Home Gold complexes: a new frontier in the battle against lung cancer
Article Open Access

Gold complexes: a new frontier in the battle against lung cancer

  • Aqsa Hanif , Sawsan S. Al-Rawi , Ahmad H. Ibrahim , Abbas Washeel Salman EMAIL logo , Ayesha Zafar , Muhammad Adnan Iqbal ORCID logo EMAIL logo , Sana Batool and Ghazanfar Abbas
Published/Copyright: November 26, 2024
Download Article (PDF)
Reviews in Inorganic Chemistry
From the journal Reviews in Inorganic Chemistry Volume 45 Issue 3

Abstract

Lung cancer is the second leading cause of the mortality related to the cancer. So, it is very necessary to explore the novel strategies to eradicate it. Currently, gold based medicinal compounds have emerged as remarkable anticancer agents and expressed strong potential against the lung cancer cell lines. This review provides a comprehensive overview of the history, advancements, and recent state of gold complexes in the treatment of the lung cancer. We discuss the biological evaluation in relation with the chemical structures of numerous gold complexes, including those featuring thiosemicarbazone, N-heterocyclic imine, N-heterocyclic carbenes, steroidyl NHC, CAACs, carbamates, and diphosphanes as ligands. Gold complexes’ cytotoxicity has been assessed and contrasted with that of standard drugs such as auranofin and cisplatin, with a special focus on IC50 values for evaluating potency. This review targets to deliver a detailed understanding of the potential of the gold complexes in lung cancer therapies, paving way for the future research and clinical applications.

Keywords: gold-NHC; Au complexes; lung cancer; auranofin; anticancer agents

1 Introduction

Life on Earth, including the proliferation of bacteria and cancer cells, depends on metal ions such as iron, copper, and zinc. 1 , 2 Trace metals, which make up roughly 0.3 % of body weight, are essential for enzyme function. On the other hand, excessive metal contamination resulting from industrial processes can be harmful and cause cancer. 3 , 4 Many biological systems depend on chelators, which bind these ions. The process of coordinating a metal ion with a polydentate ligand for the formation of a cyclic complex known as a chelate is known as chelation. 5 , 6 The metal may precipitate from this complex, or it may result in a stable, soluble chemical. Unwanted metal ions can be selectively removed using chelating agents. 7 , 8 Numerous metal complexes exhibit anticancer action, most likely through the deactivation of carcinogenic metals or the inhibition of enzymes necessary for the fast proliferation of both malignant and healthy cells. 9 Chelating agents can stop the growth of bacteria and cancerous cells by targeting their metal ion needs. 10 Instead of preventing the growth of bacteria and cancer, several chelators and drugs may unintentionally increase the availability of metals. 11 , 12 , 13 Chelating therapies are used as primary, alternative for a wide range of diseases, such as those requiring antioxidant support, metal detoxification, chemotherapy for cancer, infection control, or modification of protein activities or pathways. 14 , 15 , 16 , 17

Lung cancer is a formidable foe, ranking as one of the prominent cause of deaths related to cancer worldwide. 18 It is a malignant type of tumour which originates from the bronchial mucosa or from the lung glands with very high rate of mortality and morbidity. 19 , 20 Lung cancer ranked as the second most prevalent cause of cancer death globally in 2018 and the third most common disease among women. 21 Micronesia/Polynesia, Eastern Asia, and Europe have high incidence rates; rates exceeding 40 per 100,000 are reported in China, Japan, and South Korea. 22 , 23 More than 80 % of instances are related to cigarette smoking, while 53 % of women and 15 % of males do not smoke. 24 , 25 According to GLOBOCON 2020 predictions, lung cancer is becoming more common in Pakistan, accounting for 10,538 new cases annually, and ranking third overall and second among men. Age-standardized incidence rates (ASIRs) differ by area; Punjab has lower rates than Karachi. 26 , 27 Most cases of lung cancer occur in older persons (65 years of age or older; around 65 % of diagnosis). In Pakistan, the average age at which lung cancer reveals itself is 68.5 years for women and 63 years for men. 28 This indicates a lower life expectancy than the global average of 70 years. 29 Lung cancer survival rates range from 7 % to 18 % worldwide, and there are no data specifically for Pakistan. 30 With 5.7 % of women and 32.4 % of men smoking, tobacco use is correlated with an increase in lung cancer incidence in Pakistan. 31 The absence of a centralized cancer registry in Pakistan makes it difficult to acquire reliable data. In order to manage the rising lung cancer burden, quit smoking initiatives and a national cancer registry are crucial. 30

Lung cancer is subdivided into two categories: a) non-small cell lung cancer (NSCLC) and b) small lung cancer (SCLC) on the basis of diagnosis and treatments. 32 First type of lung cancer is more lethal; 85 % of all the cases lie in this category and are cited as the leading cause of lung cancer. It is, in most cases, diagnosed at the last stage, has least option of treatment and drug resistance usually occurred. Some of the current treatments for NSCLC are, surgery, chemotherapy, radiotherapy, targeted therapy and immunotherapy. 33 , 34 , 35 Targeted therapies and immunotherapies have developed advance procedures and give effective results. 36 Chemotherapy is basic component of the NSCLC but its effectiveness is reduced due to the drug resistance. 37 The urgency in the treatments and therapies cannot be over-elaborated. Despite the advancement in cancer research area, the current resources of treatments which includes, surgery, chemotherapy, and radiotherapy often falls short to compete this aggressive disease. The limitations in the orthodox ways of cancer treatments have glimmered a zealous quest for inventive methods, and in the recent years gold complexes have arisen as a novel frontier in the battle against lung cancer. 38 Since ancient time it has been observed that metals and inorganic compounds have been used in medicinal applications. 39 , 40 , 41 In the early 20th century 42 , 43 , 44 , 45 , 46 with the enhancement in the modern discoveries in synthetic organic chemistry many anticancer and antibiotic agents were prepared. 47 , 48 , 49 It reduced the interest to use the metal in medicinal drugs due to systematic toxicity. In 1978 when cisplatin was approved by FDA, the metal-based interest in medicinal field renewed. Alongside their extensive research in cytotoxicity and anticancer potential, metal-based drugs are commonly used for cancer immune interface and have capability to realm the pivotal characteristics of immune elusion. Platinum based drugs were first generation anticancer drugs established efficiently for head, neck and reproductive cancer. 38 , 50 , 51 , 52

Gold, a noble metal long admired for its value and versatility, has been surprisingly thrust into the spotlight as a potential weapon in the fight against cancer. The journey of gold complexes from mere curiosities to the capable therapeutics is evidence to the power of interdisciplinary research. Gold has extraordinary capability of aggregation to the intermetallic compounds and planer clusters so, it is widely persuaded by the chemists. Recent research suggested that gold(I) complexes may be less harmful anticancer drugs. 53 , 54 The d8 electronic configuration of gold(III) compounds is similar to that of platinum (II), permitting similar square planar geometries and ligand exchange processes, which is another reason for their growing interest. 55 Due to this resemblance, gold(III) presents a viable substitute for the development of metallodrugs that are modeled after cisplatin. 56 , 57 The Egyptians believe that healing capability of gold can cure all kinds of physical, mental and spiritual diseases. Geber wrote that Gold is the medicine conserving the body in youth. 58 It is an inert coinage metal and its stable oxidation state lies between −1 and +5, but +1 and +3 are very common. 58 With greater scientific basis, the use of gold medicines started in early 1920s when K [Au(CN)2] was tested for bacteriostatic effect through clinical trials. Auranofin (I), [(tetra-O-acetyl)-β-d-glucopyranosyl)-thio] (triethylphosphine)-gold(I) (II), and Gold(III) dithiocarbamate (III) evolved as second generation of the gold drugs as shown in Figure 1. The brand name of auranofin is Ridaura®. It was cited that it has the ability to inhibit the TrxR system significantly. Due to this property, it was characterized as anticancer agent. 51 A very proficient gold(III) compound IV,. which is made up of two gold(III) (C, N, C) fragments and also bridged through a bis(diphenylphosphino)propane ligand. Cited compound showed nanomolar in vitro potential against various cancer cell lines. Its tumour growth inhibition was 77 % in the mice bearing human hepatocellular carcinoma PLC cells. 59 There is a significant contribution of gold(I) compounds in the anticancer field. The structure of gold(1) complex (V) shown in Figure 1 is linear around the gold atom and ligand displacement occur in it as a key reaction in the biological system. The complex V can be modified by the change in the ancillary ligands attached with them. It can change its stability, lipophilic character and binding capability as well. 59 , 60

Figure 1: Represented the chemical structure of gold based biological potential drugs.
Figure 1:

Represented the chemical structure of gold based biological potential drugs.

2 Gold metallodrugs for non-small cell lung cancer (NSCLC)

2.1 Thiosemicarbazone based Au(III) complexes

Under physiological circumstances, gold(I) is stable, but gold(III) is typically more volatile and unstable. In order to prevent its reduction by thiols, appropriate ligands must be designed, like cyclometalated gold(III) complexes. 61 In an effort to develop gold(III) complexes with possible anticancer qualities, researchers worked on thiosemicarbazone (TSC) ligands, which are well-known for their biological activity along with metal complex properties. 56 , 62 , 63 , 64 The complexes C1, C2, and C3 were synthesized from their respective TCS ligands L1, L2, and L3 (Figure 2). 65 Their cytotoxicity against lung cancer cells, specifically mesothelioma, was examined in relation to N4-substituted thiosemicarbazones generated from salicylaldehyde. These complexes have an O–N–S chelating system. 66 An uncommon and severe malignancy that is resistant to traditional therapy, malignant pleural mesothelioma (MPM) is connected to asbestos exposure. 67 , 68 Tested on three cell lines; human lung mesothelioma H28 and H2052 and human lung cancer A549, the study assessed the efficacy of gold(III) complexes as prospective therapy alternatives. It was observed that the gold(III) complexes effectively suppressed chronic inflammation in mesothelioma cell lines H2052 and H28 by dramatically reducing Interleukin-6 (IL-6) production. The treatment may have a different effect on different cell types, as evidenced by the fact that IL-6 levels in the cells of A549 were comparable to those in untreated cells. Complexes C1–C3 strongly suppressed the growth and viability of A549, H2052, and H28 cells, according to the results of the MTT and Trypan blue assays. The ligands L1-L3, and gold(III) salt did not exhibit any cytotoxic effects up to 100 μM, indicating the selectivity of the complexes’ cytotoxicity in comparison to their constituent parts (Table 1). With IC50 values ranging from 2 to 6 μM, H28 was the cell line that responded to the gold complexes best. 65

Figure 2: Thiosemicarbazone and N-heterocyclic imine based gold complexes for the treatment of lung cancer.
Figure 2:

Thiosemicarbazone and N-heterocyclic imine based gold complexes for the treatment of lung cancer.

Table 1:

Comparison of IC50 values of gold complexes (C1–C55) with their ligands and standard drugs cisplatin as well as auranofin.

