Using bio-orthogonally catalyzed lethality strategy to generate mitochondria-targeting anti-tumor metallodrugs in vitro and in vivo

Abstract

Synthetic lethality was proposed nearly a century ago by geneticists and recently applied to develop precision anticancer therapies. To exploit the synthetic lethality concept in the design of chemical anticancer agents, we developed a bioorthogonally catalyzed lethality (BCL) strategy to generate targeting antitumor metallodrugs both in vitro and in vivo. Metallodrug Ru-rhein was generated from two nontoxic species Ru-N3 and rhein-alkyne via exclusive endogenous copper-catalyzed azide alkyne cycloaddition (CuAAC) reaction without the need of an external copper catalyst. The nontoxic species Ru-arene complex Ru-N3 and rhein-alkyne were designed to perform this strategy, and the mitochondrial targeting product Ru-rhein was generated in high yield (> 83%) and showed high antitumor efficacy in vitro. This BCL strategy achieved a remarkable tumor suppression effect on the tumor-bearing mice models. It is interesting that the combination of metal-arene complexes with rhein via CuAAC reaction could transform two nontoxic species into a targeting anticancer metallodrug both in vitro and in vivo, while the product Ru-rhein was nontoxic towards normal cells. This is the first example that exclusive endogenous copper was used to generate metal-based anticancer drugs for cancer treatment. The anticancer mechanism of Ru-rhein was studied and autophagy was induced by increased reactive oxygen species and mitochondrial damage. The generality of this BCL strategy was also studied and it could be extended to other metal complexes such as Os-arene and Ir-arene complexes. Compared with the traditional methods for cancer treatment, this work presented a new approach to generate targeting metallodrugs in vivo via the BCL strategy from nontoxic species in the metal-based chemotherapy.

A Rhein‐Based Rh(III) Arene Complex with Anti‐tumor Cell Proliferative Activity Inhibits RNA Demethylase FTO

“…[ 17 ] Other metal complexes tended to locate in mitochondria and induced caspase‐dependent apoptosis by mitochondrial damage, cellular ATP depletion, mitochondrial respiratory inhibition, and elevated production of reactive oxygen species (ROS). [ 18‐19 ] Furthermore, some metal complexes escaped and migrated to other organelles once stimulated by photoirradiation to produce ROS. [ 20 ] Therefore, such targeted luminescent metal complexes provide a structural foundation for the further design and optimization of metallodrugs.…”

The Chemical and Pharmacological Research Progress on a Kind of Chinese Herbal Medicine, Fructus Malvae

“…They have all been verified at the cellular level. Splenocytes, natural killer (NK) cells, human liver cancer cells (HepG2) [ 77 ], human gastric cancer cells (AGS), human colorectal cancer cells (HCT) and human non-small-cell lung cancer calls (A549) [ 77 , 78 ] were selected as the experimental models to verify the anti-tumor activity of Fructus Malvae. Splenocyte proliferation ability, natural killer (NK) cell activity, AGS cell apoptosis percentage, and the expression of the apoptosis proteins PARP, Cleaved APRP, Caspase-3, Cleaved Caspase-3, Bcl-2, Bax, β-actin, etc.…”

Boosting Endogenous Copper(I) for Biologically Safe and Efficient Bioorthogonal Catalysis via Self-Adaptive Metal–Organic Frameworks

“…37−39 Instead of introducing exogenous Cu, copper ions in cancer cells were used as a catalyst of CuAAC for the synthesis of an anti-tumor metallodrug. 40 However, recent studies have reported that oncogenes could drive the fluctuation of the intracellular glutathione metabolism, thus inducing a labile Cu(I) deficiency. 41 The intratumoral Cu(I) is far from sufficient to efficiently catalyze the CuAAC reaction.…”