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A pH‐Activatable Prodrug and Metal Prodrug Conjugate of Gossypol: Synthesis, Emergent Photophysical, Nanoscopic, Computational, and in‐Vitro Cellular Studies
Ist Teil von
Chemistry : a European journal, 2023-05, Vol.29 (28), p.n/a
Ort / Verlag
Weinheim: Wiley Subscription Services, Inc
Erscheinungsjahr
2023
Link zum Volltext
Quelle
Wiley Online Library
Beschreibungen/Notizen
The major hurdle to the success of many potent chemotherapeutic drugs is the lack of stability of their active form suited for a particular mode of action. Efforts are needed to stabilize such functionalities by employing new and novel strategies to overcome challenges. In this study, tumor‐environment‐specific, pH‐activatable prodrug and metal‐prodrug conjugate has been developed to ameliorate the side effects of chemotherapeutic drugs bearing reactive functionalities. As a proof of concept, a pre‐clinically tested natural compound, gossypol, was modified to form a pH‐responsive prodrug by incorporating an imine linkage amenable to form confined molecular structures through coordination with a bio‐relevant and nontoxic zinc metal ion. Detailed photophysical, computational, and nanoscopic studies revealed the unique zinc ion coordination behavior and its effect on molecular confinement. Computational studies demonstrated that an increasing degree of complexation, with Zn‐N−Py coordination, gradually turns off fluorescence by reducing the band gap that allows nonradiative decay. In‐vitro prodrug activation and release of gossypol from gossyzid and gossyzid‐Zn were assessed by ESI‐MS and RP‐HPLC studies. The gossyzid and gossyzid‐Zn demonstrated pH‐specific cytotoxicity validated by the number of in‐vitro cellular assays. Such a strategy can essentially be adapted to strengthen many chemotherapeutic drugs to enhance their efficacy and reduce side effects.
Inspired by the reversible metal coordination behavior of metallothionine, we hypothesized that a similar strategy could be used to protect and stabilize the reactive functionality of the drug gossypol for its stimuli‐responsive release. The reactive functionalities can be masked in two‐stages by introducing pH‐activatable imine bonds followed by metal ion coordination stabilizing and forming confined molecular structures to release the active drug at the site of action.