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Expanding Transition Metal-Mediated Bioorthogonal Decaging to Include C–C Bond Cleavage Reactions

[Image: see text] The ability to control the activation of prodrugs by transition metals has been shown to have great potential for controlled drug release in cancer cells. However, the strategies developed so far promote the cleavage of C–O or C–N bonds, which limits the scope of drugs to only thos...

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Autores principales: Dal Forno, Gean M., Latocheski, Eloah, Beatriz Machado, Ana, Becher, Julie, Dunsmore, Lavinia, St. John, Albert L., Oliveira, Bruno L., Navo, Claudio D., Jiménez-Osés, Gonzalo, Fior, Rita, Domingos, Josiel B., Bernardes, Gonçalo J. L.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Chemical Society 2023
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10197128/
https://www.ncbi.nlm.nih.gov/pubmed/37133984
http://dx.doi.org/10.1021/jacs.3c01960
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author Dal Forno, Gean M.
Latocheski, Eloah
Beatriz Machado, Ana
Becher, Julie
Dunsmore, Lavinia
St. John, Albert L.
Oliveira, Bruno L.
Navo, Claudio D.
Jiménez-Osés, Gonzalo
Fior, Rita
Domingos, Josiel B.
Bernardes, Gonçalo J. L.
author_facet Dal Forno, Gean M.
Latocheski, Eloah
Beatriz Machado, Ana
Becher, Julie
Dunsmore, Lavinia
St. John, Albert L.
Oliveira, Bruno L.
Navo, Claudio D.
Jiménez-Osés, Gonzalo
Fior, Rita
Domingos, Josiel B.
Bernardes, Gonçalo J. L.
author_sort Dal Forno, Gean M.
collection PubMed
description [Image: see text] The ability to control the activation of prodrugs by transition metals has been shown to have great potential for controlled drug release in cancer cells. However, the strategies developed so far promote the cleavage of C–O or C–N bonds, which limits the scope of drugs to only those that present amino or hydroxyl groups. Here, we report the decaging of an ortho-quinone prodrug, a propargylated β-lapachone derivative, through a palladium-mediated C–C bond cleavage. The reaction’s kinetic and mechanistic behavior was studied under biological conditions along with computer modeling. The results indicate that palladium (II) is the active species for the depropargylation reaction, activating the triple bond for nucleophilic attack by a water molecule before the C–C bond cleavage takes place. Palladium iodide nanoparticles were found to efficiently trigger the C–C bond cleavage reaction under biocompatible conditions. In drug activation assays in cells, the protected analogue of β-lapachone was activated by nontoxic amounts of nanoparticles, which restored drug toxicity. The palladium-mediated ortho-quinone prodrug activation was further demonstrated in zebrafish tumor xenografts, which resulted in a significant anti-tumoral effect. This work expands the transition-metal-mediated bioorthogonal decaging toolbox to include cleavage of C–C bonds and payloads that were previously not accessible by conventional strategies.
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spelling pubmed-101971282023-05-20 Expanding Transition Metal-Mediated Bioorthogonal Decaging to Include C–C Bond Cleavage Reactions Dal Forno, Gean M. Latocheski, Eloah Beatriz Machado, Ana Becher, Julie Dunsmore, Lavinia St. John, Albert L. Oliveira, Bruno L. Navo, Claudio D. Jiménez-Osés, Gonzalo Fior, Rita Domingos, Josiel B. Bernardes, Gonçalo J. L. J Am Chem Soc [Image: see text] The ability to control the activation of prodrugs by transition metals has been shown to have great potential for controlled drug release in cancer cells. However, the strategies developed so far promote the cleavage of C–O or C–N bonds, which limits the scope of drugs to only those that present amino or hydroxyl groups. Here, we report the decaging of an ortho-quinone prodrug, a propargylated β-lapachone derivative, through a palladium-mediated C–C bond cleavage. The reaction’s kinetic and mechanistic behavior was studied under biological conditions along with computer modeling. The results indicate that palladium (II) is the active species for the depropargylation reaction, activating the triple bond for nucleophilic attack by a water molecule before the C–C bond cleavage takes place. Palladium iodide nanoparticles were found to efficiently trigger the C–C bond cleavage reaction under biocompatible conditions. In drug activation assays in cells, the protected analogue of β-lapachone was activated by nontoxic amounts of nanoparticles, which restored drug toxicity. The palladium-mediated ortho-quinone prodrug activation was further demonstrated in zebrafish tumor xenografts, which resulted in a significant anti-tumoral effect. This work expands the transition-metal-mediated bioorthogonal decaging toolbox to include cleavage of C–C bonds and payloads that were previously not accessible by conventional strategies. American Chemical Society 2023-05-03 /pmc/articles/PMC10197128/ /pubmed/37133984 http://dx.doi.org/10.1021/jacs.3c01960 Text en © 2023 The Authors. Published by American Chemical Society https://creativecommons.org/licenses/by/4.0/Permits the broadest form of re-use including for commercial purposes, provided that author attribution and integrity are maintained (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Dal Forno, Gean M.
Latocheski, Eloah
Beatriz Machado, Ana
Becher, Julie
Dunsmore, Lavinia
St. John, Albert L.
Oliveira, Bruno L.
Navo, Claudio D.
Jiménez-Osés, Gonzalo
Fior, Rita
Domingos, Josiel B.
Bernardes, Gonçalo J. L.
Expanding Transition Metal-Mediated Bioorthogonal Decaging to Include C–C Bond Cleavage Reactions
title Expanding Transition Metal-Mediated Bioorthogonal Decaging to Include C–C Bond Cleavage Reactions
title_full Expanding Transition Metal-Mediated Bioorthogonal Decaging to Include C–C Bond Cleavage Reactions
title_fullStr Expanding Transition Metal-Mediated Bioorthogonal Decaging to Include C–C Bond Cleavage Reactions
title_full_unstemmed Expanding Transition Metal-Mediated Bioorthogonal Decaging to Include C–C Bond Cleavage Reactions
title_short Expanding Transition Metal-Mediated Bioorthogonal Decaging to Include C–C Bond Cleavage Reactions
title_sort expanding transition metal-mediated bioorthogonal decaging to include c–c bond cleavage reactions
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10197128/
https://www.ncbi.nlm.nih.gov/pubmed/37133984
http://dx.doi.org/10.1021/jacs.3c01960
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