Anthranilamide-based 2-phenylcyclopropane-1-carboxamides, 1,1 '-biphenyl-4-carboxamides and 1,1'-biphenyl-2-carboxamides: Synthesis biological evaluation and mechanism of action

作者：Raffa Demetrio^*; Plescia Fabiana; Maggio Benedetta^*; Raimondi Maria Valeria; D'Anneo Antonella; Lauricella Marianna; Daidone Giuseppe

来源：European Journal of Medicinal Chemistry, 2017, 132: 262-273.

DOI：10.1016/j.ejmech.2017.03.051

• 2-Phenylcyclopropane-l-carboxamides
• 1,1 '-biphenyl-4-carboxamides
• 1,1 '-biphenyl-2-carboxamides
• G2/M arrest
• Phospho-ATM and gamma H2AX increase

Several anthranilamide-based 2-phenylcyclopropane-l-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 (15,2S)-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. Derivatives13a-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 gamma H2AX, 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.

• 出版日期2017-5-26