Ruthenium complexes for the treatment of protozoan diseases of medical and veterinary importance
Options
BORIS DOI
Abstract
The auxotrophic parasite Toxoplasma gondii is a cause of toxoplasmosis. It affects all warm-blooded species, and around one third of the world human population is affected.
The Current medication consists in combination treatments based on pyrimethamine with sulfadiazine. Drugs clinically used to treat toxoplasmosis are not specific, being mainly developed for other diseases, have important side effects, and only effective during the acute stage of infection but they do not eradicate bradyzoite tissue cysts. In consequence, the development of new effective anti-Toxoplasma medications, exhibiting also improved tolerability, is of great importance.
Trithiolato-bridged dinuclear ruthenium(II)-arene compounds demonstrated interesting antiparasitic efficacy against Toxoplasma gondii, Neospora caninum and Trypanosoma brucei. Very little is known about their cellular targets and potential mode of action.
It was hypothesized that improved in vivo properties and a better knowledge of their exact cellular targets and mode of action can be obtained using the 'conjugate approach' consisting in anchoring judiciously chosen bioactive molecules onto the diruthenium core.
This thesis was focused on the synthesis and biological activity evaluation of various hybrid molecules in which fluorophores, metabolites and drugs were appended on the trithiolato-bridged dinuclear ruthenium(II)-arene moiety. The aims of this approach were: (i) to investigate the cellular targets/mode of action by tracing fluorophore-tagged compounds inside cells/parasites, (ii) to improve the cellular uptake of the complexes by conjugating metabolites necessary for the parasites growth, exploiting the parasite auxotrophies and metabolic peculiarities in Trojan horse strategy, and (iii) to obtain compounds with increased antiparasitic efficacy by coupling with a drug relevant to the treatment of toxoplasmosis.
Five libraries of dyads based on the diruthenium moiety were synthesized and fully characterized. Where applicable (conjugates with fluorophores), photophysical properties were also measured.
The new conjugates and representative intermediates were investigated to assess the impact of compound exposure upon T. gondii β-gal tachyzoites grown in HFF (human foreskin fibroblasts) and noninfected HFF. For each series the influence of the nature of the anchored organic fragment, the type and length of the linking unit were evaluated. The most active and selective compounds were also submitted to dose-response studies. Seven compounds with IC50 values in nanomolar range displayed promising activity and selectivity. For some compounds TEM (transmission electron microscopy) and confocal microscopy tests were also performed. The TEM images suggest that the parasite’s mitochondrion is the preferred targets of the compounds and, importantly, that the host’s mitochondrion (HFF) is not affected.
Overall a library of 93 trithiolato-bridged dinuclear ruthenium(II)-arene complexes decorated with different organic substituents were developed. 7 compounds with interesting cytotoxicity/selectivity profile were identified and can be submitted for further in vivo studies.
The Current medication consists in combination treatments based on pyrimethamine with sulfadiazine. Drugs clinically used to treat toxoplasmosis are not specific, being mainly developed for other diseases, have important side effects, and only effective during the acute stage of infection but they do not eradicate bradyzoite tissue cysts. In consequence, the development of new effective anti-Toxoplasma medications, exhibiting also improved tolerability, is of great importance.
Trithiolato-bridged dinuclear ruthenium(II)-arene compounds demonstrated interesting antiparasitic efficacy against Toxoplasma gondii, Neospora caninum and Trypanosoma brucei. Very little is known about their cellular targets and potential mode of action.
It was hypothesized that improved in vivo properties and a better knowledge of their exact cellular targets and mode of action can be obtained using the 'conjugate approach' consisting in anchoring judiciously chosen bioactive molecules onto the diruthenium core.
This thesis was focused on the synthesis and biological activity evaluation of various hybrid molecules in which fluorophores, metabolites and drugs were appended on the trithiolato-bridged dinuclear ruthenium(II)-arene moiety. The aims of this approach were: (i) to investigate the cellular targets/mode of action by tracing fluorophore-tagged compounds inside cells/parasites, (ii) to improve the cellular uptake of the complexes by conjugating metabolites necessary for the parasites growth, exploiting the parasite auxotrophies and metabolic peculiarities in Trojan horse strategy, and (iii) to obtain compounds with increased antiparasitic efficacy by coupling with a drug relevant to the treatment of toxoplasmosis.
Five libraries of dyads based on the diruthenium moiety were synthesized and fully characterized. Where applicable (conjugates with fluorophores), photophysical properties were also measured.
The new conjugates and representative intermediates were investigated to assess the impact of compound exposure upon T. gondii β-gal tachyzoites grown in HFF (human foreskin fibroblasts) and noninfected HFF. For each series the influence of the nature of the anchored organic fragment, the type and length of the linking unit were evaluated. The most active and selective compounds were also submitted to dose-response studies. Seven compounds with IC50 values in nanomolar range displayed promising activity and selectivity. For some compounds TEM (transmission electron microscopy) and confocal microscopy tests were also performed. The TEM images suggest that the parasite’s mitochondrion is the preferred targets of the compounds and, importantly, that the host’s mitochondrion (HFF) is not affected.
Overall a library of 93 trithiolato-bridged dinuclear ruthenium(II)-arene complexes decorated with different organic substituents were developed. 7 compounds with interesting cytotoxicity/selectivity profile were identified and can be submitted for further in vivo studies.
Date of Publication
2021
Year of graduation
2021
Theses Type
dissertation
Language(s)
en
Author(s)
Desiatkina, Oksana |
Faculty/Graduate School
Access(Rights)
open.access
Primary OA Publication
true