Platinum-Triggered Bond-Cleavage of Pentynoyl Amide and N -Propargyl Handles for Drug-Activation.

Autor: Oliveira BL; Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, United Kingdom.; Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Avenida Professor Egas Moniz, 1649-028 Lisboa, Portugal., Stenton BJ; Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, United Kingdom., Unnikrishnan VB; Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, United Kingdom., de Almeida CR; Champalimaud Centre for the Unknown, Champalimaud Foundation, Avenida Brasilia, 1400-038 Lisboa, Portugal., Conde J; Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Avenida Professor Egas Moniz, 1649-028 Lisboa, Portugal., Negrão M; Champalimaud Centre for the Unknown, Champalimaud Foundation, Avenida Brasilia, 1400-038 Lisboa, Portugal., Schneider FSS; Department of Chemistry, Federal University of Santa Catarina-UFSC, Campus Trindade, Florianópolis, Santa Catarina 88040-900, Brazil., Cordeiro C; Laboratório de FT-ICR e Espectrometria de Massa Estrutural, Faculdade de Ciências da Universidade de Lisboa, Campo-Grande, 1749-016 Lisboa, Portugal., Ferreira MG; Champalimaud Centre for the Unknown, Champalimaud Foundation, Avenida Brasilia, 1400-038 Lisboa, Portugal.; Institute for Research on Cancer and Aging of Nice (IRCAN), Université Côte d'Azur, UMR7284 U1081 UNS, 06107 Nice, France., Caramori GF; Department of Chemistry, Federal University of Santa Catarina-UFSC, Campus Trindade, Florianópolis, Santa Catarina 88040-900, Brazil., Domingos JB; Department of Chemistry, Federal University of Santa Catarina-UFSC, Campus Trindade, Florianópolis, Santa Catarina 88040-900, Brazil., Fior R; Champalimaud Centre for the Unknown, Champalimaud Foundation, Avenida Brasilia, 1400-038 Lisboa, Portugal., Bernardes GJL; Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, United Kingdom.; Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Avenida Professor Egas Moniz, 1649-028 Lisboa, Portugal.
Jazyk: angličtina
Zdroj: Journal of the American Chemical Society [J Am Chem Soc] 2020 Jun 17; Vol. 142 (24), pp. 10869-10880. Date of Electronic Publication: 2020 Jun 09.
DOI: 10.1021/jacs.0c01622
Abstrakt: 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 5-fluorouracil (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.
Databáze: MEDLINE
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