small molecule prodrugs
The potential of bioorthogonal bond cleavage reactions holds great promise, especially in the realm of cancer treatment, where the demand for highly selective therapies is more urgent than ever. Conventional chemotherapies indiscriminately attack all rapidly dividing cells, blurring the line between healthy and malignant tissue. The resulting toxicity narrows the therapeutic window, caps allowable doses, and keeps many otherwise-promising warheads from ever reaching patients.
We design switchable small‑molecule prodrugs whose activity is unleashed only inside or immediately next to tumours. Central to this strategy is a family of bioorthogonal bond‑cleavage reactions that operate cleanly in water, at low metal loadings, and without disturbing native biology. Our work forms the basis of a new class of bond cleavage reaction for prodrug activation that follows a cyclization mechanism through an intramolecular nucleophilic attack. For instance, we recently unveiled an Au(III)‑mediated “molecular safety‑pin” that snaps open a pentenoic linker, simultaneously ejecting a fluorescent reporter and a cytotoxic warhead. The reaction is fast, traceless, and fully compatible with antibody–drug conjugates, allowing us to watch in real time drug release happening precisely where it’s needed.
By turning external, exogenous metals into molecular scalpels, we are redefining what “selective” can mean in chemotherapy, liberatingn ultrapotent cargos at micromolar–nanomolar trigger concentrations, sparing healthy tissue, and providing spatiotemporal control unattainable with endogenous cues.
We are now expanding this toolbox across a broader palette of metals, payloads, and disease models, with the ultimate goal of integrating therapy and diagnostics into a single, finely tuned chemical event.
1. Unnikrishnan, V. B.; Sabatino, V.; Amorim, F.; Estrada, M. F.; Navo, C. D.; Jimenez-Oses, G.; Fior, R.; Bernardes, G. J. L. Gold (III)-Induced Amide Bond Cleavage In Vivo: A Dual Release Strategy via π-acid Catalysed Allyl Substitution. J. Am. Chem. Soc. 2024, 146, 23240-2325.
2. Oliveira, B. L.; Stenton, B. J.; Unnikrishnan, V. B.;, Conde, J.; Almeida, C.; Negrao, M.; Ferreira, M. G.; Caramori, G. F.; Domingos, J. B.; Fior, R.; Bernardes, G. J. L. Platinum-triggered bond cleavage of pentynoyl amide and N-propargyl handles for drug activation in vivo. J. Am. Chem. Soc. 2020, 24, 10869–10880.
(Featured as the supplementary cover page for the Journal of American Chemical Society)
We design switchable small‑molecule prodrugs whose activity is unleashed only inside or immediately next to tumours. Central to this strategy is a family of bioorthogonal bond‑cleavage reactions that operate cleanly in water, at low metal loadings, and without disturbing native biology. Our work forms the basis of a new class of bond cleavage reaction for prodrug activation that follows a cyclization mechanism through an intramolecular nucleophilic attack. For instance, we recently unveiled an Au(III)‑mediated “molecular safety‑pin” that snaps open a pentenoic linker, simultaneously ejecting a fluorescent reporter and a cytotoxic warhead. The reaction is fast, traceless, and fully compatible with antibody–drug conjugates, allowing us to watch in real time drug release happening precisely where it’s needed.
By turning external, exogenous metals into molecular scalpels, we are redefining what “selective” can mean in chemotherapy, liberatingn ultrapotent cargos at micromolar–nanomolar trigger concentrations, sparing healthy tissue, and providing spatiotemporal control unattainable with endogenous cues.
We are now expanding this toolbox across a broader palette of metals, payloads, and disease models, with the ultimate goal of integrating therapy and diagnostics into a single, finely tuned chemical event.
Selected Publications
2. Oliveira, B. L.; Stenton, B. J.; Unnikrishnan, V. B.;, Conde, J.; Almeida, C.; Negrao, M.; Ferreira, M. G.; Caramori, G. F.; Domingos, J. B.; Fior, R.; Bernardes, G. J. L. Platinum-triggered bond cleavage of pentynoyl amide and N-propargyl handles for drug activation in vivo. J. Am. Chem. Soc. 2020, 24, 10869–10880.
(Featured as the supplementary cover page for the Journal of American Chemical Society)