ZFIN ID: ZDB-PUB-200528-6
Platinum-triggered Bond-cleavage of Pentynoyl amide and N-propargyl handles for Drug-Activation
Oliveira, B.L., Stenton, B.J., V B, U., de Almeida, C.R., Conde, J., Negrão, M., Schneider, F.S.S., Cordeiro, C., Godinho Ferreira, M., Caramori, G.F., Domingos, J.B., Fior, R., Bernardes, G.J.L.
Date: 2020
Source: Journal of the American Chemical Society   142(24): 10869-10880 (Journal)
Registered Authors: Fior, Rita
Keywords: none
MeSH Terms:
  • Amides/chemistry*
  • Animals
  • Antineoplastic Agents/chemistry
  • Antineoplastic Agents/pharmacology*
  • Cell Line, Tumor
  • Cell Proliferation/drug effects
  • Cisplatin/chemistry
  • Cisplatin/pharmacology*
  • Drug Liberation
  • Drug Screening Assays, Antitumor
  • Humans
  • Molecular Structure
  • Morphinans/chemistry*
  • Neoplasms, Experimental/drug therapy
  • Neoplasms, Experimental/pathology
  • Platinum/chemistry*
  • Zebrafish
PubMed: 32456416 Full text @ J. Am. Chem. Soc.
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ABSTRACT
The ability to create ways to control drug activation at specific tissues while sparing healthy tissues remains a major challenge. The admin-istration 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 complex-es[K2PtCl4 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 rap-idly in aqueous systems. In cells, the protected analogues of cytotoxic drugs 5-fluorouracil (5-FU) and monomethyl auristatin E (MMAE) are partially activated by non-toxic amounts of platinum salts. Additionally, a non-internalizing 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 ex-pands the application of platinum complexes beyond those in catalysis and cancer therapy.
ADDITIONAL INFORMATION