Anticancer activity and DNA interaction of ruthenium acetate clusters bearing azanaphthalene ancillary ligands

摘要

Six triruthenium complexes (1-6) ([Ru3O(CH3COO)(6)(L)(3)]PF6, L = quinazoline (qui) (complex 1), 5-nitroisoquinoline (5-nitroiq) (complex 2), 5-bromoisoquinoline (5-brig) (complex 3), isoquinoline (iq) (complex 4), 5-aminoisoquinoline (5-amiq) (complex 5), and 5,6,7,8-tetrahydroisoquinoline (thiq) (complex 6)) have been studied regarding their anti-cancer activity (B16F10 and A549 cells) and their interactions with fish sperm DNA (fs-DNA). The crystallographic data of complex 4 show the typical triangular geometry, where the three isoquinoline ligands display different degrees of co-planarity with the [Ru3O] unit. In the range of 2 to 200 mu M, these complexes make B16F10 cells less viable. The overall cytotoxicity order is complex 4 > complex 6 > complex 2 > complex 5 > complex 1. The two first complexes have IC50 of 10 and 50 mu M, respectively, being less toxic to L929 non-tumoral cells. The complexes can displace ethidium bromide (EB) from DNA, but the intercalation constant values (K-app similar to 10(5) M-1) are low due to the smaller size of the azanaphtalene ligands as compared to classic intercalating molecules. Complex 5 provides the highest constants in both the EB displacement (K-app = 12.5 x 10(5) M-1) and direct spectrophotometric titration with fs-DNA (K-b = 6.3 x 10(4) M-1) assays, possibly because its amino group can assist interaction with DNA through hydrogen bonds. Hypochromism of complexes IC band was observed (T = 310 K), suggesting hydrophobic contributions. Low values of K-app and circular dichroism spectra for DNA-compound 6 mixtures, suggest semi-intercalative and major groove binding interaction modes. Compared to cisplatin, incubation of complexes 1-6 with plasmid pUC19 shows no DNA cleavage. Results for the interaction with DNA do not correlate with cytotoxicity, which suggests that DNA is not the pharmacological target of this class of compounds. (C) 2019 Elsevier Ltd. All rights reserved.