Compound IC50 (μM) values against lung cancer cell lines
A549 H28 5 H20522 MRC-5M-5
L1 > 100 > 100 > 100 –
L2 > 100 > 100 > 100 –
L3 > 100 > 100 > 100 –
C1 14 ± 1 2.2 ± 0.5 9.5 ± 0.9 –
C2 32 ± 1 2 ± 1 14 ± 1 –
C3 19 ± 1 6.4 ± 0.8 9.3 ± 0.8 –
L4 0.9 ± 0.1 – – –
C4 0.4 ± 0.0 – – –
Cisplatin 3.4 ± 0.0 – – –
Auranofin 3.1 ± 0.7 – – –
C5 – – – 16.3
C6 – – – 22.2
C7 – – – 15.8
C8 – – – 19.7
C9 – – – 19.0
C10 – – – 16.6
C11 – – – 17.1
C12 – – – 17.4
Cisplatin – – – > 50
Auranofin – – – 3.78
L5 > 100 – – –
C13 11.99 – – –
C14 6.23 – – –
C15 16.35 – – –
C16 13.10 – – –
C17 7.05 – – –
C18 11.64 – – –
C19 7.50 – – –
C20–C23 > 100 – – –
Cisplatin 20.26 – – –
C24 5.2 ± 0.3 – – –
C25 7.7 ± 0.1 – – –
C26 4.4 ± 0.2 – – –
C27 5.8 ± 0.2 – – –
Cisplatin 9 ± 1 – – –
C28 101.63 ± 2.3 – – –
C29 129.49 ± 2.09 – – –
C30 110.65 ± 2.68 – – –
C31 108.6 ± 2.44 – – –
C32 102.17 ± 2.57 – – –
C33 89.98 ± 2.41 – – –
C34 90.25 ± 1.78 – – –
C35 83.36 ± 0.71
C36 77.90 ± 1.58 – – –
Cisplatin 42.2 ± 2.01 – – –
C37 63.3 ± 1.1 – – –
C37-k 17.5 – – –
C37-l 13.1 ± 2.8 – – –
C37-m 13.1 ± 4.0 – – –
C38 36.6 ± 4.7 – – –
C38-l 4.4 ± 1.2 – – –
C38-m 10.7 ± 0.2 – – –
C39 0.115 nM – – –
C40 1.16 nM – – –
Auranofin 4.41 nM – – –
C41 10 ± 1 – – –
C42 20 ± 2 – – –
Cisplatin 38 ± 2 – – –
C43 7.9 ± 0.7 – – –
C44 10.1 ± 0.2 – – –
C45 25.7 ± 0.1 – – –
C46 10.9 ± 0.9 – – –
C47 >100 – – –
L8 76 ± 34 – – –
C48 0.07 ± 0.06 – – –
C49 4.5 ± 0.7 – – –
C50 6.6 ± 2.5 – – –
Auranofin 3.7 ± 0.6 – – –
C51 16 ± 2 – – –
C52 5.4 ± 0.7 – – –
AuCl(PPh3) 18.6 ± 1.3 – – –
Cisplatin 40 ± 3 – – –
C53 0.22 ± 0.06 – – –
C54 0.26 ± 0.04 – – –
C55 0.13 ± 0.05 – – –
Cisplatin 6.21 ± 0.72 – – –

2.2 N-heterocyclic imine based Au(I) complexes

N-heterocyclic imines (NHIs) and their carbene equivalents are examples of strongly electron-donating ligands that have drawn interest for isolating electron-deficient metallic complexes. 69 , 70 In comparison to non-substituted NHCs, the exocyclic nitrogen at the two-position improves their σ- and π-donating abilities. Compounds belonging to the main group have recently been added to the list of documented mono- and bis-NHI transition metal complexes over the previous 20 years. 71 , 72 Though there have been some studies on catalysis, their biological applications remain mainly unexplored. Mihyun Park and his colleagues by using a potent bis-N-heterocyclic imine ligand (L4), a binuclear gold(I) complex (C4) was designed and characterized by SC-XRD (Figure 2). It showed decreased toxicity toward non-tumorigenic VERO cells while exhibiting specific antiproliferative activities in vitro, especially towards A549 non-small cell lung cancer cells. In comparison to existing metallodrugs such as, cisplatin, and auranofin, the efficiency of dinuclear complex C4 against A549 lung cancer cells was assessed. With an IC50 of 0.4 ± 0.0 μM, C4 has the highest potency among the standard compounds as well as ligand L4, according to the IC50 values, which are listed in Table 1. With respect to cisplatin and auranofin, C4 is 8–9 times more effective, demonstrating its greater efficacy in targeting these cancer cells. In addition to introducing novel bioactive ligands for controlling metallodrug behavior in biological systems, this work highlighted the potential of metal-based NHI complexes in medicine. 73

2.3 N-heterocyclic carbene Au(I) complexes

The Industrial Property Office of the Czech Republic has confirmed the uniqueness and practicality of Au(I)-iPr complexes with 6-mercaptopurine derivatives. National patent CZ 307954, which deals with N-heterocyclic carbene complexes of gold with bicyclic N-donor ligands, describes this recognition. The use of these type of complexes in the development of anticancer treatment drugs is also highlighted in the patent. 74 Researchers were used sixth-mercaptopurine and 1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene derivatives for synthesizing eight N-heterocyclic carbene (NHC) gold(I) complexes (C5–C12) as shown in Figure 3. In vitro cytotoxicity tests were performed with human lung fibroblast normal cell line MRC-5 to evaluate the potential of these complexes as anticancer agents together with standard drugs auranofin and cisplatin. The results presented in Table 1, showed that all the complexes (C5–C12) exhibit lower toxicity towards the MRC-5 cell line with IC50 values in between 15.8 and 22.2 μM, as compared to cisplatin (IC50 = >50 μM). However, in comparison to auranofin (IC50 = 3.78 μM) the synthesized complexes (C5–C12) showed higher toxicity to normal lung cells MRC-5 as well as less effective. Moreover, the complex C7 was more effective among the synthesized complexes as well as the ligands with an IC50 value of 15.8 μM. The order of effectiveness against MRC-5 cell line were the following; auranofin > C7 > C5 > C10 > C11 > C12 > C9 > C8 > C6 > cisplatin. 75 Dithiocarbamates (DTCs) have attracted a lot of attention in medicinal and organic chemistry because of their wide range of biological activity. 76 Their potential for treating cancer has been highlighted by recent studies, with ruthenium (II) and platinum/palladium (II) complexes showing particularly promising outcomes. 77 Increased anticancer activity has also been shown in Au(I) NHC-DTC complexes. 78 When alkynyl ligands are used with Au(I) complexes, stability problems can be resolved since they have potent antiproliferative effects upon ethynylation. 79 , 80 , 81 While the combination of Au(I) NHC with multi-active moieties offers a new approach to the development of antitumor drugs, the anticancer activity of paeonol, a derivative of flavonoids, seems promising. 82 , 83 , 84 New Au(I) NHC complexes were synthesized by the researchers, using alkynyl or DTC groups as additional ligands and a paeonol ligand in the side chain. The CCK8 test was used to assess the cytotoxic activity of imidazolium salt Pa-NHC (L5), Pa–NHC–Au-Cl (C13), and Au(I) N-heterocyclic carbene complexes (C14–C19) against A549 human lung cancer cells. 85 Cisplatin was used as the reference drug, and the IC50 values are shown in Table 1. The pro ligand L5 showed insufficient cytotoxic activity (IC50 = >100). Au(I) complex C13 demonstrated good cytotoxicity. Also, its cytotoxicity was higher than the standard drug cisplatin. The DTC ligands showed no activity against tumor cell line. The cytotoxicity against A549 was significantly increased by substituting DTCs in place of Cl-in Pa–NHC–Au complexes (C14–C19). The IC50 values for A549 ranged from 6.23 to 7.50 µM, indicating a 3.2-fold increase in activity against cisplatin. By comparison, DTC containing complex C14, C17 and C19 showed excellent cytotoxic activity among all the synthesized complexes and higher than the complex C13. As reported previously, adding alkynyl groups to gold(I) NHC complexes (C20–C23) had no effect on anticancer activity. 86 The researcher has synthesized neutral digold(I) complexes (C24–C27) with diNHC along with thiolato/alkynyl ligands. They treated the human lung cancer cell line A549 for 96 h with digold–thiolato and digold–alkynyl complexes, while cisplatin was used as a positive control, to examine the anticancer potential of these compounds. This method sought to assess and contrast their potency against cancerous cells. The results revealed that all the complexes C24–C27 exhibited excellent cytotoxic activity against the A549 cell line as compared to standard drug cisplatin (IC50 = 9 ± 1 µM). However, complexes C26 and C24 outperformed among the synthesized complexes with IC50 values of 4.4 ± 0.2 µM and 5.2 ± 0.3 µM, respectively (Table 1). There is significant increase in anticancer activity for the complexes bearing a meta-xylene spacer (Mes). The order of increasing the cytotoxic activity of complexes were following C26 > C24 > C27 > C25 > Cisplatin. 87

Figure 3: Structural representation of N-heterocyclic carbene based gold complexes.
Figure 3:

Structural representation of N-heterocyclic carbene based gold complexes.

The stable Au–C bond and flexible co-ligand choices of Au(I)–NHC complexes facilitate selective gold ion release and improved drug delivery. Scholars have investigated secondary ligands such as sulfur donors and phosphines to develop potent drugs against cancer cells. 78 , 88 Through the reaction of Au(Ipr)Cl with various thiones (a, b, c, d), Sughra Gulzar and her coworkers designed four novel Au(I)–NHC complexes (C28–C36), as their structural framework shown in Figure 4. The A549 human lung cancer cell line was used to test these complexes for anticancer properties. The results showed that, although these gold NHC complexes showed some activity, they were not as cytotoxic as the standard drug cisplatin. 89 Compared to the precursor [Au(IPr)Cl] with IC50 values of 180 ± 2 µM, complexes C28 and C29 exhibited enhanced anticancer activity (Table 1). The sulfur atoms are responsible for the complexes’ increased solubility in aqueous conditions through ionic interactions, which contributes to their higher efficiency. Their enhanced solubility is a contributing factor to their higher inhibitory efficacy against cancerous cells. 90 On the other hand, mostly due to the large IPr ligand and the large ring size of the thione ligands (a-j), the Au(I) complexes (C28–C36) showed less anticancer activity when compared to cisplatin. 91 Au(I)–NHC-thione complexes’ large carbene ligands may prevent the Au(I) ion from interacting with cancer cells, which would reduce efficacy and increase IC50 values. 92 , 93 Although, five membered rings containing complex C36, C35, and C33 demonstrated better cytotoxic activity in comparison to six and seven membered rings containing thionic complexes C29 and C30. 89 , 94 It seems that the thione co-ligand is a factor in the overall stability and effectiveness of these gold(I) complexes in the fight against cancer.

Figure 4: NHC based Au(I) complexes.
Figure 4:

NHC based Au(I) complexes.

Transition metal-mediated bioorthogonal activation is a method that uses regulated chemical stimulants to change inactive prodrugs, profluorophores, or caged proteins into their active versions. 95 , 96 This comprises reactions including cycloaddition, uncaging, and cross coupling. 97 , 98 , 99 , 100 The scope of bioorthogonal reactions in biological systems is still growing, despite the effectiveness of these techniques. Crucial for cross coupling, organometallic transmetallation is the process of moving groups such as aryl or alkynyl to metal catalysts (like Pd) in order to break strong metal-carbon bonds and form labile metal-ligand species. 101 , 102 , 103 Scientists have shown that Pd(II) can effectively initiate transmetallation and activate organogold(I) complexes within biological systems. In living cells and zebrafish, this activation generates active gold(I) species that can accelerate π-bond activation events and have anti-cancer properties. When Pd(II) compounds (k-m) were tested to increase the cytotoxicity of gold complexes (C37–C38), compound k caused the IC50 of C37 in A549 cells to increase from 63.3 μM to 17.5 μM. The cytotoxicity of C37 was enhanced by non-toxic Pd(II) compounds l and m, which also decreased its IC50 to 13.1 μM. The cytotoxicity of complex C38 was greatly enhanced by l and m activating agents; under f co-treatment, the IC50 dropped from 36.6 μM to 4.4 μM. According to these findings, Pd(II) compounds (k-m) have the ability to boost the thiol-reactivity and cytotoxicity of organogold(I) complexes C37 and C38 in cancer cells, suggesting that they may be more successful in treating cancer (Table 1). 104 The antimalarial properties of artemisinin and its derivatives are well known, but there is growing interest in the potential of these compounds to treat cancer and viral disorders. 105 , 106 , 107 Reactive oxygen species (ROS) are produced when iron activates free heme, which mostly happens in mitochondria, and this is one way in which they have anticancer properties. 108 , 109 Artemisinin derivatives that specifically target mitochondria have a greater anticancer impact. Similarly, N-heterocyclic carbene (NHC) gold(I) complexes with cationic properties have demonstrated potential for use in cancer treatment. 110 , 111 Most recent work has been devoted to the anticancer optimization of these NHC gold(I) complexes. They developed a novel class of hybrid complexes (C39–C40) by fusing cationic bis(NHC)Au(I) units with derivatives of artemisinin. Interestingly, one compound, C39, outperformed conventional therapies in its substantial anticancer effectiveness against human lung A549 and liver HepG2 carcinoma cells. Compound C39 showed higher cytotoxic activity for cancer cell line A549 compared to HepG2 cell line. Even the cytotoxic potential of complex C39 (IC50 = 0.115 nM) was higher than the complex C40 (IC50 = 1.16 nM) as well as standard drug auranofin (IC50 = 4.41 nM) against A549 cell line. In comparison with control molecule, hybrid complex C39 also demonstrated noticeably higher efficacy against difficult HepG2 hepatocellular carcinoma type comparedwith the standard, which is difficult to treat by chemotherapeutic drugs. 112 This indicates that hybrids of gold(I) and artemisinin may be viable candidates for new anticancer treatments. 113 Researchers used a luminous benzimidazole ligand (L7) functionalized with anthracenyl to produce and evaluate two new gold(I) and silver(I) complexes, C41 and C42 respectively. In comparison to cisplatin, these complexes (C41–C42) showed stronger antiproliferative effects and notable cytotoxicity in the micromolar range against a variety of tumor cell lines, such as SW480 (colon), A549 (lung), and HepG2 (liver). The main objective was to assess the gold complexes’ cytotoxic effects on A549 lung cancer cells in particular. The results indicated that these Au(I) complex C42 exhibit potential efficacy beyond that of cisplatin, making them attractive candidates for the development of novel treatments for lung cancer. Au(I) complex C42 has the higher cytotoxic potential than the standard drug cisplatin with an IC50 value of 20 ± 2 µM. While complex C42 does not have the same cytotoxic capacity as complex C41, it is still a more effective treatment for lung cancer cells than cisplatin. 114

