Synthesis And Antiproliferative Activity Of 9-benzylamino-acridine Derivatives

The alterations in DNA structure as well as changes in chromosome structure and number are collectively known as genomic instability,which has been recognized as the most pervasive characteristic of most cancers nowadays.As DNA damages such as single-strand breaks,double-strand breaks might lead to cell death,cells possess complex mechanisms to respond to those damages to maintain genomic integrity and cell alive.For the sake of killing cancer cells,both DNA and DNA replication related enzymes can serve as targets for cancer therapy and practiced clinically for decades.Among those enzymes,topoisomerases are studied for many years with more prominent effectiveness.Both topoisomerase I and topoisomerase II with the ability to catalyze DNA breakage and religation,facilitate the replication and transcription of DNA.Numerous anticancer drugs used in clinic are those which can interact with DNA and topoisomerases to induce DNA damage and prevent DNA lesion repairmen,such as camptothecin and etoposide which can stable TopoI-DNA and TopoI-DNA complexes,respectively.Acridines are firstly used as antibacterial and antiparasite agents with planar aromatic structures that are capable to intercalate into DNA base pairs.Since its anticancer effect has been noticed,considerable researches have been conducted to synthesize more effective and less toxic acridines as anticancer agents.A series of 9-benzylamino acridine derivatives were synthesizedas our continuous work to develop new anticancer compounds.Most of these acridine compounds displayed good antiproliferative activity with IC50 values in low micromole range and structure-activity relationships were studied.Topo I-and II-mediated relaxation studies suggested that all of our compounds displayed strong Topo II inhibitory activity at 100 ?M,while only four exhibited moderate Topo I inhibitory activity.The typical compound 8p could penetrate A549 cancer cells efficiently.Compound 8p could intercalate within the double-stranded DNA structure and induce DNA damage.Moreover,compound 8p could induce A549 cells apoptosis through caspase-dependent intrinsic pathway and arrest A549 cells at the G2/M phase.