biostudies-literatureXue XNational Natural Science Foundation of ChinaChina Postdoctoral Science Foundationnwaa286https://www.ebi.ac.uk/biostudies/studies/S-EPMC8433091biostudies-literatureUnknown8(9)Synthetic lethality was proposed nearly a century ago by geneticists and recently applied to develop precision anti-cancer therapies. To exploit the synthetic lethality concept in the design of chemical anti-cancer agents, we developed a bio-orthogonally catalyzed lethality (BCL) strategy to generate targeting anti-tumor metallodrugs both <i>in vitro</i> and <i>in vivo.</i> Metallodrug Ru-rhein was generated from two non-toxic 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 non-toxic 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 (>National science reviewUsing bio-orthogonally catalyzed lethality strategy to generate mitochondria-targeting anti-tumor metallodrugs <i>in vitro</i> and <i>in vivo</i>.PMC84330912202570121731004218070602019M651874220770662177110921420102002Lv MQian YGuo ZQian CLiu HKDong JSu ZZhao JXue XTao QDai YfalseUsing bio-orthogonally catalyzed lethality strategy to generate mitochondria-targeting anti-tumor metallodrugs <i>in vitro</i> and <i>in vivo</i>.Synthetic lethality was proposed nearly a century ago by geneticists and recently applied to develop precision anti-cancer therapies. To exploit the synthetic lethality concept in the design of chemical anti-cancer agents, we developed a bio-orthogonally catalyzed lethality (BCL) strategy to generate targeting anti-tumor metallodrugs both <i>in vitro</i> and <i>in vivo.</i> Metallodrug Ru-rhein was generated from two non-toxic 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 non-toxic 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 (>2021-01-01T00:00:00Z2021 Sep2025-05-29T20:47:18.978Z2025-05-29T20:47:18.978ZS-EPMC84330913469172810.1093/nsr/nwaa286