RESUMO
A high-content bioorthogonal prodrug with multiple outputs using the "click, cyclize, and release" concept is described. The proof of concept is established by the co-delivery of a gasotransmitter carbon monoxide, an anticancer drug floxuridine, and an in situ generated fluorescent reporter molecule for real-time monitoring of the prodrug activation. Bioorthogonal prodrugs as such are invaluable tools for the co-delivery of other drug payloads for multimodal therapy.
Assuntos
Antineoplásicos/química , Pró-Fármacos/química , Antineoplásicos/farmacologia , Monóxido de Carbono/química , Ciclização , Humanos , Estrutura MolecularRESUMO
Bioorthogonally activated smart probes greatly facilitate the selective labeling of biomolecules in living system. Herein, we described a novel type of smart probes with tunable reaction rates, high fluorescence turn-on ratio, and easy access. The practicality of such probes was demonstrated by selective labeling of lipid and hCAII in Hela cells.
Assuntos
Anidrase Carbônica II/química , Fluorescência , Corantes Fluorescentes/química , Lipídeos/química , Imagem Óptica , Anidrase Carbônica II/metabolismo , Química Click , Células HeLa , Humanos , Estrutura MolecularRESUMO
Prodrug strategies have been proven to be a very effective way of addressing delivery problems. Much of the chemistry in prodrug development relies on the ability to mask an appropriate functional group, which can be removed under appropriate conditions. However, developing organic prodrugs of gasotransmitters represent unique challenges. This is especially true with carbon monoxide, which does not have an easy "handle" for bioreversible derivatization. By taking advantage of an intramolecular Diels-Alder reaction, we have developed a prodrug strategy for preparations of organic CO prodrugs that are stable during synthesis and storage, and yet readily release CO with tunable release rates under near physiological conditions. The effectiveness of the CO prodrug system in delivering a sufficient quantity of CO for possible therapeutic applications has been studied using a cell culture anti-inflammatory assay and a colitis animal model. These studies fully demonstrate the proof of concept, and lay a strong foundation for further medicinal chemistry work in developing organic CO prodrugs.