New spiro-acridines: DNA interaction, antiproliferative activity and inhibition of human DNA topoisomerases.

Abstract Two new spiro-acridines were synthesized by introducing cyano- N -acylhydrazone between the acridine and phenyl rings followed by spontaneous cyclization. The final compounds ( E )-1⿲-(benzylideneamino)-5⿲-oxo-1⿲,5⿲-dihydro-10 H -spiro[acridine-9,2⿲-pyrrole]-4⿲-carbonitrile ( AMTAC-01 ) and ( E )-1⿲-((4-methoxybenzylidene)amino)-5⿲-oxo-1⿲,5⿲-dihydro-10 H -spiro[acridine-9,2⿲-pyrrole]-4⿲-carbonitrile ( AMTAC-02 ) were evaluated for their interactions with calf thymus DNA, antiproliferative and human topoisomerase I and IIα inhibitory activities. Both compounds presented ability to bind DNA. The binding constant determined by UV⿿vis spectroscopy was found to be 10 4  M ⿿1 . Antiproliferative assay demonstrated that AMTAC-01 and AMTAC-02 were most active against prostate and melanoma tumor cell lines, respectively. The compound did not present Topo I inhibitory activity. However, both derivatives displayed topoisomerase IIα inhibitory activity comparable to amsacrine, and AMTAC-02 was more potent than AMTAC-01 with methoxy substituent group on phenyl ring. This study demonstrates that the new derivatives are promising molecules with topoisomerase IIα inhibitory and antiproliferative activities.