Anticancer Activity and DNA Binding of a Bifunctional Ru(II) Arene Aqua-Complex with the 2,4-Diamino-6-(2-pyridyl)-1,3,5-triazine Ligand

Abstract

The synthesis and full characterization of the new aqua-complex [(η(6)-p-cymene)Ru(OH2)(κ(2)-N,N-2-pydaT)](BF4)2, [2](BF4)2, and the nucleobase derivative [(η(6)-p-cymene)Ru(9-MeG)(κ(2)-N,N-2-pydaT)](BF4)2, [4](PF6)2, where 2-pydaT = 2,4-diamino-6-(2-pyridyl)-1,3,5-triazine and 9-MeG = 9-methylguanine, are reported here. The crystal structures of both [4](PF6)2 and the chloro complex [(η(6)-p-cymene)RuCl(κ(2)-N,N-2-pydaT)](PF6), [1](PF6), have been elucidated by X-ray diffraction. The former provided relevant information regarding the interaction of the metallic fragment [(η(6)-p-cymene)Ru(κ(2)-N,N-2-pydaT)](2+) and a simple model of DNA. NMR and kinetic absorbance studies have proven that the aqua-complex [2](BF4)2 binds to the N7 site of guanine in nucleobases, nucleotides, or DNA. A stable bifunctional interaction (covalent and partially intercalated) between the [(η(6)-p-cymene)Ru(κ(2)-N,N-2-pydaT)](2+) fragment and CT-DNA has been corroborated by kinetic, circular dichroism, viscometry, and thermal denaturation experiments. The reaction mechanism entails the very fast formation of the Ru-O-(PO3) linkage prior to the fast intercalation of the 2-pydaT fragment. Then, a Ru-N7-(G) covalent bond is formed at the expense of the Ru-O-(PO3) bond, yielding a bifunctional complex. The dissociation rate of the intercalated fragment is slow, and this confers additional interest to [2](BF4)2 in view of the likely correlation between slow dissociation and biological activity, on the assumption that DNA is the only biotarget. Furthermore, [2](BF4)2 displays notable pH-dependent cytotoxic activity in human ovarian carcinoma cells (A2780, IC50 = 11.0 μM at pH = 7.4; IC50 = 6.58 μM at pH = 6.5). What is more, complex [2](BF4)2 is not cross-resistant with cisplatin, exhibiting a resistance factor, RF(A2780cis), of 0.28, and it shows moderate selectivity toward the cancer cell lines, in particular, A2780cis (IC50 = 3.0 5 ± 0.08 μM), relative to human lung fibroblast cells (MRC-5; IC50 = 24 μM), the model for healthy cells.

Ru(II)‐η6‐benzene Complexes of Dibenzosuberenyl Appended Aroyl/Acylthiourea Ligands: In vitro Biomolecular Interaction Studies and Catalytic Transfer Hydrogenation

“…There are some reports in which complexes having higher IC50 value than the standard drugs (in vitro) and showed good activity in vivo. [35] The outcome of this study would be helpful to develop the potential probes for DNA and BSA, and new chemotherapeutic drugs. This paper also describes the catalytic efficiency of the complexes toward transfer hydrogenation and the process is economic and relatively mild.…”

“…The cytotoxicity of the complexes is superior when compared to ruthenium(II)(h 6 -N-benzylmaleimide) containing 1,3,5-triaza-7-phosphaadamantane (PTA) (IC 50 , 640 mM) and the complexes 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 containing phenoxazine based ligands (IC 50 > 100 mM) against A549 cancer cell line. [52,35] The similar Ru-arene complexes containing aroylthiourea exhibited less activity (IC 50 , 102.1 mM) towards A549 cancer cell line (Figure 6c). Ruthenium-benzene complexes bearing 4-(biphenyl-4-carbonyl)-3-methyl-1-phenyl-5-pyrazolonate or anthraldehyde benzhydrazone ligands showed similar half-inhibitory concentration (35-26.4 mM) against HepG2 cancer cell line.…”

“…[34,9] The Ru-benzene centroid distances were 1.675 and 1.663 Å for 2 and 3 respectively. [35,9] The S À Ru À Cl and Cl À Ru À Cl bond angles lay in the range of 85.64-94.078. In the complexes, the coordinated chloride involved in hydrogen bonding with the N À H hydrogen (N À H···Cl).…”

[(η6-p-cymene)Ru(H2O)3]2+ binding capability of aminohydroxamates — A solution and solid state study

“…The interaction of 2 with 9-methylguanine was monitored in D 2 O using 1:1 and 1:2 molar ratios at 298 K adopting the method in Ref. [51].…”

Fingerprinting the junctions of RNA structure by an open-paddlewheel diruthenium compound

“…1A, right panel) is higher than that of paddlewheel diruthenium species (Barral et al 2007(Barral et al , 2008, we decided to test the reactivity of the compound [Ru 2 Cl 2 (µ-DPhF) 3 (DMSO)] (designated OPW-Ru) (DPhF = N,N ′ -diphenylformamidinate) toward RNA. Numerous ruthenium compounds have been designed to interact with nucleic acid such as mononuclear ruthenium complexes with labile ligands (Busto et al 2013;Wu et al 2013;Adhireksan et al 2014) or tris(chelate)ruthenium(II) compounds (Song et al 2012;Li et al 2015). The existence of labile ligands in the first type of compounds allows establishing direct ruthenium-nucleic acid bonds; the coordination mode implies bond angles of 90°.…”