PUBLICATION
Gold(III)-Induced Amide Bond Cleavage In Vivo: A Dual Release Strategy via π-Acid Mediated Allyl Substitution
- Authors
- Unnikrishnan, V.B., Sabatino, V., Amorim, F., Estrada, M.F., Navo, C.D., Jimenez-Oses, G., Fior, R., Bernardes, G.J.L.
- ID
- ZDB-PUB-240808-8
- Date
- 2024
- Source
- Journal of the American Chemical Society 146(33): 23240-23251 (Journal)
- Registered Authors
- Keywords
- none
- MeSH Terms
-
- Gold/chemistry
- Zebrafish*
- Molecular Structure
- Animals
- Amides*/chemistry
- Cell Line, Tumor
- Humans
- Prodrugs*/chemical synthesis
- Prodrugs*/chemistry
- Immunoconjugates/chemistry
- Oligopeptides/chemistry
- Antineoplastic Agents*/chemical synthesis
- Antineoplastic Agents*/chemistry
- Antineoplastic Agents*/pharmacology
- Apoptosis/drug effects
- PubMed
- 39113488 Full text @ J. Am. Chem. Soc.
Citation
Unnikrishnan, V.B., Sabatino, V., Amorim, F., Estrada, M.F., Navo, C.D., Jimenez-Oses, G., Fior, R., Bernardes, G.J.L. (2024) Gold(III)-Induced Amide Bond Cleavage In Vivo: A Dual Release Strategy via π-Acid Mediated Allyl Substitution. Journal of the American Chemical Society. 146(33):23240-23251.
Abstract
Selective cleavage of amide bonds holds prominent significance by facilitating precise manipulation of biomolecules, with implications spanning from basic research to therapeutic interventions. However, achieving selective cleavage of amide bonds via mild synthetic chemistry routes poses a critical challenge. Here, we report a novel amide bond-cleavage reaction triggered by Na[AuCl4] in mild aqueous conditions, where a crucial cyclization step leads to the formation of a 5-membered ring intermediate that rapidly hydrolyses to release the free amine in high yields. Notably, the reaction exhibits remarkable site-specificity to cleave peptide bonds at the C-terminus of allyl-glycine. The strategic introduction of a leaving group at the allyl position facilitated a dual-release approach through π-acid catalyzed substitution. This reaction was employed for the targeted release of the cytotoxic drug monomethyl auristatin E in combination with an antibody-drug conjugate in cancer cells. Finally, Au-mediated prodrug activation was shown in a colorectal zebrafish xenograft model, leading to a significant increase in apoptosis and tumor shrinkage. Our findings reveal a novel metal-based cleavable reaction expanding the utility of Au complexes beyond catalysis to encompass bond-cleavage reactions for cancer therapy.
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