Ru(III) Complexes with Lonidamine-Modified Ligands.

Ilya A Shutkov,Yulia A Gracheva,Yulia N Okulova,Alexey A Nazarov,Claudia Schmidt,Ingo Ott,Alexander A Spasov,Elena V Sokolova,Elena F Shevtsova,Vladimir Yu Tyurin,Elena R Milaeva,Alexander A Shtil,Olga M Redkozubova,Kirill I Kirsanov,Denis A Babkov

doi:10.3390/ijms222413468

Abstract

A series of bifunctional Ru(III) complexes with lonidamine-modified ligands (lonidamine is a selective inhibitor of aerobic glycolysis in cancer cells) was described. Redox properties of Ru(III) complexes were characterized by cyclic voltammetry. An easy reduction suggested a perspective for these agents as their whole mechanism of action seems to be based on activation by metal atom reduction. New compounds demonstrated a more pronounced antiproliferative potency than the parental drug; individual new agents were more cytotoxic than cisplatin. Stability studies showed an increase in the stability of complexes along with the linker length. A similar trend was noted for antiproliferative activity, cellular uptake, apoptosis induction, and thioredoxin reductase inhibition. Finally, at concentrations that did not alter water solubility, the selected new complex evoked no acute toxicity in Balb/c mice.

Highlights

Since the discovery of the antitumour activity of cisplatin, organic complexes with other metals such as ruthenium, gold, osmium, gallium, rhodium, titanium, etc., have been investigated
KP1019 and NAMI-A
Lonidamine is widely investigated in clinical trials for the treatment of different types of cancer [22,23,24] and has recently been recognised as a drug candidate for COVID-19 patients [25], alongside some metal-based compounds [26]

Summary

Introduction

Since the discovery of the antitumour activity of cisplatin, organic complexes with other metals such as ruthenium, gold, osmium, gallium, rhodium, titanium, etc., have been investigated. KP1019 (eventually changed to the sodium salt known as KP1339; BOLD 100) and NAMI-A (Figure 1) became the first metal-based non-platinum drugs that entered clinical trials [1,2,3,4,5,6,7]. Lonidamine (Figure 2) is an inhibitor of mitochondrial hexokinase. This agent stimulates lactate production in normal cells and inhibits glycolysis in malignant counterparts [20,21]. Lonidamine is widely investigated in clinical trials for the treatment of different types of cancer [22,23,24] and has recently been recognised as a drug candidate for COVID-19 patients [25], alongside some metal-based compounds [26]

Methods

Results

Conclusion