Based on literature, 115 in order to facilitate concerted-metallation-deprotonation (CMD) between [Au(NHC)Cl] and ethisterone, researchers synthesized Au-steroidyl complexes (C43–C47) with a variety of saturated and unsaturated NHC ligands using the weak base K2CO3 (Figure 5). There was no complicated work-up for this process, which runs under air. A thorough investigation of these complexes’ antiproliferative effects on A549 lung cancer cells showed promise for their ability to target the disease. Among the gold-steroidyl complexes evaluated, compound C43 was shown to be the most effective anticancer agent by the study. Its IC50 value against A549 lung cancer cells was 7.9 ± 0.7 µM (Table 1). The inadequate solubility of complex C47 in the stock solutions and cell culture media may have contributed to its inactive nature. The cytotoxic potential of complexes C44 and C46 was comparable. An intriguing discovery from the structure-activity relationship (SAR) analysis was the significant reduction in activity that resulted from replacing the imidazole-derived NHC ligand in C43 with an imidazoline-based NHC in C45. This finding highlighted, how important ligand structure is to these gold complexes’ anticancer properties and shows the importance of precise ligand selection in the development of successful treatments. 116

Figure 5: Structural representation of Au-steroidyl NHC complexes.
Figure 5:

Structural representation of Au-steroidyl NHC complexes.

2.4 Cyclic (alkyl) (amino) carbene based Au(I) complexes

The special steric and electrical properties of cyclic (alkyl) (amino) carbenes, or CAACs, have made them useful tools in chemistry. 117 , 118 , 119 Having a quaternary carbon instead of a nitrogen, CAACs have a lower LUMO and a higher HOMO than N-heterocyclic carbenes (NHCs). 120 CAACs are extremely basic and π-acidic due to their structure. 121 CAACs are extremely basic due to their strong electron-donating properties and π-acidic due to their ability to accept electron pairs through π-bonding. 122 Developing strong pre-catalysts, producing compounds with peculiar shapes or oxidation states, and successfully isolating active catalytic intermediates are some of its advantages. 123 , 124 NHC analogs lack the stronger metal-carbene bonds found in CAAC-bound metal complexes, such as those containing copper, silver, and gold. This could result in less side effects and more targeted medication interactions. According to certain metal-dependent pathways, recent investigations demonstrate their efficacy as cytotoxic agents. 125 As shown in Figure 6, Gold(I) complexes (C48–C50) with CAAC accessory ligands were examined in detail for their potential antitumor effects in vitro. Considerable antitumor activity was found in complexes that were evaluated, supporting their potential as therapeutic agents. The cytotoxicity of the CAACEtH+TfO− salt (L8) and the gold(I) complexes C48–C50 against the human cancer cell lines HeLa, A549, HT1080, and Caov-3 was investigated. All cell lines exhibited significant antitumoral activity, with the main focus on strong effects against lung cancer cell line A549. Complex C48 outperformed C49, C50, and the medication auranofin in terms of cytotoxicity against the A549 cell line. C48 > > C49 > Auranofin > C50 > L8 was the sequence in which the cytotoxic activity against A549 increased. The tendency for Au(I) complexes that has been seen has to do with their capacity to pass through hydrophobic barriers and mitochondrial membranes. 126 Compared to the complex C50, auranofin had somewhat higher activity. This suggested that, out of all the complexes studied and the reference drug, C48 (IC50 = 0.07 ± 0.06 µM) is the most effective and results for their IC50 values enlisted in Table 1. 127 The significance of the gold core in antitumor activity is highlighted by the reduced cytotoxicity of L8. Because bulkier CAAC-ligands are less active than CAACEt-ligand-containing gold complexes, it is clear that hydrophilic/lipophilic balance and steric interactions are important considerations. 128

Figure 6: CAAC and carbamates-based Au(I) complexes.
Figure 6:

CAAC and carbamates-based Au(I) complexes.

2.5 Carbamate based Au(I) complexes

Monoanionic carbamato ligands exhibit tunable properties, exhibiting bridging, chelating, or monodentate behavior in response to their surroundings. Oxides and hydroxides of metals are formed when they combine with protic species such as water, resulting in their breakdown into amine and CO2. Exploration of biological applications of these metals has been limited due to their quick disintegration, particularly with high-valent, oxophilic metals, which has forced handling under inert circumstances. 129 , 130 Because of their significant water stability and cytotoxicity, Pt (IV) complexes with axial carbamato ligands have been investigated recently as possible treatments for cancer. 131 When these complexes are activated within the cells, they release bioactive amines that are more effective than their carboxylato counterparts. 132 These results, along with the potential medical benefits of carbamates, are driving efforts to assess their antiproliferative properties and being appropriate for biological applications. 133 The compounds [Ag(O2CNEt2)] (C51) and [Au(O2CNMe2) (PPh3)] (C52) shown in Figure 6, exhibited notable stability in aqueous solutions and noteworthy cytotoxicity in vitro when tested against the A549 lung cancer cell line. 134 Two reference compounds were utilized: cisplatin (CDDP) and [Au(Cl)PPh3]. Compared to other vanadocene compounds with bidentate nitrogen ligands, vanadocene bis-carbamate exhibited a lower IC50 value against A549 cells, indicating a moderate level of cytotoxicity. 135 The results indicated that the complex C40 was more effective compared to the standard drug and C51 Pt complex. The potential of C52 (IC50 = 5.4 ± 0.7 µM) as a strong anticancer agent was highlighted by the fact that its cytotoxicity was either equal to or greater than that of other reported Au(I) triphenylphosphine complexes including chloro (triphenylphosphine)Au(I) (Table 1). 136 , 137

2.6 Diphosphane based Au(I) complexes

Motivated by encouraging results from previous investigations on Au(I)-diphosphane complexes, 138 , 139 scientists have explored three novel gold(I)-carbene complexes (C53–C55) with diphosphane co-ligands (Figure 7). Based on their proven antitumor efficaciousness and their function in stabilizing gold(I) complexes, diphosphanes were selected. 140 , 141 By adding diphosphane ligands, these complexes become more lipophilic and stable, which improves their cellular uptake and bioavailability. Their anticancer activity is greatly enhanced, by this enhanced stability, in addition to their higher lipophilicity. The results suggested that these gold(I)-carbene-diphosphane complexes (C53–C55) have potential as effective cancer treatment options and demonstrate how changes in the complex’s composition might affect the compounds’ therapeutic potential. The cytotoxic potential of the complexes (C53–C55) was assessed by using cell line A549. In comparison, cisplatin used as standard with an IC50 value of 6.2 µM. According to IC50 values, all the newly synthesized complexes C53–C55 were more potent than the standard cisplatin by possessing lower IC50 values in between 0.13 and 0.22 µM. However, among the complexes C55 showed excellent cytotoxic potential than the C53 and C54. The order of increasing the cytotoxic was the following; C55 > C53 > C54 > cisplatin (Table 1). 142

Figure 7: Structural illustration of diphosphane based Au(I) complexes.
Figure 7:

Structural illustration of diphosphane based Au(I) complexes.

3 Mechanism of action

Metal based drugs show variety of anticancer mechanisms, but their efficiency is limited due to toxicity, resistance and erratic action across cancer types. Basic mechanisms include the damage of DNA, redox modulation, inhibition of angiogenesis, and immunomodulation but optimum utilisation of these mechanisms needs deeper investigation. In NSCLC cells the visual representation of the mechanism of action of the metallodrugs is shown in the Figure 8. The protein which targets the metallodrugs such as gold(I) thiol reactive complex auranofin, an inhibitor of the selenoenzyme thioredoxin reductase (TrxR), showed cytotoxic potential by disrupting redox homeostasis during the preclinical studies. There are limitations in the clinical activity of the single agent because of the compensatory mechanism which moderate the redox effect. Efficacy of such agents can be enhanced by the addition of other stressors. For example, auranofin increased the potential of cisplatin in the lung cancer by further potentiating oxidative stress. The diverse processes like apoptosis and cell cycle arrest can also be modulated by the metallodrugs. 143

Figure 8: Schematic representation of the mechanism of action of Au(III) drug in NSCLC cells.
Figure 8:

Schematic representation of the mechanism of action of Au(III) drug in NSCLC cells.

4 Conclusions

In conclusion, the gold complexes have arisen as prominent novel frontiers in the battle to fight against lung cancer. They provide a new perspective/strategy on the treatment of this devastating disease. Limited investigations in early preclinical phases and limited in vivo data distinguish it as relatively recent field. Treatment efficacy of gold complexes is generally increased when different ligands are added because this increases the selectivity of compounds for cancer cells that overexpress a particular target. The potential for boosting the anticancer activity of gold(I) and gold(III) complexes has been demonstrated by the insertion of diverse ligands, including thiosemicarbazone, N-heterocyclic imine, N-heterocyclic carbenes, steroidyl NHC, carbamates, and diphosphanes. A variety of lung cancer cell lines, such as A549, H28, H2052, and MRC-5, are effectively inhibited by these modified gold complexes. The gold complexes are stabilized and their bioactivity is increased by the addition of different ligands, which makes them attractive options for targeted cancer treatment. As in this field, research continues to evolve, it is very clear that gold complexes hold marvellous potential for developing the novel, efficient therapies with the ultimate objective of translating these results into the clinical practice and enlightening patient outcomes.

Corresponding authors: Abbas Washeel Salman, Department of Production, College of Agriculture, Wasit University, Al Kut, Wasit, Iraq, E-mail: ; and Muhammad Adnan Iqbal, Department of Chemistry, University of Agriculture Faisalabad, Faisalabad, Pakistan, E-mail:

Funding source: Pakistan Science Foundation

Award Identifier / Grant number: PSF/CRP/Consr-676

  1. Research ethics: Not applicable.

  2. Informed consent: Not applicable.

  3. Author contributions: Aqsa Hanif: Writing-original draft, Software. Sawsan.S Al-Rawi: Resources and Validation. Ibrahim Ahmad H.: Data curation, Visualization. Abbas Washeel Salman: Review and editing, Software. Ayesha Zafar: Review and formatting; Muhammad Adnan Iqbal: Conceptualization, Resources, Supervision, Overall guidance. Sana Batool: Grammatical analysis. Ghazanfar Abbas: Formal analysis.

  4. Use of Large Language Models, AI and Machine Learning Tools: None declared.

  5. Conflict of interest: The authors state no conflict of interest.

  6. Research funding: The authors are thankful to the Pakistan Science Foundation (PSF) for awarding the research grant PSF/Cons/676.

