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21 January 2026

Anticancer Applications of Gold Complexes: Structure–Activity Review

,
and
1
Department of General and Inorganic Chemistry with Methodology of Chemistry Education, Faculty of Chemistry, University of Plovdiv, “Tzar Assen” Str. 24, 4000 Plovdiv, Bulgaria
2
Department of Microbiology and Biotechnology, University of Food Technologies, 26 Maritza Blvd., 4002 Plovdiv, Bulgaria
3
Department of Organic Chemistry, Faculty of Chemistry, University of Plovdiv, 4000 Plovdiv, Bulgaria
*
Author to whom correspondence should be addressed.
Appl. Sci.2026, 16(2), 1114;https://doi.org/10.3390/app16021114
This article belongs to the Special Issue Synthesis, Application, and Biological Evaluation of Inorganic and Organic Compounds
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Abstract

Background: Gold (Au) complexes have emerged as promising anticancer candidates due to their distinct coordination chemistry and ability to modulate thiol-dependent and redox-regulated cellular pathways, particularly thioredoxin reductase (TrxR). In recent years, structurally diverse Au(I) and Au(III) complexes have been reported with potent in vitro anticancer activity; however, cross-study comparability and design principles remain unclear. Aim: This systematic review critically evaluates anticancer Au(I/III) complexes reported since 2016, with the specific aim of identifying how oxidation state, coordination geometry, and ligand class influence in vitro potency, selectivity, and translational potential. Methods: A PRISMA-guided literature search was performed in Scopus, Web of Science, PubMed, and ScienceDirect for studies published between January 2016 and March 2025. Two independent reviewers screened titles/abstracts and full texts according to predefined inclusion criteria. Only original studies reporting anticancer activity of structurally characterized Au(I/III) complexes in human cancer models were included. After the removal of duplicates, 1100 records were screened at the title and abstract level. Of these, 240 articles were assessed in full text for eligibility. Ultimately, 128 studies reporting anticancer activity of structurally characterized Au(I/III) complexes met the inclusion criteria and were included in the qualitative synthesis. Biological potency data were harmonized to μM units where applicable, and results were synthesized qualitatively due to heterogeneity in experimental design. Results: A total of 128 studies met the inclusion criteria. Au(I) complexes—particularly phosphine- and N-heterocyclic carbene (NHC)-based compounds—consistently showed sub-micromolar cytotoxicity in TrxR-dependent cancer cell lines, whereas Au(III) complexes displayed greater structural diversity but variable stability and redox behavior. In vivo efficacy was reported for a limited subset of compounds and was frequently constrained by solubility, systemic toxicity, or metabolic instability. Conclusions: The available evidence indicates that anticancer activity of gold complexes is strongly dependent on oxidation state, ligand environment, and redox stability. While Au(I) scaffolds show more reproducible in vitro potency, successful translation to in vivo models remains limited. This review defines structure–activity and structure–liability relationships that can guide the rational design of next-generation gold-based anticancer agents.

