Synthesis and characterization of mixed-ligand diimine-piperonal thiosemicarbazone complexes of ruthenium(II): Biophysical investigations and biological evaluation as anticancer and antibacterial agents

Abstract

We have used a novel microwave-assisted method developed in our laboratories to synthesize a series of ruthenium-thiosemicarbazone complexes. The new thiosemicarbazone ligands are derived from benzo[d][1,3]dioxole-5-carbaldehyde (piperonal) and the complexes are formulated as [(diimine)(2)Ru(TSC)](PF(6))(2) (where the TSC is the bidentate thiosemicarbazone ligand). The diimine in the complexes is either 2,2'-bipyridine or 1,10-phenanthroline. The complexes have been characterized by spectroscopic means (NMR, IR and UV-Vis) as well as by elemental analysis. We have studied the biophysical characteristics of the complexes by investigating their anti-oxidant ability as well as their ability to disrupt the function of the human topoisomerase II enzyme. The complexes are moderately strong binders of DNA with binding constants of 10(4) M(-1). They are also strong binders of human serum albumin having binding constants on the order of 10(4) M(-1). The complexes show good in vitro anticancer activity against human colon cancer cells, Caco-2 and HCT-116 and indeed show some cytotoxic selectivity for cancer cells. The IC(50) values range from 7 - 159 μM (after 72 h drug incubation). They also have antibacterial activity against Gram-positive strains of pathogenic bacteria with IC(50) values as low as 10 μM; little activity was seen against Gram-negative strains. It has been established that all the compounds are catalytic inhibitors of human topoisomerase II.

Fig. 1

Structure of the ligands and complexes synthesized in the study.

Fig. 2

Fluorescence spectra of the EB-DNA complex in the absence and presence of increasing amounts of 2, 1_ex = 520 nm, [EB] = 0.33 mM, [DNA] = 10 mM, [2] (inM): 0 – 60 in 5 inM increments. Temperature = 303 K.

Fig. 3

Stem-Volmer plots for the reaction of the complexes with EB-DNA at 308 K.

Fig. 4

Effect of increasing concentrations of complexes 1 ,2, 4 and 5 on the relative viscosity of ct-DNA solutions at 304 K ± 1 K.

Fig. 5

Agarose gel electrophoresis diagram for the cleavage of pBR322 DNA by 1 at ambient temperature in the dark (A) and upon irradiation with 365 nm light (B) under aerobic conditions. Irradiation time was 1 h and incubation time was 1 h. Lane DNA, DNA alone; Lane 1 –8, DNA + 10, 20, 30,40, 50,100, 200 and 300 mM 1; Lane 10, DNA ladder

Fig. 6

Emission spectra of HSA in the absence and presence of increasing amounts of 2, 1_ex = 295 nm, [HSA] = 5.0 nil and [2] (mM): 0–35 in 2.5 mM increments. Temperature = 303.0 K.

Fig. 7

Stem-Volmer plots for the reaction of the complexes with HSA at 308 K.

Fig. 8

Plot of the modified Stern-Volmer equation: F₀/(F₀ − F) vs. 1/[Ru], for the reaction of the complexes with HSA.