Synergy of DNA intercalation and catalytic activity of a copper complex towards improved polymerase inhibition and cancer cell cytotoxicity

ROMO, ADOLFO IGNACIO BARROS; CAREPO, MARTA SP; LEVIN, PEDRO; NASCIMENTO, OTACIRO; DIAZ, DANIEL E; RODRIGUEZ-LOPEZ, JOAQUIN; LEÓN, IGNACIO E; BEZERRA, LUCAS FONSECA; LEMUS, LUIS A.; DIOGENES, IZAURA CIRINO NOGUEIRA

DALTON TRANSACTIONS

ROYAL SOC CHEMISTRY

Lugar: CAMBRIDGE; Año: 2021

1477-9226

Improving the binding of metal complexes to DNA to boost cancer cell cytotoxicity requires fine tuning of their structuraland chemical properties. Copper has been used as metal center in compounds containing intercalating ligands due to itsability to catalytically generate reactive oxygen species (ROS), such as hydroxyl radical (OH?). We envision the synergy ofDNA binding and ROS generation at proximity from target DNA as a powerful chemotherapy treatment. Here, we explorethe use of [Cu(2CP-Bz-SMe)]2+ (2CP-Bz-SMe = 1,3-bis(1,10-phenanthrolin-2-yloxy)-N-(4-(methylthio)benzylidene)propan-2-amine) for this purpose by characterizing its cytotoxicity, DNA binding, and ability to affect DNA replication throughpolymerase chain reaction ? PCR and nuclease assays. We determined binding (Kb) and Stern-Volmer constants (KSV) forcomplex-DNA association of 5.8 ± 0.14 x104 and 1.64 (±0.08), respectively, through absorption titration and competitivefluorescence experiments. These values were superior to those of other Cu-complex intercalators. We hypothesize that thedistorted trigonal bipyramidal geometry of [Cu(2CP-Bz-SMe)]2+ allows the phenanthroline fragments to be betteraccommodated into the DNA double helix. Moreover, the aromaticity of these fragments increases the local hydrophobicitythus increasing the affinity for the hydrophobic domains of DNA. Nuclease assays in the presence of the common reducingagents ascorbic acid, nicotinamide adenine dinucleotide, and glutathione showed effective in degradation of DNA due tothe in situ generation of OH?. The [Cu(2CP-Bz-SMe)]2+ complex showed cytotoxicity against the following human cancer cellslines A549, MCF-7, MDA-MB-231 and MG-63 with half maximal inhibitory concentration (IC50) values of 4.62 ± 0.48, 5.20 ±0.76, 5.70 ± 0.42 and 2.88 ± 0.66 M respectively. These low values of IC50, which are promising if compared to cisplatin,are ascribed to the synergistic effect of ROS generation with the intercalation ability into the DNA minor grooves andblocking DNA replication. This study introduces new principles for synergizing chemical and structural properties ofintercalation compounds for improved drug-DNA interactions targeting cancer