1. Introduction

Long-term clinical efficacy remains challenged by the emergence of resistance, systemic toxicity, and limited selectivity of many traditional treatments, despite significant advancements in cancer therapy [1,2]. Due to these constraints, there has been a persistent interest in alternative therapeutic approaches that make use of non-classical modes of action, such as targeting metal-sensitive cellular pathways and redox regulation [3].
Metal-based compounds have re-emerged as possible anticancer agents in this setting [4,5,6]. Gold (Au) is unique among transition metals because of its versatile coordination chemistry, significant attraction for biomolecules containing sulfur and selenium, and gentle Lewis acidity [7,8,9]. Gold complexes can take on a variety of coordination geometries and ligand environments, especially in the +1 and +3 oxidation states [10,11,12]. Inspired by the chemotherapeutic effects of platinum-based Cisplatin, gold(III) compounds, which are isoelectronic to platinum(II), have emerged as promising candidates for cancer treatment, including colorectal cancer [13], breast cancer [14], pancreatic cancer [15].
This allows for the fine-tuning of stability, reactivity, and biological activity. Au(I/III) complexes mostly affect protein targets involved in redox homeostasis and mitochondrial function, in contrast to platinum-based medications that mainly target DNA [16,17].
Particularly, gold(I) compounds primarily inhibit TrxR, in turn, elevating reactive oxygen species (ROS), including hydrogen peroxide (H2O2) within the mitochondria [18]. The increased ROS production is a key driver of apoptosis in cancer cells treated with gold(I) compounds.
The key mechanism of anticancer activity of gold complexes is the inhibition of thiol- and selenol-containing enzymes, particularly thioredoxin reductase [19,20]. Gold complexes can also interact with proteins involved in cell proliferation and survival pathways, rather than directly binding to DNA, which distinguishes them from classical metal-based drugs [21]. Inhibition of TrxR disrupts redox homeostasis in cancer cells, leading to oxidative stress, mitochondrial dysfunction, and induction of apoptosis [22].
Thioredoxin reductase (TrxR), a selenoenzyme that is essential for preserving intracellular redox equilibrium, is a major molecular target of anticancer gold complexes [23,24,25,26]. TrxR is often overexpressed in cancer cells, where it promotes oxidative stress resistance and fast proliferation [19,27,28,29]. By attaching to the active-site selenocysteine residue, Au(I) complexes, such as the therapeutically licensed medication auranofin, can permanently inhibit TrxR, resulting in the buildup of reactive oxygen species, mitochondrial malfunction, and apoptotic cell death [19,29,30,31,32]. Although physically more varied and frequently redox-active, Au(III) complexes may have anticancer effects through interactions with other cellular targets, redox cycling, and coupled TrxR inhibition; yet, their stability and reduction behavior continue to be significant obstacles [6,16,33,34].
The synthesis and biological evaluation of structurally varied Au(I) and Au(III) complexes with promising in vitro anticancer activity and, in certain cases, in vivo efficacy have been documented in a fast growing body of research over the past ten years [35,36]. However, this evidentiary foundation is still rather dispersed, [37,38]. Meaningful cross-study comparisons are sometimes hampered by variations in ligand classes, oxidation states, experimental methods, exposure settings, and biological outcomes [36]. Furthermore, there are currently few systematic studies that connect particular aspects of chemical design, like coordination geometry, ligand electronics, and redox stability, to anticancer efficacy, selectivity, and translational potential [39,40].
Overall, gold complexes represent a valuable platform for the development of novel anticancer therapies with alternative modes of action and potential clinical advantages [41].
Thus, the goal of this systematic review is to critically summarize research published between 2016 and 2025 that reports the anticancer efficacy of structurally defined Au(I) and Au(III) complexes. This review aims to identify strong structure–activity and structure–liability relationships, highlight current limitations in the field, and derive evidence-based design principles to direct the development of next-generation gold-based anticancer agents by integrating chemical, biological, and translational data within a PRISMA-guided framework.

2. Materials and Methods

PRISMA 2020 standards were used in conducting this systematic review. A thorough literature search was conducted in Scopus, Web of Science, PubMed/MEDLINE, and ScienceDirect. Predefined search strings containing phrases associated with cancer and gold complexes were used to retrieve articles published between January 2016 and March 2025.
After removal of duplicates, 1100 records were screened independently at the title and abstract level by two reviewers. Inter-rater agreement was assessed using Cohen’s κ statistic and indicated substantial agreement (κ = 0.68). Discrepancies were resolved through discussion until consensus was reached. Full-text screening was subsequently performed for 240 articles.
Studies that documented the synthesis and complete chemical characterization of Au(I) or Au(III) complexes, along with quantitative anticancer activity data (e.g., IC50 values) obtained in human cancer cell models, were included. Studies that reported non-comparable endpoints and review articles were excluded. Only English-language peer-reviewed publications were taken into account.
In total, 128 papers were included in the qualitative synthesis since they satisfied the inclusion criteria. A meta-analysis was not possible due to significant variation in experimental models, exposure settings, and biological outcomes. The completeness of chemical characterization, the clarity of experimental techniques, the use of suitable controls, and the openness of biological data reporting were used to qualitatively evaluate the methodological quality of the included research. PRISMA flowchart illustrating the literature review’s identification, screening, eligibility, and inclusion process are given in Figure 1.
Figure 1. PRISMA flowchart illustrating the literature review’s identification, screening, eligibility, and inclusion process.

