Affiliation:
1. Département de Chimie Moléculaire—UMR CNRS-5250, Université Grenoble Alpes, 38041 Grenoble, France
2. Institute for Advanced Biology—INSERM-UGA U823, Site Santé, 38700 La Tronche, France
Abstract
Four ligands based on the 2-tert-butyl-4-X-6-{Bis[(6-methoxy-pyridin-2-ylmethyl)-amino]-methyl}-phenol unit are synthesized: X = CHO (HLCHO), putrescine-pyrene (HLpyr), putrescine (HLamine), and 2-tert-butyl-4-putrescine-6-{Bis[(6-methoxy-pyridin-2-ylmethyl)-amino]-methyl}-phenol (H2Lbis). Complexes 1, 2, 3, and 4 are formed upon chelation to copper(II). The crystal structure of complex 1 shows a square pyramidal copper center with a very weakly bound methoxypridine moiety in the apical position. The pKa of the phenol moiety is determined spectrophotometrically at 2.82–4.39. All the complexes show a metal-centered reduction in their CV at Epc,red = −0.45 to −0.5 V vs. SCE. The copper complexes are efficient nucleases towards the ϕX174 DNA plasmid in the presence of ascorbate. The corresponding IC50 value reaches 7 μM for 2, with a nuclease activity that follows the trend: 2 > 3 > 1. Strand scission is promoted by the hydroxyl radical. The cytotoxicity is evaluated on bladder cancer cell lines sensitive (RT112) or resistant to cisplatin (RT112 CP). The IC50 of the most active complexes (2 and 4) is 1.2 and 1.0 μM, respectively, for the RT112 CP line, which is much lower than cisplatin (23.8 μM).
Funder
French National Research Agency
Labex Arcane