  7. Data availability: Data will be provided on demand.

References

1. Kontoghiorghe, C. N.; Kolnagou, A.; Kontoghiorghes, G. J. Phytochelators Intended for Clinical Use in Iron Overload, Other Diseases of Iron Imbalance and Free Radical Pathology. Molecules 2015, 20, 20841–20872; https://doi.org/10.3390/molecules201119725.Search in Google Scholar PubMed PubMed Central

2. Bánfalvi, G. Heavy Metals, Trace Elements and Their Cellular Effects. Cell. Eff. Heavy Met. 2011, 3–28; https://doi.org/10.1007/978-94-007-0428-2_1.Search in Google Scholar

3. Goyer, R. A.; Clarkson, T. W. Toxic Effects of Metals. Casarett Doull’s Toxicol. Basic Sci. Poisons 1996, 5, 691–736.Search in Google Scholar

4. Saad, A. A.; El-Sikaily, A.; Kassem, H. Essential, Non-essential Metals and Human Health. Blue Biotechnol. J. 2014, 3, 447.Search in Google Scholar

5. Raper, E. S. Complexes of Heterocyclic Thionates. Part 1. Complexes of Monodentate and Chelating Ligands. Coord. Chem. Rev. 1996, 153, 199–255; https://doi.org/10.1016/0010-8545(95)01233-8.Search in Google Scholar

6. Mukherjee, R. Coordination Chemistry with Pyrazole-Based Chelating Ligands: Molecular Structural Aspects. Coord. Chem. Rev. 2000, 203, 151–218; https://doi.org/10.1016/s0010-8545(99)00144-7.Search in Google Scholar

7. Scott, L. E.; Orvig, C. Medicinal Inorganic Chemistry Approaches to Passivation and Removal of Aberrant Metal Ions in Disease. Chem. Rev. 2009, 109, 4885–4910; https://doi.org/10.1021/cr9000176.Search in Google Scholar PubMed

8. Sinicropi, M. S.; Amantea, D.; Caruso, A.; Saturnino, C. Chemical and Biological Properties of Toxic Metals and Use of Chelating Agents for the Pharmacological Treatment of Metal Poisoning. Arch. Toxicol. 2010, 84, 501–520; https://doi.org/10.1007/s00204-010-0544-6.Search in Google Scholar PubMed

9. Tripathi, L.; Kumar, P.; Singhai, A. Role of Chelates in Treatment of Cancer. Indian J. Cancer 2007, 44, 62–71; https://doi.org/10.4103/0019-509x.35813.Search in Google Scholar PubMed

10. Chen, D.; Milacic, V.; Frezza, M.; Dou, Q. P. Metal Complexes, Their Cellular Targets and Potential for Cancer Therapy. Curr. Pharmaceut. Des. 2009, 15, 777–791; https://doi.org/10.2174/138161209787582183.Search in Google Scholar PubMed

11. Blanusa, M.; Varnai, V. M.; Piasek, M.; Kostial, K. Chelators as Antidotes of Metal Toxicity: Therapeutic and Experimental Aspects. Curr. Med. Chem. 2005, 12, 2771–2794; https://doi.org/10.2174/092986705774462987.Search in Google Scholar PubMed

12. Lui, G. Y.; Kovacevic, Z.; Richardson, V.; Merlot, A. M.; Kalinowski, D. S.; Richardson, D. R. Targeting Cancer by Binding Iron: Dissecting Cellular Signaling Pathways. Oncotarget 2015, 6, 18748; https://doi.org/10.18632/oncotarget.4349.Search in Google Scholar PubMed PubMed Central

13. Kontoghiorghes, G. J. Advances on Chelation and Chelator Metal Complexes in Medicine. MDPI 2020, 21, 2499; https://doi.org/10.3390/ijms21072499.Search in Google Scholar PubMed PubMed Central

14. Kontoghiorghes, G. J.; Eracleous, E.; Economides, C.; Kolnagou, A. Advances in Iron Overload Therapies. Prospects for Effective Use of Deferiprone (L1), Deferoxamine, the New Experimental Chelators ICL670, GT56-252, L1NAll and Their Combinations. Curr. Med. Chem. 2005, 12, 2663–2681; https://doi.org/10.2174/092986705774463003.Search in Google Scholar PubMed

15. Končić, M. Z.; Barbarić, M.; Perković, I.; Zorc, B. Antiradical, Chelating and Antioxidant Activities of Hydroxamic Acids and Hydroxyureas. Molecules 2011, 16, 6232–6242; https://doi.org/10.3390/molecules16086232.Search in Google Scholar PubMed PubMed Central

16. Al‐Azemi, A.; Fielder, M. D.; Abuknesha, R. A.; Price, R. G. Effects of Chelating Agent and Environmental Stresses on Microbial Biofilms: Relevance to Clinical Microbiology. J. Appl. Microbiol. 2011, 110, 1307–1313; https://doi.org/10.1111/j.1365-2672.2011.04983.x.Search in Google Scholar PubMed

17. Nielsen, K.; Kelly, L.; Gall, D.; Smith, P.; Bosse, J.; Nicoletti, P.; Kelly, W. The Use of Divalent Cation Chelating Agents (EDTA/EGTA) to Reduce Non-specific Serum Protein Interaction in Enzyme Immunoassay. Vet. Res. Commun. 1994, 18, 433–437; https://doi.org/10.1007/bf01839419.Search in Google Scholar

18. Cooley, M. E.; Kaiser, L. R.; Abrahm, J. L.; Giarelli, E. The Silent Epidemic: Tobacco and the Evolution of Lung Cancer and its Treatment. Cancer Invest. 2001, 19, 739–751; https://doi.org/10.1081/cnv-100106149.Search in Google Scholar PubMed

19. Franklin, W. A. Pathology of Lung Cancer. J. Thorac. Imag. 2000, 15, 3–12; https://doi.org/10.1097/00005382-200001000-00003.Search in Google Scholar PubMed

20. Walter, J.; Pryce, D. The Site of Origin of Lung Cancer and its Relation to Histological Type. Thorax 1955, 10, 117; https://doi.org/10.1136/thx.10.2.117.Search in Google Scholar PubMed PubMed Central

21. Bray, F.; Ferlay, J.; Soerjomataram, I.; Siegel, R. L.; Torre, L. A.; Jemal, A. Global Cancer Statistics 2018: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA A Cancer J. Clin. 2018, 68, 394–424; https://doi.org/10.3322/caac.21492.Search in Google Scholar PubMed

22. Wu, Y.-L.; Planchard, D.; Lu, S.; Sun, H.; Yamamoto, N.; Kim, D.-W.; Tan, D.; Yang, J.-H.; Azrif, M.; Mitsudomi, T.; Park, K.; Soo, R.; Chang, J.; Alip, A.; Peters, S.; Douillard, J. Y. Pan-Asian Adapted Clinical Practice Guidelines for the Management of Patients with Metastatic Non-small-cell Lung Cancer: a CSCO–ESMO Initiative Endorsed by JSMO, KSMO, MOS, SSO and TOS. Ann. Oncol. 2019, 30, 171–210; https://doi.org/10.1093/annonc/mdy554.Search in Google Scholar PubMed

23. Jung, K.-W.; Kang, M. J.; Park, E. H.; Yun, E. H.; Kim, H.-J.; Kong, H.-J.; Im, J.-S.; Seo, H. G. Prediction of Cancer Incidence and Mortality in Korea, 2023. Cancer Res. Treat. Off. J. Kor. Cancer Assoc. 2023, 55, 400–407; https://doi.org/10.4143/crt.2023.448.Search in Google Scholar PubMed PubMed Central

24. Balata, H.; Fong, K. M.; Hendriks, L. E.; Lam, S.; Ostroff, J. S.; Peled, N.; Wu, N.; Aggarwal, C. Prevention and Early Detection for NSCLC: Advances in Thoracic Oncology 2018. J. Thorac. Oncol. 2019, 14, 1513–1527; https://doi.org/10.1016/j.jtho.2019.06.011.Search in Google Scholar PubMed

25. Sun, S.; Schiller, J. H.; Gazdar, A. F. Lung Cancer in Never Smokers—A Different Disease. Nat. Rev. Cancer 2007, 7, 778–790; https://doi.org/10.1038/nrc2190.Search in Google Scholar PubMed

26. Bhurgri, Y.; Bhurgri, A.; Usman, A.; Sheikh, N.; Faridi, N.; Malik, J.; Ahmed, R.; Kayani, N.; Pervez, S.; Hasan, S. H. Patho-epidemiology of Lung Cancer in Karachi (1995-2002). Asian Pac. J. Cancer Prev. APJCP 2006, 7, 60.Search in Google Scholar

27. Sheikh, H. S.; Munawar, K.; Sheikh, F.; Qamar, M. F. U. Lung Cancer in Pakistan. J. Thorac. Oncol. 2022, 17, 602–607; https://doi.org/10.1016/j.jtho.2022.01.009.Search in Google Scholar PubMed

28. Sarwar, M. R.; Saqib, A. Cancer Prevalence, Incidence and Mortality Rates in Pakistan in 2012. Cogent Med. 2017, 4, 1288773; https://doi.org/10.1080/2331205x.2017.1288773.Search in Google Scholar

29. Torre, L. A.; Siegel, R. L.; Jemal, A. Lung Cancer Statistics. Lung Cancer Personalized Med. Curr. Knowl. Ther. 2016, 1–19; https://doi.org/10.1007/978-3-319-24223-1_1.Search in Google Scholar PubMed

30. Majeed, F. A.; Azeem, A. R.; Farhan, N. Lung Cancer in Pakistan, where Do We Stand. JPMA 2019, 69, 405–408.Search in Google Scholar

31. Proctor, R. N. Tobacco and the Global Lung Cancer Epidemic. Nat. Rev. Cancer 2001, 1, 82–86; https://doi.org/10.1038/35094091.Search in Google Scholar PubMed

32. Ding, L.; Getz, G.; Wheeler, D. A.; Mardis, E. R.; McLellan, M. D.; Cibulskis, K.; Sougnez, C.; Greulich, H.; Muzny, D. M.; Morgan, M. B.; Fulton, L.; Fulton, R. S.; Zhang, Q.; Wendl, M. C.; Lawrence, M. S.; Larson, D. E.; Chen, K.; Dooling, D. J.; Sabo, A.; Hawes, A. C.; Shen, H.; Jhangiani, S. N.; Lewis, L. R.; Hall, O.; Zhu, Y.; Mathew, T.; Ren, Y.; Yao, J.; Scherer, S. E.; Clerc, K.; Metcalf, G. A.; Ng, B.; Milosavljevic, A.; Gonzalez-Garay, M. L.; Osborne, J. R.; Meyer, R.; Shi, X.; Tang, Y.; Koboldt, D. C.; Lin, L.; Abbott, R.; Miner, T. L.; Pohl, C.; Fewell, G.; Haipek, C.; Schmidt, H.; Dunford-Shore, B. H.; Kraja, A.; Crosby, S. D.; Sawyer, C. S.; Vickery, T.; Sander, S.; Robinson, J.; Winckler, W.; Baldwin, J.; Chirieac, L. R.; Dutt, A.; Fennell, T.; Hanna, M.; Johnson, B. E.; Onofrio, R. C.; Thomas, R. K.; Tonon, G.; Weir, B. A.; Zhao, X.; Ziaugra, L.; Zody, M. C.; Giordano, T.; Orringer, M. B.; Roth, J. A.; Spitz, M. R.; Wistuba, I. I.; Ozenberger, B.; Good, P. J.; Chang, A. C.; Beer, D. G.; Watson, M. A.; Ladanyi, M.; Broderick, S.; Yoshizawa, A.; Travis, W. D.; Pao, W.; Province, M. A.; Weinstock, G. M.; Varmus, H. E.; Gabriel, S. B.; Lander, E. S.; Gibbs, R. A.; Meyerson, M.; Wilson, R. K. Somatic Mutations Affect Key Pathways in Lung Adenocarcinoma. Nature 2008, 455, 1069–1075; https://doi.org/10.1038/nature07423.Search in Google Scholar PubMed PubMed Central

33. Zappa, C.; Mousa, S. A. Non-small Cell Lung Cancer: Current Treatment and Future Advances. Transl. Lung Cancer Res. 2016, 5, 288; https://doi.org/10.21037/tlcr.2016.06.07.Search in Google Scholar PubMed PubMed Central

