Conformational analysis by NMR and molecular dynamics of adamantane-doxorubicin prodrugs and their assemblies with β-cyclodextrin: A focus on the design of platforms for controlled drug delivery
| Autor: | Kendra Sorroza-Martínez, Ernesto Rivera, Pasquale Porcu, Laura Dominguez, José D. Solano, Israel González-Méndez, Rodrigo Aguayo-Ortiz |
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| Rok vydání: | 2020 |
| Předmět: |
Cell Membrane Permeability
Magnetic Resonance Spectroscopy Cell Survival Drug Compounding Adamantane Clinical Biochemistry Molecular Conformation Supramolecular chemistry Pharmaceutical Science Antineoplastic Agents Molecular Dynamics Simulation 01 natural sciences Biochemistry chemistry.chemical_compound Amide Drug Discovery Humans Prodrugs Amines Molecular Biology chemistry.chemical_classification Drug Carriers Cyclodextrin 010405 organic chemistry beta-Cyclodextrins Organic Chemistry Hydrazones Hexosamines Prodrug Combinatorial chemistry 0104 chemical sciences Drug Liberation 010404 medicinal & biomolecular chemistry Daunosamine chemistry Doxorubicin Drug delivery Molecular Medicine Linker |
| Zdroj: | Bioorganic & Medicinal Chemistry. 28:115510 |
| ISSN: | 0968-0896 |
| Popis: | Nanoscale design and construction of affinity-based drug delivery systems (ADDS) is an active research area with enormous potential for the improvement of cancer treatment. For the therapeutic load of these ADDS, a promising strategy is the design of pH-sensitive prodrugs based on the construction of conjugates between adamantane and doxorubicin (Ad-Dox), which stands out as an excellent model system to obtain novel supramolecular materials. Construction of these prodrugs involves a modification of three zones of doxorubicin which in principle does not affect the action mechanism: the carbonyl group C13 (hydrazone linker), the primary alcohol neighboring the carbonyl (ester linker) and the 3' amino group of daunosamine sugar (amide linker). These modifications are aimed to improve the efficacy and reduce the systemic toxicity of the drug chemotherapy by controlling its release in cancer cells. In this work, we performed 2D NMR experiments and molecular dynamics simulations to characterize the conformational changes of three constructed prodrugs. Our results demonstrated that ring A and the daunsamine sugar of the hydrazone and amide linkers conserve the half-chair state 9H8, while the ester linker disrupts this conformation. Our study also showed that the hydrazone-linked compound (Ad-h-Dox) does not modify the conformation of the original drug and maintains cytotoxic activity. Moreover, the inclusion complex (IC) of Ad-h-Dox with β-cyclodextrin (βCD) generated a highly soluble platform in water, whereas the ester-linked compound (Ad-e-Dox) causes the loss of biological activity. This study proves that Ad-h-Dox prodrug can be an optimum prodrug and act as a building block for a more complex drug transport system. |
| Databáze: | OpenAIRE |
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