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

作者：Vitalino de Almeida Sinara Monica; Lafayett Elizabeth Almeida; Silva Willams Leal; Serafim Vanessa de Lima; Menezes Thais Meira; Neves Jorge Luiz; Tasca Gois Ruiz Ana Lucia; de Carvalho Joao Ernesto; de Moura Ricardo Olimpio; Carneiro Beltrao Eduardo Isidoro; de Carvalho Junior Luiz Bezerra; Alves de Lima Maria do Carmo

来源：International Journal of Biological Macromolecules, 2016, 92: 467-475.

DOI：10.1016/j.ijbiomac.2016.07.057

• Spiro-acridine
• DNA-binding
• Topoisomerase

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-10H-spiro[acridine-9,2'-pyrrole]-4'-carbonitrile (AMTAC-01) and (E)-1'-((4-methoxybenzylidene)amino)-5'-oxo-1',5'-dihydro-10H-spiro[acridine-9,2'-pyrrole]-4'-carbonitrile (AMTAC-02) were evaluated for their interactions with calf thymus DNA, antiproliferative and human topoisomerase I and II alpha 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 IIa 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 II alpha inhibitory and antiproliferative activities.

• 出版日期2016-11