Mechanistic Insights into Gold Organometallic Compounds and their Biomedical Applications

Abstract

The application of gold in medicine can be traced back several thousand years and Au(i) compounds have been used in the treatment of rheumatoid arthritis since the last century. Recently research into gold-based drugs for a number of human diseases has seen a renaissance due to their markedly different modes of action with respect to the classical platinum chemotherapeutic compounds. Within this research area, organometallic gold complexes have been particularly explored, mainly due to their higher stability in physiological conditions guaranteed by the presence of a direct Au-C bond. Thus, a number of compounds have been tested for their uses as anticancer, antibacterial, antiprotozoal as well as anti-HIV agents. In this review a selection of the main results obtained on the synthesis, chemical properties and biological activities of two of the most explored families of organometallics - Au(i) N-heterocyclic carbenes (NHCs) and cyclometalated Au(iii) compounds - are summarized. Their structure-activity relationships and modes of action at the cellular level are also discussed, which constitute the basis for future drug design.

Antiproliferative effects of two gold(I)-N-heterocyclic carbene complexes in A2780 human ovarian cancer cells: a comparative proteomic study

“…Based on the great structural variety of the used ligands and their role in controlling the reactivity of the gold centre, a unique mode of action or pharmacological profile is unlikely to exist. Gold compounds can trigger cell death through a multitude of mechanisms by affecting mitochondria and the redox balance, by modulating cell cycle, by controlling proteolysis and signal transduction [ 18 – 23 ]. Though the detailed mechanisms of action remain unclear, the inhibition of the seleno-enzyme thioredoxin reductase (TrxR) seems to be a common mechanistic trait to explain, at least partially, the cytotoxic actions of several gold(I) and gold(III) complexes, as strong TrxR inhibition may eventually lead to cancer cell apoptosis through activation of a mitochondrial pathway [ 24 – 28 ].…”

A Cytotoxic Bis(1,2,3‐triazol‐5‐ylidene)carbazolide Gold(III) Complex Targets DNA by Partial Intercalation

“…The complexes also elicit strong cytotoxicity against cancer cells and can bind to DNA noncovalently via intercalation. Enhancing the selectivity of Au III pincer complexes towards cancer cells remains a formidable challenge but is improved using non‐toxic ligands such as NHCs (N‐heterocyclic carbenes), which are renowned strong σ‐donors that effectively stabilize both Au I and Au III under physiological conditions [41–52] . For metallodrug design, 1,2,3‐triazol‐5‐ylidene (trz) ligands, which are a subclass of NHCs, offer facile modulation, high functional group tolerance, and stabilization of metals in both high‐ and low oxidation states [53–58] .…”

Exploring Ruthenium-based organometallic inhibitors against Plasmodium Calcium Dependent Kinase 2 (PfCDPK2): a combined ensemble docking, QM paramterization and molecular dynamics study

“…Recent progress in structural biology have provided new avenues with therapeutically and pharmacologically important targets for structure-based drug design (SBDD). This opens up a new landscape for organometallic chemistry which has recently delivered promiscuous organometallic compounds with unique properties (Babak & Ang, 2018;Jürgens & Casini, 2017;Parveen, Arjmand, & Tabassum, 2019). Interestingly, over the past decade, the growth of medicinal organometallic compounds has increased rapidly with approximately 670 reports as evidenced from the published literature (Ndagi, Mhlongo, & Soliman, 2017;Ravera, Moreno-Viguri, Paucar, Pérez-Silanes, & Gabano, 2018).…”