3. Results and Discussion

3.1. Overview of Included Studies

The medicinal use of gold dates back to antiquity, with Au(I) and Au(III) identified as the therapeutically active oxidation states. These gold-based compounds exhibit excellent biocompatibility and possess a broad spectrum of pharmacological activities, including anticancer, anti-inflammatory, and antirheumatic properties [42,43]. Gold-based complexes, particularly those containing carbene, phosphine, porphyrin, or dithiocarbamate ligands, act via mechanisms such as DNA disruption, apoptosis induction, and angiogenesis inhibition. Gold nanoparticles can also serve as targeted delivery systems, minimizing harm to healthy tissues [44]. Advances in Au(I)–N-heterocyclic carbene structures and other noble metal complexes highlight their promise as selective anticancer agents [6,45]. Figure 2 depicts representative Au(I) and Au(III) complexes investigated for anticancer activity.
Figure 2. Au(I) and Au(III) complexes, reported in the literature for their effects as possible anticancer drugs [6].
Gold(I) phosphine complexes showed strong cytotoxic effects against colon, lung, and ovarian cancer cells, with IC50 values comparable to or surpassing cisplatin [46]. Four novel mononuclear gold(I) complexes also exhibited potent effects against HeLa, PC-3, A549, and HT-1080 cell lines, with one complex displaying IC50 values as low as 0.08 μM [47]. Their anticancer mechanism involves inhibition of TrxR and disruption of ATP levels, ultimately leading to cell death [6].
In 1985, Mirabelli et al. highlighted the anticancer potential of auranofin, a gold(I) complex, opening new avenues in gold-based chemotherapy [48]. Subsequent developments include doxorubicin-loaded, PEG-functionalized gold nanoparticles, which have shown selective cytotoxicity in cancer cells in vitro and in vivo [49]. Despite challenges including poor solubility, drug resistance, and systemic toxicity, ongoing research focuses on improving pharmacokinetic properties and minimizing adverse effects of gold-based therapeutics.
Approximately 65–70% of the 128 papers that made up this systematic review concentrated on Au(I) complexes, with the remaining studies focusing on Au(III) compounds. The majority of studies used a small panel of human cancer cell lines and only assessed anticancer efficacy in vitro. The most commonly used cancer models were ovarian (A2780 and A2780cis) [44,50], breast (MCF-7) [51], and colorectal (HCT116) [52], which reflects both historical precedent in metallodrug research and the accessibility of comparison data.
Although experimental conditions, composition, and control substances varied significantly between investigations, quantitative biological endpoints were primarily reported as IC50 values after exposure periods ranging from 24 to 72 h [53,54]. Cross-study evaluation of selectivity was limited since only a small percentage of papers included parallel screening in non-malignant cell lines [55]. Additionally, a continuous translational gap between in vitro potency and preclinical efficacy was highlighted by the fact that fewer than one-fifth of the included research expanded biological evaluation to in vivo models, most frequently mouse xenografts [56].
From a chemical standpoint, the studied literature showed a great deal of variation in oxidation states, coordination environments, and ligand types. However, structure–activity connections were frequently deduced from small chemical series, and thorough head-to-head comparisons across ligand classes or oxidation states were uncommon. All of these characteristics point to the necessity of standardized synthesis and reporting guidelines in order to facilitate insightful comparisons of anticancer gold complexes.
Therefore, our primary goal was to assess Au(I/III) complexes with anticancer activity critically and, more precisely, to determine how ligand class, coordination geometry, and oxidation state affect in vitro potency, selectivity, and translational potential.

