title: Anthranilamide-based 2-phenylcyclopropane-1-carboxamides, 1,1'-biphenyl-4-carboxamides and 1,1'-biphenyl-2-carboxamides: Synthesis biological evaluation and mechanism of action.
abstract: Several anthranilamide-based 2-phenylcyclopropane-1-carboxamides 13a-f, 1,1'-biphenyl-4-carboxamides 14a-f and 1,1'-biphenyl-2-carboxamides 17a-f were obtained by a multistep procedure starting from the (1S,2S)-2-phenylcyclopropane-1-carbonyl chloride 11, the 1,1'-biphenyl-4-carbonyl chloride 12 or the 1,1'-biphenyl-2-carbonyl chloride 16 with the appropriate anthranilamide derivative 10a-f. Derivatives 13a-f, 14a-f and 17a-f showed antiproliferative activity against human leukemia K562 cells. Among these derivatives 13b, 14b and 17b exerted a particular cytotoxic effect on tumor cells. Derivative 17b showed a better antitumoral effect on K562 cells than 13b and 14b. Analyses performed to explore 17b mode of action revealed that it induced an arrest in G2/M phase of cell cycle which was consequent to DNA lesions as demonstrated by the increase in phospho-ATM and γH2AX, two known markers of DNA repair response system. The effect of 17b was also related to ROS generation, activation of JNK and induction of caspase-3 dependent apoptosis.
authors.affiliation: Department of Biological, Chemical and Pharmaceutical Sciences and Technologies, Medicinal Chemistry and Pharmaceutical Technologies Section, University of Palermo, Via Archirafi 32, 90123 Palermo, Italy. Electronic address: demraffa@unipa.it.
authors.forename: Demetrio
authors.initials: D
authors.lastname: Raffa
authors.affiliation: Department of Biological, Chemical and Pharmaceutical Sciences and Technologies, Medicinal Chemistry and Pharmaceutical Technologies Section, University of Palermo, Via Archirafi 32, 90123 Palermo, Italy.
authors.forename: Fabiana
authors.initials: F
authors.lastname: Plescia
authors.affiliation: Department of Biological, Chemical and Pharmaceutical Sciences and Technologies, Medicinal Chemistry and Pharmaceutical Technologies Section, University of Palermo, Via Archirafi 32, 90123 Palermo, Italy. Electronic address: benedetta.maggio@unipa.it.
authors.forename: Benedetta
authors.initials: B
authors.lastname: Maggio
authors.affiliation: Department of Biological, Chemical and Pharmaceutical Sciences and Technologies, Medicinal Chemistry and Pharmaceutical Technologies Section, University of Palermo, Via Archirafi 32, 90123 Palermo, Italy.
authors.forename: Maria Valeria
authors.initials: MV
authors.lastname: Raimondi
authors.affiliation: Department of Biological, Chemical and Pharmaceutical Sciences and Technologies, Laboratory of Biochemistry, University of Palermo, 90127, Palermo, Italy.
authors.forename: Antonella
authors.initials: A
authors.lastname: D'Anneo
authors.affiliation: Department of Experimental Biomedicine and Clinical Neurosciences, Laboratory of Biochemistry, University of Palermo, 90127, Palermo, Italy.
authors.forename: Marianna
authors.initials: M
authors.lastname: Lauricella
authors.affiliation: Department of Biological, Chemical and Pharmaceutical Sciences and Technologies, Medicinal Chemistry and Pharmaceutical Technologies Section, University of Palermo, Via Archirafi 32, 90123 Palermo, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Daidone
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004249:DNA Damage / Q000187:drug effects; D004260:DNA Repair; D016195:G2 Phase; D006801:Humans; D020014:K562 Cells; D062367:ortho-Aminobenzoates / Q000138:chemical synthesis / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D062367:ortho-Aminobenzoates; C000219:anthranilamide
keywords: 1,1’-biphenyl-2-carboxamides; 1,1’-biphenyl-4-carboxamides; 2-Phenylcyclopropane-1-carboxamides; G2/M arrest; Phospho-ATM and γH2AX increase