Chinese scholars have made progress in the study of supercoordinated carbon-gold cluster function

Figure Intracellular mechanism of action of supercarbohydra

With the support of the National Natural Science Foundation of China (approval number: 22025105, 21772111, 21821001), Zhao Liang's team of Tsinghua University cooperated with Wang Hao of the National Center for Nanoscience, Wang Golin of the School of Pharmacy of Tsinghua University, and Xu Wanhai of the Fourth Affiliated Hospital of Harbin Medical University to reveal the collaborative dissociation mechanism of supercoordinated carbon-gold clusters and their application
in the new iron death anticancer prodrugs 。 The research results were recently published in the journal "Pro-oxidant response and accelerated ferroptosis caused by synergetic Au(I) release in hypercarbon-centered gold(I) cluster prodrugs" Nature? Nature Communications
.
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Metal coordination compounds have attracted widespread attention as chemotherapy drugs and prodrugs in the past half century, and metal drugs represented by platinum drugs have been widely used
in clinical treatment.
Gold-containing coordination compounds are expected to develop into a new generation of metallic anticancer drugs
due to the formation of stable Au-S bonds and specific inhibition effects on sulfur-containing and selenium-containing enzymes.
However, some sulfur-containing short peptides in cells (such as glutathione, etc.
) are also prone to interact with gold complexes, thereby poisoning gold-containing drugs
.

In recent years, Zhao Liang's research group has developed a new method for the synthesis of organometallic clusters by cyclization reaction, and prepared a series of RC-M n(_n = 2-4) organometallic clusters with carbon-polymetallic bonds and nuclei ranging from binuclear to quad-nuclei
.
Among them, the quadruple-core gold cluster [Ar-CAu^I₄]⁺ centered on hypercoordination carbon has good stability
in the physiological environment.
When it interacts with strong ligands such as mercapols and glutathione, it can trigger the continuous and coordinated fracture of multiple carbon-metal bonds and quickly release Au(I).

It has been found that when such supercoordinated carbon-gold clusters enter tumor cells, they can be enriched in mitochondria because of their lipophilic cationic properties, so in glutathione overexpressed bladder cancer cells, Au(I) released rapidly by synergistic dissociation of ultracarbogold clusters can effectively inhibit
a variety of enzymes represented by thiophorein reductase (TrxR).
。 At the same time, the rapid release of a large number of monovalent gold ions also triggers the cellular oxygen response (pro-oxidant response), which promotes the rapid increase of intracellular oxidation levels in a short period of time, thereby stimulating tumor cells to activate the iron death (ferroptosis) pathway
.
The antitumor activity of such supercoordinated carbon-gold cluster prodrugs (prodrug) was confirmed
in mouse experiments for the treatment of in situ bladder cancer models.
The discovery of supercoordinated carbon-gold cluster prodrugs based on iron death mechanism not only promotes the research of anticancer drugs related to iron death cell pathways, but also overcomes the drug resistance problems caused by anticancer golden drugs dominated by apoptosis (apoptosis) mechanism at this stage, and provides new ideas for the development of metal drugs (figure).