3.2. Au(I) Complexes: Coordination Chemistry and Anticancer Activity

3.2.1. Au(I)–Phosphine Complexes

Due to their favorable kinetic stability, significant affinity for biomolecules containing thiols and selenium, and linear coordination geometry, Au(I)–phosphine complexes are the most investigated class of anticancer gold compounds [57,58]. In terms of structure, these complexes usually consist of a linear P–Au–X motif, where halides, thiolates, or other soft donors occupy the second coordination site, and phosphine ligands regulate lipophilicity and steric bulk [59,60].
Mihajlović et al. described Au(I)–phosphine complexes with sub-micromolar IC50 values in a variety of TrxR-dependent cancer cell lines, such as A2780, MCF-7, and HCT116, in several independent investigations [61]. The median IC20 values for representative phosphine-based series in some cases dropped below 1 μM when data were harmonized to standard units and exposure conditions [62]. The ability of Au(I) centers to irreversibly bind the selenocysteine residue in the active site of thioredoxin reductase, resulting in oxidative stress, mitochondrial malfunction, and apoptotic cell death, is mechanistically consistent with this potency [63]. Mechanism of action of auranofin and gold complexes by interfering with thioredoxin reductase inhibition and destabilizing adenosine triphosphate levels, causing cell death [6] are presented in Figure 3.
Figure 3. Mechanism of action of auranofin and gold complexes by interfering with TrxR (thioredoxin reductase inhibition) and destabilizing ATP (adenosine triphosphate) levels, causing cell death [6].
Au(I)–phosphine complexes frequently show little selectivity toward cancer cells over their non-malignant counterparts, despite their strong in vitro performance [64]. Although it is advantageous for cellular absorption, high lipophilicity has frequently been linked to off-target toxicity and limited therapeutic windows [65]. Further limitations, such as low water solubility and dose-limiting systemic toxicity, which often prevented prolonged tumor growth inhibition, were discovered by in vivo evaluations when they were reported [25]. It has been demonstrated that Au(I) phosphane derivatives significantly affect the cytotoxicity across a wide range of human cancer cells, including those resistant to cisplatin or multiple drugs [66]. Gambini et al. described seven gold(I) azolate/phosphane complexes with N-Au-P or P-Au-Cl backbones. The compounds were evaluated for their anti-cancer properties both in vitro and in vivo. Using ligands such as 4,5-dichloro-imidazolate-1-yl-gold(I)-(triphenylphosphane) and 4,5-dicyano-imidazolate-1-yl-gold(I)-(triphenylphosphane), the authors found these Au-complexes to be significantly more cytotoxic than cisplatin, with fewer adverse effects and generally better tolerated by mice [67]. The authors reported IC50 values of 19.28 µM for 4,5-dichloro-imidazolate-1-yl-gold(I)-(triphenylphosphane) Au- 14.83 µM for 4,5-dicyano-imidazolate-1-yl-gold(I)-(triphenylphosphane) on MDA-MB-231 cells, while cisplatin showed an IC50 value of 50.49 µM. Similar results were observed on HMLE/FoxQ1 cells, with IC50 of 7.41 µM for 4,5-dichloro-imidazolate-1-yl-gold(I)-(triphenylphosphane and 9.27 µM for 4,5-dicyano-imidazolate-1-yl-gold(I)-(triphenylphosphane), compared with 34.12 µM for cisplatin with [35,67].
Derivatives of bioactive cinnamic acid are well known for their medicinal applications, including cancer therapy [68]. Scheffler et al. found that the introduction of methoxy substituents to the molecular structures of gold complexes can effectively balance the substance’s hydrophilicity and lipophilicity, which is essential for intracellular distribution, pharmacokinetic properties, and cellular uptake [69]. Reddy et al. combined alkynylgold(I) phosphine with methoxy-substituted cinnamide scaffolds to obtain stable gold(I) complexes. The authors found that these complexes demonstrated broad chemotherapeutic potential against A549, D24, and HT1080 tumor cells with IC50 values in the low micromolar range. The cytotoxicity of the compounds was influenced by the amount of methoxy groups in the alkyne moiety; complexes with three methoxy substituents displayed higher cytotoxicity to tumor cells than those with only one [70].
Collectively, the available evidence shows that Au(I)–phosphine complexes offer a dependable platform for strong TrxR-targeted anticancer activity, while also highlighting the need for improved ligand design techniques to strike a compromise between potency, selectivity, and pharmacokinetic behavior [20,71]. In order to outline transferable design concepts, these properties are compared with different Au(I) ligand classes and Au(III) scaffolds. Table 1 presents a comparative in vitro anticancer activity of some Au(I)–phosphine complexes.
Table 1. Comparative in vitro anticancer activity of representative Au(I)–phosphine complexes.

