Cancemi
authors: Centro Interdipartimentale di Ricerca in Oncologia Clinica e Dipartimento Biomedico di Medicina Interna e Specialistica, Sezione di Malattie Infettive, Università degli Studi di Palermo, Via del Vespro 129, 90127 Palermo, Italy.
authors: Manlio
authors: M
authors: Tolomeo
authors: Sezione di Gastroenterologia, Dipartimento di Biomedicina Interna e Specialistica, Università degli Studi di Palermo, Via del Vespro 129, 90127 Palermo, Italy.
authors: Stefania
authors: S
authors: Grimaudo
authors: Dipartimento di Scienze e Tecnologie Biologiche, Chimiche e Farmaceutiche, Università degli Studi di Palermo, Via Archirafi 32, 90123 Palermo, Italy.
authors: Giuseppe
authors: G
authors: Daidone
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001381:Azepines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D018922:HL-60 Cells; D006801:Humans; D020014:K562 Cells; D015394:Molecular Structure; D011720:Pyrazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: C000604901:3-(2-chloroethyl)-5-methyl-6-phenyl-8-(trifluoromethyl)-5,6-dihydropyrazolo(3,4-f)(1,2,3,5)tetrazepin-4-(3H)-one; D000970:Antineoplastic Agents; D001381:Azepines; D011720:Pyrazoles
keywords: 1,2,3,5-Tetrazepinones; Antiproliferative activity; Apoptosis; Drug resistance; Pyrazolo[3,4-f][1,2,3,5]-tetrazepinones