Zero Hunger (SDG 2), Good Health & Well-being (SDG 3) 1 ,2,3,7 School of Chemistry and Physics, University of KwaZulu-Natal, Pietermaritzburg, South Africa 4-6 Centre for Chemico and Biomedicinal Research, Department of Biochemistry and Microbiology, Rhodes University E-mail: MaikooS@ukzn.ac.za Biomolecular interactions of Cytotoxic Ruthenium compounds with Thiosemicarbazone or Benzothiazole Schiff Base Chelates Sanam Maikoo* 1 , Bheki Xulu 1 , Allen Mambanda 1 , Ntando Mkhwanazi 2 , Candace Davison 2 , Jo-Anne de la Mare 2 , Irvin Noel Booysen 1 1 School of Chemistry and Physics, University of KwaZulu-Natal, Pietermaritzburg, South Africa 2 Centre for Chemico and Biomedicinal Research, Department of Biochemistry and Microbiology, Rhodes University Recent advances in the formulation of metal-based chemotherapeutics, see the utilization of biocompatible ligands which may can tailor the biodistribution patterns 1 . Herein, we illustrate the formation and characterization of new paramagnetic ruthenium compounds, trans-P - [RuCl(PPh 3 ) 2 (pmt)]Cl ( 1 ) (Hpmt = 1-((pyridin-2-yl)methylene)thiosemicarbazide), trans-P - [RuCl(PPh 3 ) 2 (tmc)]Cl ( 2 ) (Htmc = 1-((thiophen-2-yl)methylene)thiosemicarbazide) and a diamagnetic ruthenium complex, cis-Cl, trans-P -[RuCl 2 (PPh 3 ) 2 (btm)] ( 3 ) (btm = 2-((5- hydroxypentylimino)methyl)benzothiazole). Agarose gel electrophoresis experiments of the metal compounds illustrated dose-dependent binding to gDNA by 1 – 3 , while methylene blue competition assays suggested that 1 and 2 , were also DNA intercalators Assessment of the effects of the compounds on topoisomerase function indicated that 1 – 3 were capable of inhibiting topoisomerase I activity in terms of the ability to nick supercoiled plasmid DNA. The cytotoxic activities of the complexes were determined against a range of cancer cell lines vs. a non-tumorigenic control cell line and the complexes were, in general, more cytotoxic towards the cancer cells, displaying IC 50 values in the low micromolar range. Time-dependent stability studies showed that in the presence of strong nucleophilic species (such as DMSO), the chloride co-ligands of 1 – 3 are rapidly substituted by the former as proven by the suppression of the substitution reactions in the presence of an excess amount of chloride ions. The metal complexes are stable in both DCM and an aqueous phosphate buffer containing 2% DMSO. Recent advances in the formulation of metal-based chemotherapeutics, see the utilization of biocompatible ligands which may can tailor the biodistribution patterns1. Herein, we illustrate the formation and characterization of new paramagnetic ruthenium compounds, trans-P-[RuCl(PPh 3 ) 2 (pmt)] Cl (1) (Hpmt = 1-((pyridin-2-yl)methylene)thiosemicarbazide), trans-P-[RuCl(PPh 3 ) 2 (tmc)]Cl (2) (Htmc = 1-((thiophen-2-yl)methylene)thiosemicarbazide) and a diamagnetic ruthenium complex, cis-Cl, trans-P- [RuCl 2 (PPh 3 ) 2 (btm)] (3) (btm = 2-((5-hydroxypentylimino)methyl)benzothiazole). Agarose gel electrophoresis experiments of the metal compounds illustrated dose-dependent binding to gDNA by 1 – 3, while methylene blue competition assays suggested that 1 and 2, were also DNA intercalators Assessment of the effects of the compounds on topoisomerase function indicated that 1 – 3 were capable of inhibiting topoisomerase I activity in terms of the ability to nick supercoiled plasmid DNA. The cytotoxic activities of the complexes were determined against a range of cancer cell lines vs. a non-tumorigenic control cell line and the complexes were, in general, more cytotoxic towards the cancer cells, displaying IC50 values in the low micromolar range. Time-dependent stability studies showed that in the presence of strong nucleophilic species (such as DMSO), the chloride co-ligands of 1 – 3 are rapidly substituted by the former as proven by the suppression of the substitution reactions in the presence of an excess amount of chloride ions. The metal complexes are stable in both DCM and an aqueous phosphate buffer containing 2% DMSO.
Figure 1: The ORTEP diagram of trans-P-[RuCl(PPh 3 ) 2 (tmc)]Cl (2) (a), accompanied by its methylene blue competition assay (b). References 1. P. Kumar, S. Swagatika, S. Dasari, R. S. Tomar, A. K. Patra, Journal of Inorganic Biochemistry 2019, 199, 110769-110782. Figure 1: The ORTEP diagram of trans-P -[RuCl(PPh 3 ) 2 (tmc)]Cl ( 2 ) (a), accompanied by its methylene blue competition assay (b). References 1. P. Kumar, S. Swagatika, S. Dasari, R. S. Tomar, A. K. Patra, Journal of Inorganic Biochemistry 2019 , 199 , 110769-110782.
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