3.2.2. Au(I)–NHC Complexes

Like phosphines, NHCs have valuable biological potentials and donor characteristics that make them an attractive family of ligands [74]. Under healthy settings, N-heterocyclic carbene (NHC) ligands offer a robust platform for stabilizing Au(I) centers, providing both kinetic and thermodynamic stability [62,75]. The potent σ-donating capabilities of NHCs strengthen the metal-ligand bond, preventing premature ligand dissociation and enabling more consistent interactions with biological targets [76,77]. Although the steric bulk and electronic characteristics of the NHC ligand can be systematically tuned to modify lipophilicity, cellular uptake, and cytotoxicity, the majority of Au(I)–NHC complexes retain the distinctive linear P–Au–X shape seen in phosphine analogs [36,78,79].
Curran et al. found that Au(I)–NHC complexes exhibit sub-micromolar to low micromolar IC50 values in human cancer cell lines such as A2780, MCF-7, and HCT116 [80,81]. Compared with phosphine-based scaffolds, harmonization of the presented data shows somewhat greater variability, which is mostly caused by variations in NHC substituents, counterions, and experimental procedures [48,82]. Mechanistic research indicate that TrxR inhibition continues to be the principal mechanism of action, sometimes accompanied by the production of ROS, mitochondrial malfunction, and the triggering of apoptosis. Bulky or extremely lipophilic NHC substituents occasionally reduce the therapeutic window, while increasing absorption, and selectivity over non-malignant cells varies.
One attractive feature of NHC chemistry is the ease of generating a range of structurally similar molecules with varying lipophilicity may by simply modifying the substituents on the imidazolium derivatives. Metal-NHCs are a family of prospective anti-cancer agents, forming a recent and swiftly developing field of study. Liu et al. found that NHC-containing ligands of Au exhibit significant cytotoxic effects and highly modular moieties that are primarily suited to drug development [83]. The authors tested a number of halo and pseudohalo Au(I)-NHC compounds containing 4,5-diarylimidazoles against HepG2, SMMC-7721, and Hep3B cancer cell lines. The complexes exhibited exceptional cytotoxic efficacy [84]. Walther et al. investigated two carbene-based Au antitumor candidates, 1,3-dibenzyl-4,5-diphenyl-imidazol-2-ylidene Au(I) dimethylamino dithiocarbamate and 2,3,4,6-tetra-O-acetyl-α-D-glucopyranosyl-1-thiolate derivative containing a gold(I)-sulfur bond. The compounds were examined both in vitro and in vivo. The authors found that the human prostate cancer cell line PC3 showed pronounced sensitivity to the new gold complex 1,3-dibenzyl-4,5-diphenyl-imidazol-2-ylidene Au(I) dimethylamino dithiocarbamate (GI50 = 720 nmol/L). The compound exhibited also a dose-dependent decrease in Ki67, demonstrating its superior anti-cancer effect. Both compounds inhibited tumor growth in the PC3 in vivo model by lowering Ki67 levels [85].
In order to assess the in vivo biodistribution of this class of complexes using positron emission tomography (PET), Guarra and colleagues synthesized an AuIII-NHC complex by direct oxidation with radioactive [124I]I2. The authors found that the Au-NHCs complexes showed strong antiproliferative properties, with IC50 values in the low micromolar range.
Mechanistic studies indicate that TrxR inhibition remains the primary mode of action, accompanied in some cases by ROS generation, mitochondrial dysfunction, and apoptosis induction [19,86,87]. Selectivity toward non-malignant cells varies, with bulky or highly lipophilic NHC substituents sometimes decreasing therapeutic window despite enhancing uptake [88].
Although in vivo studies of Au(I)–NHC complexes are limited, available data shows that some analogs with ideal solubility and steric profiles can prevent tumor growth in mouse xenograft models without being overtly hazardous [35]. Collectively, these results demonstrate that NHC ligands offer a versatile framework for optimizing Au(I) activity, stability, and selectivity [89,90,91]. They also propose design principles that can direct the creation of next-generation Au(I) anticancer agents. Table 2 presents a comparative in vitro anticancer activity of some Au(I)–NHC complexes.
Table 2. Comparative in vitro anticancer activity of representative Au(I)–NHC complexes.

3.2.3. Other Au(I) Ligand Classes (Thiolates, Alkynyls, Mixed Donors)

Del-Campo et al. synthesized Au(I) complexes with thiolate, alkynyl, or mixed donor shells. The authors found that the compounds can form ultrasmall gold nanoclusters and nanoparticles in addition to traditional phosphine and NHC ligands, spanning the gap between discrete coordination compounds and nanoscale materials. In contrast to bulk gold or larger nanoparticles, thiolate-protected gold nanoclusters (such as Aun(SR)m with core diameters < 2 nm) display atomically precise structures stabilized by Au–S staples, which not only confer exceptional chemical robustness but also enable size-dependent electronic, optical, and catalytic properties. These nanoclusters have demonstrated encouraging biological activity, such as favorable surface functionalization with bioactive ligands to promote tumor targeting and selective cytotoxicity against cancer cells associated with increased ROS production [79,93].
Alkynyl-protected gold clusters are a complementary class in which π-conjugated ligands modify physicochemical properties and structural motifs, resulting in different electronic states and surface reactivity [94,95]. Dynamic interchange between alkynyl ligands and thiolates enables precise control over surface chemistry and cluster composition [96]. Engineered assemblies with customized optical, catalytic, or biological profiles are made possible by mixed-ligand clusters, which further increase structural variety and functional tunability by combining thiolate, alkynyl, phosphine, or other donor types [97,98,99,100].

