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

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Abstract

Several anthranilamide-based 2-phenylcyclopropane-1-carboxamides 13a-f, 1,1’-biphenyl-4-carboxamides14a-f and 1,1’-biphenyl-2-carboxamides 17a-f were obtained by a multistep procedure startingfrom the (1S,2S)-2-phenylcyclopropane-1-carbonyl chloride 11, the 1,1'-biphenyl-4-carbonyl chloride 12or 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. Derivative17b showed a better antitumoral effect on K562 cells than 13b and 14b. Analyses performed to explore17b mode of action revealed that it induced an arrest in G2/M phase of cell cycle which was consequentto DNA lesions as demonstrated by the increase in phospho-ATM and gH2AX, two known markers ofDNA repair response system. The effect of 17b was also related to ROS generation, activation of JNK andinduction of caspase-3 dependent apoptosis.
Original languageEnglish
Pages (from-to)262-273
Number of pages12
JournalEuropean Journal of Medicinal Chemistry
Volume132
Publication statusPublished - 2017

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All Science Journal Classification (ASJC) codes

  • Pharmacology
  • Drug Discovery
  • Organic Chemistry

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