34. Fuchs, C. S.; Tomasek, J.; Yong, C. J.; Dumitru, F.; Passalacqua, R.; Goswami, C.; Safran, H.; Dos Santos, L. V.; Aprile, G.; Ferry, D. R.; Melichar, B.; Tehfe, M.; Topuzov, E.; Zalcberg, J. R.; Chau, I.; Campbell, W.; Sivanandan, C.; Pikiel, J.; Koshiji, M.; Hsu, Y.; Liepa, A. M.; Gao, L.; Schwartz, J. D.; Tabernero, J. Ramucirumab Monotherapy for Previously Treated Advanced Gastric or Gastro-Oesophageal Junction Adenocarcinoma (REGARD): an International, Randomised, Multicentre, Placebo-Controlled, Phase 3 Trial. Lancet 2014, 383, 31–39; https://doi.org/10.1016/s0140-6736(13)61719-5.Search in Google Scholar

35. Dungo, R. T.; Keating, G. M. Afatinib: First Global Approval. Drugs 2013, 73, 1503–1515; https://doi.org/10.1007/s40265-013-0111-6.Search in Google Scholar PubMed

36. Niemira, M.; Collin, F.; Szalkowska, A.; Bielska, A.; Chwialkowska, K.; Reszec, J.; Niklinski, J.; Kwasniewski, M.; Kretowski, A. Molecular Signature of Subtypes of Non-small-cell Lung Cancer by Large-Scale Transcriptional Profiling: Identification of Key Modules and Genes by Weighted Gene Co-expression Network Analysis (WGCNA). Cancers 2019, 12, 37; https://doi.org/10.3390/cancers12010037.Search in Google Scholar PubMed PubMed Central

37. Liu, F.-S. Mechanisms of Chemotherapeutic Drug Resistance in Cancer Therapy—A Quick Review. Taiwan. J. Obstet. Gynecol. 2009, 48, 239–244; https://doi.org/10.1016/s1028-4559(09)60296-5.Search in Google Scholar

38. Kar, B.; Roy, N.; Pete, S.; Moharana, P.; Paira, P. J. I. C. A. Ruthenium and Iridium Based Mononuclear and Multinuclear Complexes: A Breakthrough of Next-Generation Anticancer Metallopharmaceuticals. Inorganica Chim. Acta 2020, 512, 119858; https://doi.org/10.1016/j.ica.2020.119858.Search in Google Scholar

39. Kumar Singh, A.; Kumar, A.; Singh, H.; Sonawane, P.; Pathak, P.; Grishina, M.; Pal Yadav, J.; Verma, A.; Kumar, P. Metal Complexes in Cancer Treatment: Journey So Far. Chem. Biodivers. 2023, 20, e202300061; https://doi.org/10.1002/cbdv.202300061.Search in Google Scholar PubMed

40. Chaudhary, V.; Chowdhury, R.; Thukral, P.; Pathania, D.; Saklani, S.; Rustagi, S.; Gautam, A.; Mishra, Y. K.; Singh, P.; Kaushik, A.; Kaushik, A. Biogenic Green Metal Nano Systems as Efficient Anti-cancer Agents. Environ. Res. 2023, 229, 115933; https://doi.org/10.1016/j.envres.2023.115933.Search in Google Scholar PubMed

41. Khorasani, A.; Shahbazi-Gahrouei, D.; Safari, A. Recent Metal Nanotheranostics for Cancer Diagnosis and Therapy: a Review. Diagnostics 2023, 13, 833; https://doi.org/10.3390/diagnostics13050833.Search in Google Scholar PubMed PubMed Central

42. Hussain, A.; Alajmi, M. F.; Lone, M. A.; Wani, W. A. Introduction: Metal Complexes as Therapeutic Agents. In Therapeutic Rhodium Complexes; Springer: Cham, 2023; pp 1–9.10.1007/978-3-031-35631-5_1Search in Google Scholar

43. Dube, N. P.; Thatyana, M.; Mokgalaka-Fleischmann, N. S.; Mansour, A. M.; Tembu, V. J.; Manicum, A.-L. E. Review on the Applications of Selected Metal-Based Complexes on Infectious Diseases. Molecules 2024, 29, 406; https://doi.org/10.3390/molecules29020406.Search in Google Scholar PubMed PubMed Central

44. Machado, I.; Gambino, D. Metallomics: An Essential Tool for the Study of Potential Antiparasitic Metallodrugs. ACS Omega 2024, 9, 15744–15752; https://doi.org/10.1021/acsomega.3c10200.Search in Google Scholar PubMed PubMed Central

45. Gambino, D. Organometallics in Medicinal Chemistry: Antiparasitic Agents. J. Braz. Chem. Soc. 2024, 35, e-20240104; https://doi.org/10.21577/0103-5053.20240104.Search in Google Scholar

46. Jimenez-Falcao, S.; Mendez-Arriaga, J. M. Recent Advances in Metal Complexes Based on Biomimetic and Biocompatible Organic Ligands against Leishmaniasis Infections: State of the Art and Alternatives. Inorganics 2024, 12, 190; https://doi.org/10.3390/inorganics12070190.Search in Google Scholar

47. Maqsood, F.; Al-Rawi, S. S.; Ibrahim, A. H.; Jamil, F.; Zafar, A.; Iqbal, M. A.; Shoukat, U. S.; Asad, M.; Zia, S. U.; Ahmad, F.; Atif, M. Recent Trends in Medicinal Applications of Mercury Based Organometallic and Coordination Compounds. Rev. Inorg. Chem. 2025, 45, 375–396. https://doi.org/10.1515/revic-2024-0033.Search in Google Scholar

48. Zhao, Y.-Y.; Kim, H.; Nguyen, V.-N.; Jang, S.; Jang, W. J.; Yoon, J. Recent Advances and Prospects in Organic Molecule-Based Phototheranostic Agents for Enhanced Cancer Phototherapy. Coord. Chem. Rev. 2024, 501, 215560; https://doi.org/10.1016/j.ccr.2023.215560.Search in Google Scholar

49. Ashraf, M.; Kamal, A.; Ahmed, E.; Bhatti, H. N.; Arshad, M.; Iqbal, M. A. Tetra-azolium Salts Induce Significant Cytotoxicity in Human Colon Cancer Cells In Vitro. Curr. Org. Synth. 2024, 21, 1075–1080; https://doi.org/10.2174/1570179421666230824151219.Search in Google Scholar PubMed

50. Bai, Y.; Aodeng, G.; Ga, L.; Hai, W.; Ai, J. J. P. Research Progress of Metal. Anti Cancer Drugs 2023, 15, 2750; https://doi.org/10.3390/pharmaceutics15122750.Search in Google Scholar PubMed PubMed Central

51. Cirri, D.; Bartoli, F.; Pratesi, A.; Baglini, E.; Barresi, E.; Marzo, T. J. B. Strategies for the Improvement of Metal-Based Chemotherapeutic Treatments. Biomedicines 2021, 9, 504; https://doi.org/10.3390/biomedicines9050504.Search in Google Scholar PubMed PubMed Central

52. Malik, S. N.; Altaf, A.; Mawat, T. H.; Iqbal, M. A.; Majeed, A.; Riaz, A.; Zafar, A.; Iram, G.; Khalid, S.; Haider, M. T. In Vitro Cytotoxicity of Zinc (II) Complexes: Synthesis, Characterization, and Biological Potential. Chem. Afr. 2024, 1–14; https://doi.org/10.1007/s42250-024-01014-0.Search in Google Scholar

53. Casini, A.; Thomas, S. R. The Beauty of Gold: Knowledge of Mechanisms Leads to Different Applications of Organogold Compounds in Medicine and Catalysis. Chem. Lett. 2021, 50, 1516–1522; https://doi.org/10.1246/cl.210238.Search in Google Scholar

54. Schlagintweit, J. F.; Jakob, C. H.; Wilke, N. L.; Ahrweiler, M.; Frias, C.; Frias, J.; König, M.; Esslinger, E.-M. H.; Marques, F.; Machado, J. F.; Reich, R. M.; Morais, T. S.; Correia, J. D. G.; Prokop, A.; Kühn, F. E. Gold (I) Bis (1, 2, 3-Triazol-5-Ylidene) Complexes as Promising Selective Anticancer Compounds. J. Med. Chem. 2021, 64, 15747–15757; https://doi.org/10.1021/acs.jmedchem.1c01021.Search in Google Scholar PubMed

55. Rocchigiani, L.; Bochmann, M. Recent Advances in Gold (III) Chemistry: Structure, Bonding, Reactivity, and Role in Homogeneous Catalysis. Chem. Rev. 2020, 121, 8364–8451; https://doi.org/10.1021/acs.chemrev.0c00552.Search in Google Scholar PubMed

56. Zhang, J.; Zhang, Z.; Jiang, M.; Li, S.; Yuan, H.; Sun, H.; Yang, F.; Liang, H. Developing a Novel Gold (III) Agent to Treat Glioma Based on the Unique Properties of Apoferritin Nanoparticles: Inducing Lethal Autophagy and Apoptosis. J. Med. Chem. 2020, 63, 13695–13708; https://doi.org/10.1021/acs.jmedchem.0c01257.Search in Google Scholar PubMed

57. Majeed, A.; Zafar, A.; Mushtaq, Z.; Iqbal, M. A. Advances in Gold Catalyzed Synthesis of Quinoid Heteroaryls. RSC Adv. 2024, 14, 21047–21064; https://doi.org/10.1039/d4ra03368j.Search in Google Scholar PubMed PubMed Central

58. Abbasi, M.; Yaqoob, M.; Haque, R. A.; Iqbal, M. A. J. M. R. i. M. C. Potential of Gold Candidates against Human Colon. Cancer 2021, 21, 69–78; https://doi.org/10.2174/1389557520666200807130721.Search in Google Scholar PubMed

59. Simpson, P. V.; Desai, N. M.; Casari, I.; Massi, M.; Falasca, M. J. F. M. C. Metal-based Antitumor Compounds: Beyond Cisplatin. Future Med. Chem. 2019, 11, 119–135; https://doi.org/10.4155/fmc-2018-0248.Search in Google Scholar PubMed

60. Fernández-Moreira, V.; Herrera, R. P.; Gimeno, M. C. J. P.; Chemistry, A. Anticancer Properties of Gold Complexes with Biologically Relevant Ligands. Pure Appl. Chem. 2019, 91, 247–269; https://doi.org/10.1515/pac-2018-0901.Search in Google Scholar

61. Huang, K.-B.; Wang, F.-Y.; Tang, X.-M.; Feng, H.-W.; Chen, Z.-F.; Liu, Y.-C.; Liu, Y.-N.; Liang, H. Organometallic Gold (III) Complexes Similar to Tetrahydroisoquinoline Induce ER-Stress-Mediated Apoptosis and Pro-death Autophagy in A549 Cancer Cells. J. Med. Chem. 2018, 61, 3478–3490; https://doi.org/10.1021/acs.jmedchem.7b01694.Search in Google Scholar PubMed

62. Pioli, M.; Orsoni, N.; Scaccaglia, M.; Alinovi, R.; Pinelli, S.; Pelosi, G.; Bisceglie, F. A New Photoactivatable Ruthenium (II) Complex with an Asymmetric Bis-Thiocarbohydrazone: Chemical and Biological Investigations. Molecules 2021, 26, 939; https://doi.org/10.3390/molecules26040939.Search in Google Scholar PubMed PubMed Central

63. Scaccaglia, M.; Rega, M.; Bacci, C.; Giovanardi, D.; Pinelli, S.; Pelosi, G.; Bisceglie, F. Bismuth Complex of Quinoline Thiosemicarbazone Restores Carbapenem Sensitivity in NDM-1-Positive Klebsiella pneumoniae. J. Inorg. Biochem. 2022, 234, 111887; https://doi.org/10.1016/j.jinorgbio.2022.111887.Search in Google Scholar PubMed

64. Scaccaglia, M.; Rega, M.; Vescovi, M.; Pinelli, S.; Tegoni, M.; Bacci, C.; Pelosi, G.; Bisceglie, F. Gallium (III)-pyridoxal Thiosemicarbazone Derivatives as Nontoxic Agents against Gram-Negative Bacteria. Metallomics 2022, 14, mfac070; https://doi.org/10.1093/mtomcs/mfac070.Search in Google Scholar PubMed