3.3. Au(III) Complexes: Redox-Active Scaffolds and Stability Challenges

In contrast to linear Au(I) scaffolds, Au(III) complexes often adopt a square planar coordination geometry, which confers unique electronic and steric characteristics. Redox cycling, which can increase the production of ROS and interact with redox-sensitive protein targets like TrxR, is made possible by this geometry, which also permits fine-tuning of ligand electronics and steric bulk.
Au(III) complexes can be divided into three classes: Au(III)-dithiocarbamates and associated chelates, cyclometalated Au(III) complexes, and non-cyclometalated Au(III) complexes.
Dithiocarbamate ligands offer redox-activity adjustment in addition to chelation [101,102,103]. It was found that the Au(III) complexes may interact with several cellular targets and exhibit moderate to strong in vitro cytotoxicity, frequently in the sub-micromolar range. However, under physiological settings, they are prone to decrease, and their stability is highly dependent on the ligand environment, which may restrict their bioavailability and the reproducibility of biological effects.
The cyclometalation stabilizes the Au(III) center by creating a chelate resisting reduction to Au(I), a common problem for non-chelated Au(III) complexes [104]. In human cancer cell lines such as A2780, MCF-7, and HCT116, cyclometalated Au(III) complexes consistently show low micromolar IC50 values [105]. According to mechanistic research, these substances cause apoptosis by combining ROS-mediated mitochondrial stress with TrxR inhibition [106]. Although in vitro potency shows promise, solubility and metabolic instability hinder in vivo assessment.
Non-chelated Au(III) complexes, on the other hand, are less stable and frequently reduce to Au(I) before engaging the target [37,103]. As a result, their anticancer activity is less consistent, with low selectivity indices and fluctuating IC50 values. These substances serve as examples of how crucial ligand design is in regulating both chemical stability and biological efficacy. Overall, Au(III) scaffolds broaden the mechanistic range of gold-based anticancer medicines, but their clinical translation necessitates meticulous ligand design optimization to improve stability, selectivity, and in vivo application [107]. Although Au(III) compounds can access alternative biological processes, their chemical fragility continues to be a significant barrier for preclinical development, as demonstrated by a comparison with Au(I) complexes [37,102,108,109]. Table 3 show a comparative in vitro anticancer effect of some Au(III) complexes.
Table 3. Comparative in vitro anticancer activity of representative Au(III) complexes.

3.4. Comparative Analysis of Au(I) vs. Au(III) Anticancer Performance

Across common cancer cell lines (A2780, MCF-7, HCT116), Au(I)–phosphine and Au(I)–NHC complexes consistently show sub-micromolar IC50 values, with median IC50 values usually below 1 μM [111,112]. These complexes mainly cause ROS buildup, mitochondrial malfunction, and apoptosis by irreversibly inhibiting TrxR. Compared to phosphines, Au(I)–NHC complexes have better chemical stability and customizable ligand characteristics, offering a flexible platform for maximizing selectivity and cellular uptake despite having a little more variable potency [62,113].
Au(III) complexes, on the other hand, typically exhibit low micromolar IC50 values with greater diversity, especially among dithiocarbamate and non-cyclometalated derivatives [93,114]. While non-cyclometalated Au(III) species are vulnerable to reduction to Au(I), which complicates reproducibility and translational predictability, cyclometalated Au(III) complexes preserve superior stability and show equivalent in vitro potency to Au(I) scaffolds [37,104]. Au(III) scaffolds can mechanistically interact with several processes, including as redox cycling and TrxR inhibition, providing complementing cytotoxic methods [115]. However, the chemical fragility of these complexes frequently restricts their use in vivo.
Selectivity profiles favor Au(I) scaffolds, particularly NHC derivatives, where toxicity and absorption can be balanced through ligand tweaking [116]. Despite their mechanistic versatility, Au(III) complexes often exhibit lower selectivity indices and more vulnerability to off-target effects, underscoring the significance of stabilizing ligands like cyclometalating chelates [104]. Both scaffolds still have poor in vivo translation; nevertheless, non-cyclometalated Au(III) and optimized Au(I)–NHC counterparts show potential in xenograft models without significant systemic toxicity [117].
The anticancer performance of Au(I) and Au(III) complexes is determined by different and complimentary design concepts. In order to effectively inhibit TrxR in Au(I) complexes, linear coordination geometry becomes essential for selective interaction with the active-site selenocysteine residue [36,109]. To maximize cellular absorption while preserving target selectivity and reducing off-target toxicity, ligand steric bulk and electronic characteristics must be carefully adjusted. N-heterocyclic carbene (NHC) ligands provide a particularly useful platform in this regard since they improve chemical and metabolic stability and enable systematic tweaking of structure–activity correlations through modular replacement [62,116].
On the other hand, methods to maintain the higher oxidation state under physiological conditions are necessary for the formation of Au(III) complexes. Preventing premature reduction to Au(I) requires the employment of highly donating ligands and non-cyclometalated coordination environments [118]. Redox-active ligands can further increase cytotoxic potency by inducing oxidative stress. Overall, logical ligand design that balances stability, redox behavior, and biological activity is essential for the selective anticancer activity and in vivo efficacy of Au(III) complexes.
In summary, Au(I) and Au(III) complexes complement one another mechanistically: Au(I) offers strong, consistent TrxR-mediated potency, while Au(III) increases mechanistic diversity via redox regulation [36]. Essential in the development of these scaffolds into therapeutically useful anticancer drugs are rational design guided by coordination geometry, ligand electronics, and SAR trends.

