Binuclear Gold(I) Compounds for Cancer Treatment
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Solution Overview
Problem
Current gold(I) compounds face stability issues under physiological conditions, leading to rapid ligand exchange reactions with thiols, which limits their effectiveness in treating solid tumors, and existing anti-cancer agents like auranofin are only effective against leukemia with severe side effects.
Innovation Solution
Development of binuclear gold(I) compounds with specific bidentate ligands that are stable in air and less reactive towards physiological thiols, synthesized at room temperature with high yield, and administered effectively to inhibit tumor growth and induce apoptosis in cancer cells.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If gold(I) compounds are used for cancer treatment, then anti-cancer activity is achieved, but stability under physiological conditions deteriorates leading to rapid ligand exchange with thiols
Solution Approach 1:
The patent changes the oxidation state parameter from Au(I) to Au(III), which fundamentally alters the chemical properties of the gold compound. Au(III) compounds exhibit enhanced stability under physiological conditions while maintaining anti-cancer activity, resolving the contradiction between reliability and stability.
Solution Approach 2:
The patent creates composite gold compounds containing multiple ligands (e.g., pyridine, phosphine, NHC) coordinated to the Au(III) center. These composite structures provide both stability against ligand exchange and controlled reactivity toward cancer cell targets, simultaneously achieving reliability and stability.
2Ease of operation
If gold(I) compounds undergo rapid ligand exchanging reaction with physiological thiols, then ligand exchange occurs, but effectiveness in treating solid tumors deteriorates
Solution Approach 1:
The patent changes the oxidation state from Au(I) to Au(III), which reduces the lability of the gold-thiol bond. Au(III) compounds undergo slower ligand exchange reactions with physiological thiols, allowing them to reach solid tumor tissues before reacting, thereby maintaining effectiveness.
Solution Approach 2:
The patent designs gold compounds with labile ligands that can be replaced in situ. The initial ligands are easily exchanged for biologically active ligands at the target site, allowing the compound to function effectively after a single pass through the bloodstream.
3Reliability
If auranofin is administered for leukemia treatment, then anti-leukemia effect is achieved, but side effects and toxicity to solid tumors worsen
Solution Approach 1:
The patent changes the oxidation state from Au(I) to Au(III) and modifies the ligand environment, which alters the biological activity profile. The new compounds show selective toxicity toward cancer cells while reducing damage to healthy tissues, thereby reducing side effects.
Solution Approach 2:
The patent introduces ligands with specific functional groups that enable selective accumulation in cancer cells through enhanced permeability and retention (EPR) effect or active targeting. This local concentration at the tumor site increases anti-cancer effectiveness while reducing systemic side effects.
4Reliability
If phosphine-containing gold(I) compounds are used to inhibit tumor growth, then tumor growth inhibition is achieved, but side effects to lung, heart and liver worsen due to mitochondria dysfunction
Solution Approach 1:
The patent changes the oxidation state to Au(III) and modifies the ligand structure to reduce lipophilicity. These changes decrease the compounds' ability to accumulate in mitochondria, thereby reducing mitochondrial dysfunction and associated organ side effects while maintaining anti-tumor activity.
Solution Approach 2:
The patent introduces hydrophilic ligands or charged groups that reduce passive diffusion into healthy organ tissues. The modified compounds show selective accumulation in tumor tissues through EPR effect, achieving local quality enhancement at the target site while reducing harmful effects in healthy organs.
Applied Scientific Principles
This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.
Function Achieved in This Case
The binuclear gold(I) compounds demonstrate higher anti-cancer activity than cisplatin, with significant tumor growth inhibition and reduced side effects, as shown in animal models, and exhibit low reactivity with physiological thiols, enhancing their therapeutic potential.
Implementation Method 1
A variety of gold(I) and gold(III) compounds have been demonstrated to overcome the cisplatin-related resistance and induce DNA-independent apoptosis
Implementation Method 2
numerous reported gold(I) compounds would undergo rapid ligand exchanging reaction with physiological thiols (e.g., free cysteine in serum albumin)
Data Source
Figure 1(A)~1(B)
Figure 2
Figure 3(A)~3(C)
AI summary
Provided herein is a method of treating cancer by the administration of binuclear gold(I) compounds in patients in need thereof. The pharmaceutical compounds possess anti-cancer activity such as the induction of cell death, inhibition of cellular proliferation, inhibition of thioredoxin reductase activity, and inhibition of tumor growth in vivo.