Platinum-triggered Bond-cleavage of Pentynoyl amide and N-propargyl handles for Drug-Activation - Archive ouverte HAL Accéder directement au contenu
Article Dans Une Revue Journal of the American Chemical Society Année : 2020

Platinum-triggered Bond-cleavage of Pentynoyl amide and N-propargyl handles for Drug-Activation

Résumé

The ability to create ways to control drug activation at specific tissues while sparing healthy tissues remains a major challenge. The administration of exogenous target-specific triggers offers the potential for traceless release of active drugs on tumor sites from antibody−drug conjugates (ADCs) and caged prodrugs. We have developed a metal-mediated bond-cleavage reaction that uses platinum complexes [K 2 PtCl 4 or Cisplatin (CisPt)] for drug activation. Key to the success of the reaction is a water-promoted activation process that triggers the reactivity of the platinum complexes. Under these conditions, the decaging of pentynoyl tertiary amides and N-propargyls occurs rapidly in aqueous systems. In cells, the protected analogues of cytotoxic drugs 5fluorouracil (5-FU) and monomethyl auristatin E (MMAE) are partially activated by nontoxic amounts of platinum salts. Additionally, a noninternalizing ADC built with a pentynoyl traceless linker that features a tertiary amide protected MMAE was also decaged in the presence of platinum salts for extracellular drug release in cancer cells. Finally, CisPt-mediated prodrug activation of a propargyl derivative of 5-FU was shown in a colorectal zebrafish xenograft model that led to significant reductions in tumor size. Overall, our results reveal a new metal-based cleavable reaction that expands the application of platinum complexes beyond those in catalysis and cancer therapy.
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Dates et versions

hal-02737120 , version 1 (26-11-2020)

Identifiants

Citer

Bruno Oliveira, Benjamin Stenton, V. B. Unnikrishnan, Cátia Rebelo de Almeida, João Conde, et al.. Platinum-triggered Bond-cleavage of Pentynoyl amide and N-propargyl handles for Drug-Activation. Journal of the American Chemical Society, 2020, 142 (24), pp.10869 - 10880. ⟨10.1021/JACS.0C01622⟩. ⟨hal-02737120⟩
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