Synthesis, cytotoxicity evaluation, and molecular modeling studies of 2,N¹⁰-substituted acridones as DNA-intercalating agents

Abstract

Acridine-based compounds possess anticancer activities by intercalating to DNA. Although they have chemotherapeutic potential, acridine-based compounds are not used to treat cancer. In this study, 2, N10-acridone derivatives are designed and synthesized based on acridone, a ketone derivative of acridine. Herein, acridone is functionalized with alkyl side chains containing terminal nitrogen-based moieties at the N10-position and substituted at the C2-position. The products are evaluated for in vitro cytotoxicity against four cancer cell lines: Molt-3, HepG2, A549, and HuCCA-1. The derivative bearing two butyl piperidine side chains at the C2- and N10-positions is the most active, with IC50 values ranging from 2.96 to 9.46 µM. Molecular modeling studies supported the binding of the derivatives to DNA by intercalation, thereby confirming the observed cytotoxic effects.

The Discovery of Potent SHP2 Inhibitors with Anti-Proliferative Activity in Breast Cancer Cell Lines

“…It is worth mentioning that compound 13030 belongs to the acridines family which usually demonstrates antitumor activity, particularly as intercalating agents. Due to the planarity present in their tricyclic system, acridines are able to slide in between the DNA nitrogen bases, and block the DNA replication and transcription processes [27][28][29]. Similarly, compound 57774 has a phenoxazine ring system in its structure which was experimentally proven to bind to DNA and exert anticancer effect [30,31].…”