65. Scaccaglia, M.; Pinelli, S.; Manini, L.; Ghezzi, B.; Nicastro, M.; Heinrich, J.; Kulak, N.; Mozzoni, P.; Pelosi, G.; Bisceglie, F. Gold (III) Complexes with Thiosemicarbazone Ligands: Insights into Their Cytotoxic Effects on Lung Cancer Cells. J. Inorg. Biochem. 2024, 251, 112438; https://doi.org/10.1016/j.jinorgbio.2023.112438.Search in Google Scholar PubMed

66. Zafar, A.; Iqbal, M. A.; Iram, G.; Shoukat, U. S.; Jamil, F.; Saleem, M.; Yousif, M.; ul Abidin, Z.; Asad, M. Advances in Organocatalyzed Synthesis of Organic Compounds. RSC Adv. 2024, 14, 20365–20389; https://doi.org/10.1039/d4ra03046j.Search in Google Scholar PubMed PubMed Central

67. Schillebeeckx, E.; van Meerbeeck, J. P.; Lamote, K. Clinical Utility of Diagnostic Biomarkers in Malignant Pleural Mesothelioma: a Systematic Review and Meta-Analysis. Eur. Respir. Rev. 2021, 30; https://doi.org/10.1183/16000617.0057-2021.Search in Google Scholar PubMed PubMed Central

68. Sinn, K.; Mosleh, B.; Hoda, M. A. Malignant Pleural Mesothelioma: Recent Developments. Curr. Opin. Oncol. 2021, 33, 80–86; https://doi.org/10.1097/cco.0000000000000697.Search in Google Scholar PubMed

69. Wu, X.; Tamm, M. Transition Metal Complexes Supported by Highly Basic Imidazolin-2-Iminato and Imidazolin-2-Imine N-Donor Ligands. Coord. Chem. Rev. 2014, 260, 116–138; https://doi.org/10.1016/j.ccr.2013.10.007.Search in Google Scholar

70. Ochiai, T.; Franz, D.; Inoue, S. Applications of N-Heterocyclic Imines in Main Group Chemistry. Chem. Soc. Rev. 2016, 45, 6327–6344; https://doi.org/10.1039/c6cs00163g.Search in Google Scholar PubMed

71. Raja, P.; Revathi, S.; Ghatak, T. Recent Advances of Imidazolin-2-Iminato in Transition Metal Chemistry. Eng. Sci. 2020, 12, 23–37.Search in Google Scholar

72. Tschernuth, F. S.; Hanusch, F.; Szilvási, T.; Inoue, S. Isolation and Reactivity of Chlorotetryliumylidenes Using a Bidentate Bis (N-Heterocyclic Imine) Ligand. Organometallics 2020, 39, 4265–4272; https://doi.org/10.1021/acs.organomet.0c00320.Search in Google Scholar

73. Park, M.; Schmidt, C.; Türck, S.; Hanusch, F.; Hirmer, S. V.; Ott, I.; Casini, A.; Inoue, S. Potent Anticancer Activity of a Dinuclear Gold (I) bis‐N‐Heterocyclic Imine Complex Related to Thioredoxin Reductase Inhibition In Vitro. ChemPlusChem 2024, 89, e202300557; https://doi.org/10.1002/cplu.202300557.Search in Google Scholar PubMed

74. Belza, J.; Trávníček, Z.; Vančo, J.; Čajan, M.; Hošek, J.; Dvořák, Z. Gold(I) N-Heterocyclic Carbene Complexes with 7-Azaindoles Demonstrates In Vitro Antiproliferative Effects on Ovarian Cancer Cells and Anti-inflammatory Activity. Organometallics. 2024, 43, 1155–1164; https://doi.org/10.1021/acs.organomet.4c00093.Search in Google Scholar

75. Trávníček, Z.; Vančo, J.; Čajan, M.; Belza, J.; Popa, I.; Hošek, J.; Lenobel, R.; Dvořák, Z. Gold (I) N‐heterocyclic Carbene (NHC) Complexes Containing 6‐mercaptopurine Derivatives and Their In Vitro Anticancer and Anti‐inflammatory Effects. Appl. Organomet. Chem. 2024, 38, e7401; https://doi.org/10.1002/aoc.7401.Search in Google Scholar

76. Adokoh, C. K. Therapeutic Potential of Dithiocarbamate Supported Gold Compounds. RSC Adv. 2020, 10, 2975–2988; https://doi.org/10.1039/c9ra09682e.Search in Google Scholar PubMed PubMed Central

77. Xu, S. D.; Wu, X. H. Bimetallic DppfM (II)(M= Pt and Pd) Dithiocarbamate Complexes: Synthesis, Characterization, and Anticancer Activity. J. Chem. Res. 2019, 43, 437–442; https://doi.org/10.1177/1747519819871029.Search in Google Scholar

78. Altaf, M.; Monim-ul-Mehboob, M.; Seliman, A. A.; Isab, A. A.; Dhuna, V.; Bhatia, G.; Dhuna, K. Synthesis, X-Ray Structures, Spectroscopic Analysis and Anticancer Activity of Novel Gold (I) Carbene Complexes. J. Organomet. Chem. 2014, 765, 68–79; https://doi.org/10.1016/j.jorganchem.2014.04.029.Search in Google Scholar

79. Zhang, J. J.; Abu el Maaty, M. A.; Hoffmeister, H.; Schmidt, C.; Muenzner, J. K.; Schobert, R.; Wölfl, S.; Ott, I. A Multitarget Gold (I) Complex Induces Cytotoxicity Related to Aneuploidy in HCT‐116 Colorectal Carcinoma Cells. Angew. Chem. Int. Ed. 2020, 59, 16795–16800; https://doi.org/10.1002/anie.202006212.Search in Google Scholar PubMed PubMed Central

80. Andermark, V.; Göke, K.; Kokoschka, M.; El Maaty, M. A. A.; Lum, C. T.; Zou, T.; Sun, R. W.-Y.; Aguiló, E.; Oehninger, L.; Rodríguez, L.; Bunjes, H.; Wölfl, S.; Che, C. M.; Ott, I. Alkynyl Gold (I) Phosphane Complexes: Evaluation of Structure–Activity-Relationships for the Phosphane Ligands, Effects on Key Signaling Proteins and Preliminary In-Vivo Studies with a Nanoformulated Complex. J. Inorg. Biochem. 2016, 160, 140–148; https://doi.org/10.1016/j.jinorgbio.2015.12.020.Search in Google Scholar PubMed

81. Chen, Q. M.; Chen, Y.; Wu, X. H. Synthesis and Antitumor Activity of Novel Alkynyl (Phosphine) Digold (I) Complexes. Transit. Met. Chem. 2021, 46, 495–501; https://doi.org/10.1007/s11243-021-00467-3.Search in Google Scholar

82. Lei, Y.; Li, H.-X.; Jin, W.-S.; Peng, W.-R.; Zhang, C.-J.; Bu, L.-J.; Du, Y.-Y.; Ma, T.; Sun, G.-P. The Radiosensitizing Effect of Paeonol on Lung Adenocarcinoma by Augmentation of Radiation-Induced Apoptosis and Inhibition of the PI3K/Akt Pathway. Int. J. Radiat. Biol. 2013, 89, 1079–1086; https://doi.org/10.3109/09553002.2013.825058.Search in Google Scholar PubMed

83. Himaya, S.; Ryu, B.; Qian, Z.-J.; Kim, S.-K. Paeonol from Hippocampus kuda Bleeler Suppressed the Neuro-Inflammatory Responses In Vitro via NF-Κb and MAPK Signaling Pathways. Toxicol. Vitro 2012, 26, 878–887; https://doi.org/10.1016/j.tiv.2012.04.022.Search in Google Scholar PubMed

84. Meyer, A.; Oehninger, L.; Geldmacher, Y.; Alborzinia, H.; Wölfl, S.; Sheldrick, W. S.; Ott, I. Gold (I) N‐heterocyclic Carbene Complexes with Naphthalimide Ligands as Combined Thioredoxin Reductase Inhibitors and DNA Intercalators. ChemMedChem 2014, 9, 1794–1800; https://doi.org/10.1002/cmdc.201402049.Search in Google Scholar PubMed

85. Chen, Q. M.; Zeng, Y.; Zhang, M. R.; Jin, L.; Zhou, P.; Wu, X. H.; Ren, W. X. Synthesis and Antitumor Activity of Gold (I) N-Heterocyclic Carbene with Dithiocarbamate and Alkynyl Complexes. Inorg. Chim. Acta. 2024, 568, 122085; https://doi.org/10.1016/j.ica.2024.122085.Search in Google Scholar

86. Zhang, J.; Zou, H.; Lei, J.; He, B.; He, X.; Sung, H. H.; Kwok, R. T.; Lam, J. W.; Zheng, L.; Tang, B. Z. Multifunctional AuI‐based AIEgens: Manipulating Molecular Structures and Boosting Specific Cancer Cell Imaging and Theranostics. Angew. Chem. Int. Ed. 2020, 59, 7097–7105; https://doi.org/10.1002/anie.202000048.Search in Google Scholar PubMed

87. Ma, X.; Zhao, Y.; Caligiuri, I.; Rizzolio, F.; Pozsoni, N. B.; Van Hecke, K.; Scattolin, T.; Nolan, S. P. Dinuclear NHC–Gold (I)–thiolato And–Alkynyl Complexes: Synthesis, Anticancer Activity, and Catalytic Activity in Lactonization Reactions. Dalton Trans. 2024, 53, 7939–7945; https://doi.org/10.1039/d4dt00890a.Search in Google Scholar PubMed

88. Safir Filho, M.; Scattolin, T.; Dao, P.; Tzouras, N. V.; Benhida, R.; Saab, M.; Van Hecke, K.; Lippmann, P.; Martin, A. R.; Ott, I.; Nolan, S. P. Straightforward Synthetic Route to Gold (I)-thiolato Glycoconjugate Complexes Bearing NHC Ligands (NHC= N-Heterocyclic Carbene) and Their Promising Anticancer Activity. New J. Chem. 2021, 45, 9995–10001; https://doi.org/10.1039/d1nj02117f.Search in Google Scholar

89. Gulzar, S.; Abid, Z.; Ashraf, R. S.; Sher, M.; Isab, A. A.; Altaf, M. Synthesis, Characterization and In Vitro Cytotoxicity of Au (I) Carbene Complexes. Inorg. Chem. Commun. 2023, 148, 110351; https://doi.org/10.1016/j.inoche.2022.110351.Search in Google Scholar

90. Seliman, A. A.; Altaf, M.; Odewunmi, N. A.; Kawde, A.-N.; Zierkiewicz, W.; Ahmad, S.; Altuwaijri, S.; Isab, A. A. Synthesis, X-Ray Structure, DFT Calculations and Anticancer Activity of a Selenourea Coordinated Gold (I)-carbene Complex. Polyhedron 2017, 137, 197–206; https://doi.org/10.1016/j.poly.2017.08.003.Search in Google Scholar

91. Al-Maythalony, B. A.; Monim-ul-Mehboob, M.; Altaf, M.; Wazeer, M. I.; Isab, A. A.; Altuwaijri, S.; Ahmed, A.; Dhuna, V.; Bhatia, G.; Dhuna, K.; Kamboj, S. S. Some New [(thione) 2Au (Diamine)] Cl3 Complexes: Synthesis, Spectroscopic Characterization, Computational and In Vitro Cytotoxic Studies. Spectrochim. Acta Mol. Biomol. Spectrosc. 2013, 115, 641–647; https://doi.org/10.1016/j.saa.2013.06.086.Search in Google Scholar PubMed

92. Seliman, A. A.; Altaf, M.; Onawole, A. T.; Al-Saadi, A.; Ahmad, S.; Alhoshani, A.; Bhatia, G.; Isab, A. A. Synthesis, X-Ray Structure and Cytotoxicity Evaluation of Carbene-Based Gold (I) Complexes of Selenones. Inorg. Chim. Acta. 2018, 476, 46–53; https://doi.org/10.1016/j.ica.2018.01.032.Search in Google Scholar

