Synthesis and biological research of novel azaacridine derivatives as potent DNA-binding ligands and topoisomerase II inhibitors

Bioorganic & Medicinal Chemistry
Dan LiYuyang Jiang

Abstract

DNA and DNA-related enzymes are one of the most effective and common used intracellular anticancer targets in clinic and laboratory studies, however, most of DNA-targeting drugs suffered from toxic side effects. Development of new molecules with good antitumor activity and low side effects is important. Based on computer aided design and our previous studies, a series of novel azaacridine derivatives were synthesized as DNA and topoisomerases binding agents, among which compound 9 displayed the best antiproliferative activity with an IC50 value of 0.57μM against U937 cells, which was slightly better than m-AMSA. In addition, compound 9 displayed low cytotoxicity against human normal liver cells (QSG-7701), the IC50 of which was more than 3 times lower than m-AMSA. Later study indicated that all the compounds displayed topoisomerases II inhibition activity at 50μM. The representative compound 9 could bind with DNA and induce U937 apoptosis through the exogenous pathway.

Citations

Feb 15, 2019·Journal of Ovarian Research·Eleonora GhisoniGiorgio Valabrega
Apr 10, 2019·Anti-cancer Agents in Medicinal Chemistry·Nehmedo G FawzyAdel S Girgis
Nov 16, 2018·MedChemComm·Parteek Prasher, Mousmee Sharma
Sep 14, 2021·Journal of Applied Toxicology : JAT·Maria Kozurkova

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Apoptosis is a specific process that leads to programmed cell death through the activation of an evolutionary conserved intracellular pathway leading to pathognomic cellular changes distinct from cellular necrosis