3.5. In Vivo Efficacy, Toxicity, and Translational Constraints

Less than 20% of the studies included in this review described in vivo evaluation using orthotopic tumor models or mouse xenografts. In a small number of investigations, Au(I)–phosphine complexes showed excellent tumor growth suppression; nevertheless, their high lipophilicity and limited therapeutic windows frequently resulted in dose-limiting systemic toxicity [41]. By contrast, in a few of xenograft models, Au(I)–NHC complexes with optimized steric and electronic characteristics showed enhanced solubility, decreased off-target toxicity, and persistent tumor growth suppression, indicating better translational potential than phosphine counterparts [62,112].
The most stable Au(III) scaffolds in vivo were cyclometalated Au(III) complexes [106,119]. In murine studies, these compounds achieved quantifiable tumor suppression, preserved the integrity of the oxidative state, and had controllable systemic effects. Conversely, due to their unpredictable pharmacokinetics, non-cyclometalated Au(III) and dithiocarbamate derivatives were rarely tested in vivo. Although pharmacokinetic and pharmacodynamic data is limited, it suggests that systemic exposure and efficacy are significantly influenced by metal-ligand stability, plasma protein binding, and ligand lipophilicity [120]. Higher tumor accumulation and improved tolerability were attained by compounds with regulated lipophilicity and increased water solubility, underscoring the significance of logical ligand design. The translational gap between cell culture potency and in vivo applicability was highlighted by maximum tolerated dose experiments, which showed that even powerful in vitro scaffolds can have limited therapeutic windows.
Tan et al. obtained new gold(I) bis(N-heterocyclic carbene) complexes which show strong apoptotic activities in lung cancer cells [121]. Liver microsomal assays showed that the compounds possess comparatively long half-lives relative to midazolam and are not subject to rapid metabolic degradation or in vitro clearance. Their cytotoxicity in normal cells was low, as indicated by higher IC50 values than those observed in cancer cells, with selectivity ranging from 2- to 60-fold [121]. Additionally, Ames testing demonstrated that the compounds are non-mutagenic. Taken together, these findings indicate that the compounds exhibit metabolic stability in liver microsomes, selective anticancer activity, and no detectable genotoxic risk [121]. Assess the anticancer activity of novel biphenyl organogold(III) cationic complexes with different bisphosphine ligands against aggressive glioblastoma and triple-negative breast cancer (TNBC) cell lines [122]. One of these gold(III) complex is the first biphenyl gold-phosphine complex to uncouple mitochondria and inhibit TNBC growth in vivo. Hinderling and Hartmann presented a review and analyze published data on pH-dependent drug–protein binding in humans, identify key influencing factors, and assess the clinical relevance of these effects [123].
These results highlight the need for integrated optimization of chemical stability, pharmacokinetics, solubility, and selective target engagement for the successful translation of Au(I) and Au(III) complexes. To bridge the current preclinical-to-clinical gap, future research should focus on standardized dosing procedures, thorough pharmacokinetics/pharmacodynamics profiling, and comprehensive in vivo evaluation of lead drugs.