93. Seliman, A. A.; Altaf, M.; Onawole, A. T.; Ahmad, S.; Ahmed, M. Y.; Al-Saadi, A. A.; Altuwaijri, S.; Bhatia, G.; Singh, J.; Isab, A. A. Synthesis, X-Ray Structures and Anticancer Activity of Gold (I)-carbene Complexes with Selenones as Co-ligands and Their Molecular Docking Studies with Thioredoxin Reductase. J. Organomet. Chem. 2017, 848, 175–183; https://doi.org/10.1016/j.jorganchem.2017.07.034.Search in Google Scholar

94. Gulzar, S.; Ammara, U.; Abid, Z.; Shahid, M.; Ashraf, R. S.; Baig, N.; Kawde, A.-N.; Bhatia, G.; Isab, A. A.; Altaf, M. Synthesis, In Vitro Anticancer Activity and Reactions with Biomolecule of Gold (I)-NHC Carbene Complexes. J. Mol. Struct. 2022, 1255, 132482; https://doi.org/10.1016/j.molstruc.2022.132482.Search in Google Scholar

95. Yang, M.; Li, J.; Chen, P. R. Transition Metal-Mediated Bioorthogonal Protein Chemistry in Living Cells. Chem. Soc. Rev. 2014, 43, 6511–6526; https://doi.org/10.1039/c4cs00117f.Search in Google Scholar PubMed

96. Völker, T.; Meggers, E. Transition-metal-mediated Uncaging in Living Human Cells—An Emerging Alternative to Photolabile Protecting Groups. Curr. Opin. Chem. Biol. 2015, 25, 48–54; https://doi.org/10.1016/j.cbpa.2014.12.021.Search in Google Scholar PubMed

97. Clavadetscher, J.; Hoffmann, S.; Lilienkampf, A.; Mackay, L.; Yusop, R. M.; Rider, S. A.; Mullins, J. J.; Bradley, M. Copper Catalysis in Living Systems and In Situ Drug Synthesis. Angew. Chem. 2016, 128, 15891–15895; https://doi.org/10.1002/ange.201609837.Search in Google Scholar

98. Clavadetscher, J.; Indrigo, E.; Chankeshwara, S. V.; Lilienkampf, A.; Bradley, M. In‐Cell Dual Drug Synthesis by Cancer‐Targeting Palladium Catalysts. Angew. Chem. 2017, 129, 6968–6972; https://doi.org/10.1002/ange.201702404.Search in Google Scholar

99. Weiss, J. T.; Dawson, J. C.; Macleod, K. G.; Rybski, W.; Fraser, C.; Torres-Sánchez, C.; Patton, E. E.; Bradley, M.; Carragher, N. O.; Unciti-Broceta, A. Extracellular Palladium-Catalysed Dealkylation of 5-Fluoro-1-Propargyl-Uracil as a Bioorthogonally Activated Prodrug Approach. Nat. Commun. 2014, 5, 3277; https://doi.org/10.1038/ncomms4277.Search in Google Scholar PubMed PubMed Central

100. Zafar, A.; Takeda, C.; Manzoor, A.; Tanaka, D.; Kobayashi, M.; Wadayama, Y.; Nakane, D.; Majeed, A.; Iqbal, M. A.; Akitsu, T. Towards Industrially Important Applications of Enhanced Organic Reactions by Microfluidic Systems. Molecules 2024, 29, 398; https://doi.org/10.3390/molecules29020398.Search in Google Scholar PubMed PubMed Central

101. Hirner, J. J.; Shi, Y.; Blum, S. A. Organogold Reactivity with Palladium, Nickel, and Rhodium: Transmetalation, Cross-Coupling, and Dual Catalysis. Accounts Chem. Res. 2011, 44, 603–613; https://doi.org/10.1021/ar200055y.Search in Google Scholar PubMed

102. Khairul, W. M.; Fox, M. A.; Zaitseva, N. N.; Gaudio, M.; Yufit, D. S.; Skelton, B. W.; White, A. H.; Howard, J. A.; Bruce, M. I.; Low, P. J. Transition Metal Alkynyl Complexes by Transmetallation from Au (C [triple Bond, Length as M-Dash] CAr)(PPh 3)(Ar= C 6 H 5 or C 6 H 4 Me-4). Dalton Trans. 2009, 610–620; https://doi.org/10.1039/b809960j.Search in Google Scholar PubMed

103. Zafar, A.; Mawat, T. H.; Atiyah, E. M.; Adnan Iqbal, M.; Majeed, A.; Iram, G.; Qureshi, R.; Khalid, S. Synthesis of Group IIB and IVB Metal Complexes of 3‐Nitroaniline for Photocatalytic Degradation of Organic Dyes. ChemistrySelect 2024, 9, e202304566; https://doi.org/10.1002/slct.202304566.Search in Google Scholar

104. Long, Y.; Cao, B.; Xiong, X.; Chan, A. S.; Sun, R. W. Y.; Zou, T. Bioorthogonal Activation of Dual Catalytic and Anti‐cancer Activities of Organogold (I) Complexes in Living Systems. Angew. Chem. Int. Ed. 2021, 60, 4133–4141; https://doi.org/10.1002/anie.202013366.Search in Google Scholar PubMed

105. Montresor, A.; Mupfasoni, D.; Mikhailov, A.; Mwinzi, P.; Lucianez, A.; Jamsheed, M.; Gasimov, E.; Warusavithana, S.; Yajima, A.; Bisoffi, Z.; Buonfrate, D.; Steinmann, P.; Utzinger, J.; Levecke, B.; Vlaminck, J.; Cools, P.; Vercruysse, J.; Cringoli, G.; Rinaldi, L.; Blouin, B.; Gyorkos, T. W. The Global Progress of Soil-Transmitted Helminthiases Control in 2020 and World Health Organization Targets for 2030. PLoS Neglected Trop. Dis. 2020, 14, e0008505; https://doi.org/10.1371/journal.pntd.0008505.Search in Google Scholar PubMed PubMed Central

106. Wong, Y. K.; Xu, C.; Kalesh, K. A.; He, Y.; Lin, Q.; Wong, W. F.; Shen, H. M.; Wang, J. Artemisinin as an Anticancer Drug: Recent Advances in Target Profiling and Mechanisms of Action. Med. Res. Rev. 2017, 37, 1492–1517; https://doi.org/10.1002/med.21446.Search in Google Scholar PubMed

107. Efferth, T. Beyond Malaria: The Inhibition of Viruses by Artemisinin-type Compounds. Biotechnol. Adv. 2018, 36, 1730–1737; https://doi.org/10.1016/j.biotechadv.2018.01.001.Search in Google Scholar PubMed

108. Zhang, C. J.; Wang, J.; Zhang, J.; Lee, Y. M.; Feng, G.; Lim, T. K.; Shen, H. M.; Lin, Q.; Liu, B. Mechanism‐guided Design and Synthesis of a Mitochondria‐targeting Artemisinin Analogue with Enhanced Anticancer Activity. Angew. Chem. Int. Ed. 2016, 55, 13770–13774; https://doi.org/10.1002/anie.201607303.Search in Google Scholar PubMed

109. Ooko, E.; Saeed, M. E.; Kadioglu, O.; Sarvi, S.; Colak, M.; Elmasaoudi, K.; Janah, R.; Greten, H. J.; Efferth, T. Artemisinin Derivatives Induce Iron-dependent Cell Death (Ferroptosis) in Tumor Cells. Phytomedicine 2015, 22, 1045–1054; https://doi.org/10.1016/j.phymed.2015.08.002.Search in Google Scholar PubMed

110. Porchia, M.; Pellei, M.; Marinelli, M.; Tisato, F.; Del Bello, F.; Santini, C. New Insights in Au-NHCs Complexes as Anticancer Agents. Eur. J. Med. Chem. 2018, 146, 709–746; https://doi.org/10.1016/j.ejmech.2018.01.065.Search in Google Scholar PubMed

111. Zhang, C.; Maddelein, M.-L.; Sun, R. W.-Y.; Gornitzka, H.; Cuvillier, O.; Hemmert, C. Pharmacomodulation on Gold-NHC Complexes for Anticancer Applications–Is Lipophilicity the Key Point? Eur. J. Med. Chem. 2018, 157, 320–332; https://doi.org/10.1016/j.ejmech.2018.07.070.Search in Google Scholar PubMed

112. Ikeda, M.; Morizane, C.; Ueno, M.; Okusaka, T.; Ishii, H.; Furuse, J. Chemotherapy for Hepatocellular Carcinoma: Current Status and Future Perspectives. Jpn. J. Clin. Oncol. 2018, 48, 103–114; https://doi.org/10.1093/jjco/hyx180.Search in Google Scholar PubMed

113. Zhang, C.; Fortin, P. Y.; Barnoin, G.; Qin, X.; Wang, X.; Fernandez Alvarez, A.; Bijani, C.; Maddelein, M. L.; Hemmert, C.; Cuvillier, O.; Gornitzka, H. An Artemisinin‐Derivative–(NHC) Gold (I) Hybrid with Enhanced Cytotoxicity through Inhibition of NRF2 Transcriptional Activity. Angew. Chem. Int. Ed. 2020, 59, 12062–12068; https://doi.org/10.1002/anie.202002992.Search in Google Scholar PubMed

114. Guarra, F.; Busto, N.; Guerri, A.; Marchetti, L.; Marzo, T.; García, B.; Biver, T.; Gabbiani, C. Cytotoxic Ag (I) and Au (I) NHC-Carbenes Bind DNA and Show TrxR Inhibition. J. Inorg. Biochem. 2020, 205, 110998; https://doi.org/10.1016/j.jinorgbio.2020.110998.Search in Google Scholar PubMed

115. Scattolin, T.; Tzouras, N. V.; Falivene, L.; Cavallo, L.; Nolan, S. P. Using Sodium Acetate for the Synthesis of [Au (NHC) X] Complexes. Dalton Trans. 2020, 49, 9694–9700; https://doi.org/10.1039/d0dt02240c.Search in Google Scholar PubMed

116. Scattolin, T.; Lippmann, P.; Beliš, M.; Van Hecke, K.; Ott, I.; Nolan, S. P. A Simple Synthetic Entryway into (N‐heterocyclic Carbene) Gold‐steroidyl Complexes and Their Anticancer Activity. Appl. Organomet. Chem. 2022, e6624; https://doi.org/10.1002/aoc.6624.Search in Google Scholar

117. Jazzar, R.; Dewhurst, R. D.; Bourg, J.-B.; Donnadieu, B.; Canac, Y.; Bertrand, G. Intramolecular “Hydroiminiumation” of Alkenes: Application to the Synthesis of Conjugate Acids of Cyclic Alkyl Amino Carbenes (CAACs). Angew. Chem. 2007, 46, 2899; https://doi.org/10.1002/anie.200605083.Search in Google Scholar PubMed PubMed Central

118. Zeng, X.; Frey, G. D.; Kinjo, R.; Donnadieu, B.; Bertrand, G. Synthesis of a Simplified Version of Stable Bulky and Rigid Cyclic (Alkyl)(amino) Carbenes, and Catalytic Activity of the Ensuing Gold (I) Complex in the Three-Component Preparation of 1, 2-dihydroquinoline Derivatives. J. Am. Chem. Soc. 2009, 131, 8690–8696; https://doi.org/10.1021/ja902051m.Search in Google Scholar PubMed PubMed Central

119. Melaimi, M.; Soleilhavoup, M.; Bertrand, G. Stable Cyclic Carbenes and Related Species beyond Diaminocarbenes. Angew. Chem. Int. Ed. 2010, 49, 8810–8849; https://doi.org/10.1002/anie.201000165.Search in Google Scholar PubMed PubMed Central

120. Lavallo, V.; Canac, Y.; Donnadieu, B.; Schoeller, W. W.; Bertrand, G. CO Fixation to Stable Acyclic and Cyclic Alkyl Amino Carbenes: Stable Amino Ketenes with a Small HOMO–LUMO Gap. Angew. Chem. 2006, 45, 3488; https://doi.org/10.1002/anie.200600987.Search in Google Scholar PubMed PubMed Central

