Ein Multitarget‐Gold(I)‐Komplex induziert Zytotoxizität im Zusammenhang mit Aneuploidie in HCT‐116‐Kolorektalkarzinomzellen

Controllably activating the bio‐reactivity of metal complexes in living systems is challenging but highly desirable because it can minimize off‐target bindings and improve spatiotemporal specificity. Herein, we report a new bioorthogonal activation approach by employing Pd(II)‐triggered transmetallation reactions to conditionally activate the bio‐reactivity of NHC–Au(I)–phenylacetylide complexes (1 a) in vitro and in vivo. A combination of 1H NMR, LC‐MS, DFT calculation and fluorescence screening assays reveals that 1 a displays a reasonable stability against biological thiols, but its phenylacetylide ligand can be efficiently transferred to Pd(II), leading to in situ formation of labile NHC–Au(I) species that is catalytically active inside living cells and zebrafish, and can meanwhile effectively suppress the activity of thioredoxin reductase, potently inhibit the proliferation of cancer cells and efficiently suppress angiogenesis in zebrafish models.

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Bioorthogonal Activation of Dual Catalytic and Anti‐Cancer Activities of Organogold(I) Complexes in Living Systems

Long

Cao

Xiong

et al. 2020

Angewandte Chemie

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Interfering with Metabolic Profile of Triple‐Negative Breast Cancers Using Rationally Designed Metformin Prodrugs

et al. 2021

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Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer,c haracterized by an aberrant metabolic phenotype with high metastatic capacity, resulting in poor patient prognoses and low survival rates.W e designed as eries of novel Au III cyclometalated prodrugs of energy-disrupting Type II antidiabetic drugs namely,m etformin and phenformin. Prodrug activation and release of the metformin ligand was achieved by tuning the cyclometalated Au III fragment. The lead complex 3met was 6000-fold more cytotoxic compared to uncoordinated metformin and significantly reduced tumor burden in mice with aggressive breast cancers with lymphocytic infiltration into tumor tissues.These effects was ascribed to 3met interfering with energy production in TNBCs and inhibiting associated pro-survival responses to induce deadly metabolic catastrophe.

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Alkylgold(III) Complexes Undergo Unprecedented Photo‐Induced β‐Hydride Elimination and Reduction for Targeted Cancer Therapy

et al. 2022

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Spatiotemporally controllable activation of prodrugs within tumors is highly desirable for cancer therapy to minimize toxic side effects. Herein we report that stable alkylgold(III) complexes can undergo unprecedented photo‐induced β‐hydride elimination, releasing alkyl ligands and forming gold(III)‐hydride intermediates that could be quickly converted into bioactive [AuIII−S] adducts; meanwhile, the remaining alkylgold(III) complexes can photo‐catalytically reduce [AuIII−S] into more bioactive AuI species. Such photo‐reactivities make it possible to functionalize gold complexes on the auxiliary alkyl ligands without attenuating the metal–biomacromolecule interactions. As a result, the gold(III) complexes containing glucose‐functionalized alkyl ligands displayed efficient and tumor‐selective uptake; notably, after one‐ or two‐photon activation, the complexes exhibited high thioredoxin reductase (TrxR) inhibition, potent cytotoxicity, and strong antiangiogenesis and antitumor activities in vivo.

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Ein Multitarget‐Gold(I)‐Komplex induziert Zytotoxizität im Zusammenhang mit Aneuploidie in HCT‐116‐Kolorektalkarzinomzellen

Cited by 10 publications

References 41 publications

Bioorthogonal Activation of Dual Catalytic and Anti‐Cancer Activities of Organogold(I) Complexes in Living Systems

Bioorthogonal Activation of Dual Catalytic and Anti‐Cancer Activities of Organogold(I) Complexes in Living Systems

Interfering with Metabolic Profile of Triple‐Negative Breast Cancers Using Rationally Designed Metformin Prodrugs

Alkylgold(III) Complexes Undergo Unprecedented Photo‐Induced β‐Hydride Elimination and Reduction for Targeted Cancer Therapy

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