3.6. Design Rules and Structure–Activity Relationships

Comparative evaluation of Au(I) and Au(III) complexes reveals distinct structure–activity relationships that inform rational anticancer design. For Au(I) complexes, phosphine ligands require a linear P–Au–X geometry to enable efficient TrxR engagement. While increased steric bulk and lipophilicity often enhance cytotoxic potency, excessive hydrophobicity compromises solubility and selectivity, emphasizing the need for balanced ligand design. In this context, NHC ligands provide clear advantages: strong σ-donation and steric tunability improve chemical stability, facilitate systematic SAR exploration, and frequently maintain sub-micromolar IC50 values with improved selectivity across harmonized cancer cell models [124].
For Au(III) complexes, stabilization of the higher oxidation state is a central design challenge. Cyclometalated scaffolds effectively prevent premature reduction to Au(I), preserving redox activity and enabling TrxR inhibition both in vitro and in vivo. In contrast, dithiocarbamate and other non-cyclometalated Au(III) derivatives often rely on redox-mediated cytotoxicity but are more susceptible to off-target effects unless ligand chelation, solubility, and redox properties are carefully optimized. Across both oxidation states, coordination geometry, ligand electronics and sterics, redox stability, and lipophilicity collectively govern potency, selectivity, and translational potential. Overall, successful design of gold-based anticancer agents requires integration of oxidation-state control, tailored ligand architecture, harmonized biological evaluation, and mechanistic validation of TrxR inhibition and redox-driven apoptosis.
The structure–biological activity relationship for the gold complexes are given in Figure 4.
Figure 4. Structure–biological activity relationship of novel gold complexes (Sze, et al. 2020, Guarra et al. 2020, and Sankarganesh et al. 2019) [20,125,126].

4. Conclusions

Gold-based complexes in both Au(I) and Au(III) oxidation states constitute a versatile and mechanistically distinct class of anticancer agents, owing to their unique coordination chemistry, selective affinity for thiol- and selenol-containing biomolecules, and capacity to disrupt cellular redox homeostasis. This systematic review of studies published between 2016 and 2025 demonstrates that anticancer efficacy and translational potential are primarily governed by rational ligand design, coordination geometry, and redox stability. Au(I) complexes bearing phosphine or NHC ligands consistently induce TrxR–mediated cytotoxicity with sub-micromolar IC50 values across multiple cancer cell lines, with NHC ligands offering superior chemical stability, tunability, and selectivity. Au(III) complexes provide complementary mechanisms involving redox cycling and TrxR inhibition, particularly when cyclometalated scaffolds are employed to stabilize the higher oxidation state. In contrast, non-cyclometalated and dithiocarbamate Au(III) derivatives frequently suffer from premature reduction, variable selectivity, and limited in vivo applicability. Across both oxidation states, mechanistic validation remains uneven, and significant translational gaps persist due to limited in vivo evaluation, pharmacokinetic constraints, and dose-limiting toxicity. Future progress will require harmonized experimental protocols, early integration of pharmacokinteic/pharmacodynamic and toxicity studies, and mechanism-driven optimization of ligand architecture and redox behavior. Collectively, these findings establish actionable design principles for next-generation gold-based anticancer agents and define clear priorities for advancing the most promising Au(I/III) scaffolds toward clinical translation.

Author Contributions

Conceptualization, P.M., D.B. and S.N.; methodology, P.M.; validation, P.M., D.B. and S.N.; resources, P.M., D.B. and S.N.; data curation, P.M., D.B. and S.N.; writing—original draft preparation, P.M., D.B. and S.N.; writing—review and editing, P.M., S.N. and D.B.; visualization, P.M. and S.N.; supervision, P.M.; project administration, P.M.; funding acquisition, P.M. All authors have read and agreed to the published version of the manuscript.

Funding

Fund for Scientific Research of the Plovdiv University, project CП 23-XΦ-006 and the European Union—Next Generation EU, through the National Recovery and Resilience Plan of the Republic of Bulgaria, project DUECOS BG-RRP-2.004-0001-C01.

Institutional Review Board Statement

Not applicable.

Data Availability Statement

Not applicable.

Conflicts of Interest

The authors declare no conflicts of interest.

Abbreviations

The following abbreviations are used in this manuscript:
TrxRthioredoxin reductase
ATPadenosine triphosphate
PEGpolyethylene glycol
PETpositron emission tomography
ROSreactive oxygen species
MDA-MB-231A human breast adenocarcinoma cell line established from a patient with metastatic mammary adenocarcinoma
MCF-7Another human breast cancer cell line used in cancer research
A549A human lung carcinoma cell line
PC3A human prostate cancer cell line
SARStructure–activity relationship
A2780ovarian cancer cell line
HepG2A human liver carcinoma cell line
HeLaA common human cervical cancer cell line
SMMC-7721A human hepatocellular carcinoma cell line
COX-2cyclooxygenase-2
COXscyclooxygenases
HCT116human colorectal cell line

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