121. Jin, L.; Tolentino, D. R.; Melaimi, M.; Bertrand, G. Isolation of Bis (Copper) Key Intermediates in Cu-Catalyzed Azide-Alkyne “Click Reaction”. Sci. Adv. 2015, 1, e1500304; https://doi.org/10.1126/sciadv.1500304.Search in Google Scholar PubMed PubMed Central

122. Doddi, A.; Peters, M.; Tamm, M. N-Heterocyclic Carbene Adducts of Main Group Elements and Their Use as Ligands in Transition Metal Chemistry. Chem. Rev. 2019, 119, 6994–7112; https://doi.org/10.1021/acs.chemrev.8b00791.Search in Google Scholar PubMed

123. Weinberger, D. S.; Melaimi, M.; Moore, C. E.; Rheingold, A. L.; Frenking, G.; Jerabek, P.; Bertrand, G. Isolierung neutraler mono-und dinuklearer Goldkomplexe von cyclischen Alkyl (amino) carbenen. Angew. Chem. 2013, 125; https://doi.org/10.1002/ange.201304820.Search in Google Scholar

124. Marx, V. M.; Sullivan, A. H.; Melaimi, M.; Virgil, S. C.; Keitz, B. K.; Weinberger, D. S.; Bertrand, G.; Grubbs, R. H. Cyclic Alkyl Amino Carbene (CAAC) Ruthenium Complexes as Remarkably Active Catalysts for Ethenolysis. Angew. Chem. Int. Ed. 2015, 54, 1919–1923; https://doi.org/10.1002/anie.201410797.Search in Google Scholar PubMed PubMed Central

125. Williams, M. R.; Bertrand, B.; Fernandez-Cestau, J.; Waller, Z. A.; O’Connell, M. A.; Searcey, M.; Bochmann, M. Acridine-decorated Cyclometallated Gold (III) Complexes: Synthesis and Anti-tumour Investigations. Dalton Trans. 2018, 47, 13523–13534; https://doi.org/10.1039/c8dt02507j.Search in Google Scholar PubMed

126. Berners-Price, S. J.; Filipovska, A. The Design of Gold-Based, Mitochondria-Targeted Chemotherapeutics. Aust. J. Chem. 2008, 61, 661–668; https://doi.org/10.1071/ch08175.Search in Google Scholar

127. Proetto, M. T.; Alexander, K.; Melaimi, M.; Bertrand, G.; Gianneschi, N. C. Cyclic (Alkyl)(amino) Carbene (CAAC) Gold (I) Complexes as Chemotherapeutic Agents. Chem. Eur. J. 2021, 27, 3772–3778; https://doi.org/10.1002/chem.202004317.Search in Google Scholar PubMed

128. Bertrand, B.; Romanov, A. S.; Brooks, M.; Davis, J.; Schmidt, C.; Ott, I.; O’Connell, M.; Bochmann, M. Synthesis, Structure and Cytotoxicity of Cyclic (Alkyl)(amino) Carbene and Acyclic Carbene Complexes of Group 11 Metals. Dalton Trans. 2017, 46, 15875–15887; https://doi.org/10.1039/c7dt03189k.Search in Google Scholar PubMed

129. Bresciani, G.; Biancalana, L.; Pampaloni, G.; Marchetti, F. Recent Advances in the Chemistry of Metal Carbamates. Molecules 2020, 25, 3603; https://doi.org/10.3390/molecules25163603.Search in Google Scholar PubMed PubMed Central

130. Dell’Amico, D. B.; Calderazzo, F.; Labella, L.; Marchetti, F.; Pampaloni, G. Converting Carbon Dioxide into Carbamato Derivatives. Chem. Rev. 2003, 103, 3857–3898; https://doi.org/10.1021/cr940266m.Search in Google Scholar PubMed

131. Babu, T.; Sarkar, A.; Karmakar, S.; Schmidt, C.; Gibson, D. Multiaction Pt (IV) Carbamate Complexes Can Codeliver Pt (II) Drugs and Amine Containing Bioactive Molecules. Inorg. Chem. 2020, 59, 5182–5193; https://doi.org/10.1021/acs.inorgchem.0c00445.Search in Google Scholar PubMed

132. Singh, N.; Gupta, A.; Prasad, P.; Mahawar, P.; Gupta, S.; Sasmal, P. K. Iridium-triggered Allylcarbamate Uncaging in Living Cells. Inorg. Chem. 2021, 60, 12644–12650; https://doi.org/10.1021/acs.inorgchem.1c01790.Search in Google Scholar PubMed

133. Ghosh, A. K.; Brindisi, M. Organic Carbamates in Drug Design and Medicinal Chemistry. J. Med. Chem. 2015, 58, 2895–2940; https://doi.org/10.1021/jm501371s.Search in Google Scholar PubMed PubMed Central

134. Bresciani, G.; Busto, N.; Ceccherini, V.; Bortoluzzi, M.; Pampaloni, G.; Garcia, B.; Marchetti, F. Screening the Biological Properties of Transition Metal Carbamates Reveals Gold (I) and Silver (I) Complexes as Potent Cytotoxic and Antimicrobial Agents. J. Inorg. Biochem. 2022, 227, 111667; https://doi.org/10.1016/j.jinorgbio.2021.111667.Search in Google Scholar PubMed

135. Melounková, L.; Machálková, A.; Havelek, R.; Honzíček, J.; Řezáčová, M.; Císařová, I.; Peterová, E.; Vinklárek, J. Vanadocene Complexes Bearing N, N′-chelating Ligands: Synthesis, Structures and In Vitro Cytotoxic Studies on the A549 Lung Adenocarcinoma Cell Line. J. Inorg. Biochem. 2019, 195, 182–193; https://doi.org/10.1016/j.jinorgbio.2019.03.015.Search in Google Scholar PubMed

136. Chrysouli, M.; Banti, C.; Kourkoumelis, N.; Panayiotou, N.; Markopoulos, G.; Tasiopoulos, A. J.; Hadjikakou, S. Chloro (Triphenylphosphine) Gold (I) a Forefront Reagent in Gold Chemistry as Apoptotic Agent for Cancer Cells. J. Inorg. Biochem. 2018, 179, 107–120; https://doi.org/10.1016/j.jinorgbio.2017.11.004.Search in Google Scholar PubMed

137. Gutiérrez, A.; Gracia-Fleta, L.; Marzo, I.; Cativiela, C.; Laguna, A.; Gimeno, M. C. Gold (I) Thiolates Containing Amino Acid Moieties. Cytotoxicity and Structure–Activity Relationship Studies. Dalton Trans. 2014, 43, 17054–17066; https://doi.org/10.1039/c4dt02299h.Search in Google Scholar PubMed

138. Sulaiman, A. A.; Ahmad, S.; Hashimi, S. M.; Alqosaibi, A. I.; Peedikakkal, A. M. P.; Alhoshani, A.; Alsaleh, N. B.; Isab, A. A. Novel Dinuclear Gold (I) Complexes Containing Bis (Diphenylphosphano) Alkanes and (Biphenyl-2-yl)(di-tert-butyl) Phosphane: Synthesis, Structural Characterization and Anticancer Activity. New J. Chem. 2022, 46, 16821–16831; https://doi.org/10.1039/d2nj01680j.Search in Google Scholar

139. Abogosh, A. K.; Alghanem, M. K.; Ahmad, S.; Al-Asmari, A.; Sobeai, H. M. A.; Sulaiman, A. A.; Fettouhi, M.; Popoola, S. A.; Alhoshani, A.; Isab, A. A. A Novel Cyclic Dinuclear Gold (I) Complex Induces Anticancer Activity via an Oxidative Stress-Mediated Intrinsic Apoptotic Pathway in MDA-MB-231 Cancer Cells. Dalton Trans. 2022, 51, 2760–2769; https://doi.org/10.1039/d1dt03546k.Search in Google Scholar PubMed

140. Mirzadeh, N.; Reddy, T. S.; Bhargava, S. K. Advances in Diphosphine Ligand-Containing Gold Complexes as Anticancer Agents. Coord. Chem. Rev. 2019, 388, 343–359; https://doi.org/10.1016/j.ccr.2019.02.027.Search in Google Scholar

141. Rao, S. R. T. P. S.; Privér, S. H.; Rao, V. V.; Mirzadeh, N.; Bhargava, S. K. And Gold (III) Phosphine Complexes: Synthesis, Anticancer Activities towards 2D and 3D Cancer Models, and Apoptosis Inducing Properties. Dalton Trans. 2018, 47, 15312–15323; https://doi.org/10.1039/c8dt01724g.Search in Google Scholar PubMed

142. Casagrande, N.; Borghese, C.; Corona, G.; Aldinucci, D.; Altaf, M.; Sulaiman, A. A.; Isab, A. A.; Ahmad, S.; Peedikakkal, A. M. P. Dinuclear Gold (I) Complexes Based on Carbene and Diphosphane Ligands: Bis [2-(dicyclohexylphosphano) Ethyl] Amine Complex Inhibits the Proteasome Activity, Decreases Stem Cell Markers and Spheroid Viability in Lung Cancer Cells. JBIC, J. Biol. Inorg. Chem. 2023, 28, 751–766; https://doi.org/10.1007/s00775-023-02025-x.Search in Google Scholar PubMed

143. Xu, X.; Dai, F.; Mao, Y.; Zhang, K.; Qin, Y.; Zheng, J. J. F. i. P. Metallodrugs in the Battle against Non-small Cell Lung Cancer: Unlocking the Potential for Improved Therapeutic Outcomes. Front. Pharmacol. 2023, 14, 1242488; https://doi.org/10.3389/fphar.2023.1242488.Search in Google Scholar PubMed PubMed Central

Received: 2024-08-19
Accepted: 2024-11-08
Published Online: 2024-11-26
Published in Print: 2025-09-25

© 2025 the author(s), published by De Gruyter, Berlin/Boston

This work is licensed under the Creative Commons Attribution 4.0 International License.

Articles in the same Issue

  1. Frontmatter
  2. Advancements in CNT-based materials for optimized pharmaceutical removal via adsorption and photocatalysis
  3. Review on removal of heavy metals from industrial effluents by adsorption
  4. Cutting-edge techniques in low-temperature electrochemical water splitting: advancements in hydrogen production
  5. Biological activities of metal complexes with Schiff base
  6. Potential of organometallic complexes in medicinal chemistry
  7. Advancement in schiff base complexes for treatment of colon cancer
  8. Magnetic nanoparticles for efficient heavy metal removal: synthesis, adsorption capacity, and key experimental parameters
  9. Coal-based carbon/graphene quantum dots: formation mechanisms and applications
  10. Advancements in transition metal-catalyzed 1,2,3-triazole synthesis via azide–alkyne cycloaddition
  11. Gold complexes: a new frontier in the battle against lung cancer
https://doi.org/10.1515/revic-2024-0077
Keywords for this article
gold-NHC; Au complexes; lung cancer; auranofin; anticancer agents
Creative Commons
BY 4.0

Articles in the same Issue

  1. Frontmatter
  2. Advancements in CNT-based materials for optimized pharmaceutical removal via adsorption and photocatalysis
  3. Review on removal of heavy metals from industrial effluents by adsorption
  4. Cutting-edge techniques in low-temperature electrochemical water splitting: advancements in hydrogen production
  5. Biological activities of metal complexes with Schiff base
  6. Potential of organometallic complexes in medicinal chemistry
  7. Advancement in schiff base complexes for treatment of colon cancer
  8. Magnetic nanoparticles for efficient heavy metal removal: synthesis, adsorption capacity, and key experimental parameters
  9. Coal-based carbon/graphene quantum dots: formation mechanisms and applications
  10. Advancements in transition metal-catalyzed 1,2,3-triazole synthesis via azide–alkyne cycloaddition
  11. Gold complexes: a new frontier in the battle against lung cancer
Sign up now to receive a 20% welcome discount
Institutional Access
How does access work?
Have an idea on how to improve our website?
Please write us.
© 2025 De Gruyter Brill
Downloaded on 8.9.2025 from https://www.degruyterbrill.com/document/doi/10.1515/revic-2024-0077/html
Scroll to top button