PUBLICATION
Platinum-triggered Bond-cleavage of Pentynoyl amide and N-propargyl handles for Drug-Activation
- Authors
- 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.
- ID
- ZDB-PUB-200528-6
- 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.
Citation
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. (2020) Platinum-triggered Bond-cleavage of Pentynoyl amide and N-propargyl handles for Drug-Activation. Journal of the American Chemical Society. 142(24):10869-10880.
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.
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