Investigations of the reactivity, stability and biological activity of halido (NHC)gold(<scp>i</scp>) complexes

Goetzfried, Sina Katharina; Kapitza, Paul; Gallati, Caroline Marie; Nindl, Anna; Cziferszky, Monika; Hermann, Martin; Wurst, Klaus; Kircher, Brigitte; Gust, Ronald

doi:10.1039/d1dt03528b

Cited by 18 publications

(40 citation statements)

References 52 publications

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“…The coordination of 4-aminoquinoline CQ or AQ to gold(I) also has consequences for the mechanisms affecting thiol redox homeostasis, and it can be inferred by observing that [AuCQPQ]PF 6 (1) is more potent in inhibiting the enzymatic activity of flavoenzymes than [AuAQPQ]PF 6 (2). This supports the hypothesis that compound (1) is more prone to interact with flavoenzymes than compound (2); namely, [AuCQPQ]PF 6 (1) is liable to undergo a ligand exchange reaction [43,44] in the presence of flavoenzymes. While much work remains to be conducted to clearly define the gold(I) hybrids' effect on thiol redox homeostasis in parasite cells, we were intrigued to find that the metallic hybrids displayed selectivity for inhibiting Sec-TrxRs versus Cys-TrxR, indicating that the gold(I) compounds share some reactivity to interact with Sec-TrxR.…”

Section: Discussionmentioning

confidence: 53%

A Hybrid of Amodiaquine and Primaquine Linked by Gold(I) Is a Multistage Antimalarial Agent Targeting Heme Detoxification and Thiol Redox Homeostasis

et al. 2022

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Hybrid-based drugs linked through a transition metal constitute an emerging concept for Plasmodium intervention. To advance the drug design concept and enhance the therapeutic potential of this class of drugs, we developed a novel hybrid composed of quinolinic ligands amodiaquine (AQ) and primaquine (PQ) linked by gold(I), named [AuAQPQ]PF6. This compound demonstrated potent and efficacious antiplasmodial activity against multiple stages of the Plasmodium life cycle. The source of this activity was thoroughly investigated by comparing parasite susceptibility to the hybrid’s components, the annotation of structure–activity relationships and studies of the mechanism of action. The activity of [AuAQPQ]PF6 for the parasite’s asexual blood stages was influenced by the presence of AQ, while its activity against gametocytes and pre-erythrocytic parasites was influenced by both quinolinic components. Moreover, the coordination of ligands to gold(I) was found to be essential for the enhancement of potency, as suggested by the observation that a combination of quinolinic ligands does not reproduce the antimalarial potency and efficacy as observed for the metallic hybrid. Our results indicate that this gold(I) hybrid compound presents a dual mechanism of action by inhibiting the beta-hematin formation and enzymatic activity of thioredoxin reductases. Overall, our findings support the potential of transition metals as a dual chemical linker and an antiplasmodial payload for the development of hybrid-based drugs.

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Section: Discussionmentioning

confidence: 53%

A Hybrid of Amodiaquine and Primaquine Linked by Gold(I) Is a Multistage Antimalarial Agent Targeting Heme Detoxification and Thiol Redox Homeostasis

et al. 2022

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“…These results indicated that the bis-NHC–Au(I) complex had an obvious superiority in stability. The high cytotoxicity of this type of complex may be related to this …”

Section: Resultsmentioning

confidence: 99%

Tumor-Targeting NHC–Au(I) Complex Induces Immunogenic Cell Death in Hepatocellular Carcinoma

Bian

et al. 2023

J. Med. Chem.

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Immunogenic cell death (ICD) is a promising direction of cancer immunotherapy in hepatocellular carcinoma (HCC). A series of novel NHC–Au(I) complexes derived from 4,5-diarylimidazole, containing glycyrrhetinic acid (GA) as an efficient targeting ligand for HCC, were herein designed and synthesized. Among these, complex 4C exhibited excellent effectiveness for tumor targeting and antitumor activity, which induced the occurrence of ICD in HCC cells. Additionally, 4C can effectively inhibit TrxR enzyme activity, increase reactive oxygen species (ROS) expression, lead to redox homeostasis disorder, mediate mitochondrial dysfunction and endoplasmic reticulum stress (ERS), and cause the characteristic discharge of damage-associated molecular patterns (DAMPs) in HCC cells. More importantly, 4C showed a great ICD-inducing effect in a vaccination mouse model and activated antitumor immunity in a tumor-bearing C57BL/6 mouse model, which is consistent with the in vitro results. In conclusion, we found the potential of Au(I) complex with HCC-targeted capability for effective tumor immunotherapy.

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“…64 The reactivity observed in aqueous solvent mixtures was perfectly in line with the results reported for gold( i ) complexes. 5–7,65…”

Section: Resultsmentioning

confidence: 99%

“…64 The reactivity observed in aqueous solvent mixtures was perfectly in line with the results reported for gold(I) complexes. [5][6][7]65 In summary, compounds Au1-Au3 are stable in aqueous solvent mixtures with the retention of the NHC fragment. The equilibrium between the neutral halo-and the cationic dicarbene forms is dependent on the halide and the presence of water.…”

Section: Dalton Transactions Papermentioning

confidence: 93%

Halo complexes of gold(i) containing glycoconjugate carbene ligands: synthesis, characterization, cytotoxicity and interaction with proteins and DNA model systems

et al. 2022

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Investigations of the reactivity, stability and biological activity of halido (NHC)gold(i) complexes

Cited by 18 publications

References 52 publications

A Hybrid of Amodiaquine and Primaquine Linked by Gold(I) Is a Multistage Antimalarial Agent Targeting Heme Detoxification and Thiol Redox Homeostasis

A Hybrid of Amodiaquine and Primaquine Linked by Gold(I) Is a Multistage Antimalarial Agent Targeting Heme Detoxification and Thiol Redox Homeostasis

Tumor-Targeting NHC–Au(I) Complex Induces Immunogenic Cell Death in Hepatocellular Carcinoma

Halo complexes of gold(i) containing glycoconjugate carbene ligands: synthesis, characterization, cytotoxicity and interaction with proteins and DNA model systems

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