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. Issue 13 (1st July 2020)

• Record Type: Journal Article
• Authors: González-Méndez, Israel; Aguayo-Ortiz, Rodrigo; Sorroza-Martínez, Kendra; Solano, José D.; Porcu, Pasquale; Rivera, Ernesto; Dominguez, Laura
• Is Part Of: Bioorganic & medicinal chemistry. Volume 28:Issue 13(2020)
• Publication Date: 2020-07-01
• Subjects: Doxorubicin -- Molecular dinamic simulation -- pH sensitive assembly -- Inclusion complex; Ad adamantane -- Ad-a-Dox adamantane-amide-doxorubicin -- Ad-COOH adamantane carboxilic acid -- Ad-Dox adamantane-doxorubicin -- ADDS affinity-based drug delivery systems -- Ad-e-Dox adamantane-ester-doxorubicin -- Ad-h-Dox adamantane-hydrazone-doxorubicin -- βCD β-cyclodextrin -- COSY correlation spectroscopy -- DDS drug delivery systems -- DMEM Dulbecco's modified eagle medium -- DMSO‑d6 deuterated dimethyl sulfoxide -- D2O deuterium oxide -- Dox doxorubicin -- Dox-Boc N-boc-doxorubicin -- dRMSD distance root-mean-square deviation -- DSC differential scanning calorimetry -- EDTA ethylenediaminetetraacetic acid -- EGF epidermal growth factor -- FBS fetal bovine serum -- HMQC hetero-nuclear single quantum correlation -- IC inclusion complex -- IC50 half-maximal inhibitory concentration -- MCF-7 estrogen receptor-positive breast cancer cell line -- MCF-10A non-tumorigenic human breast epithelial -- MD molecular dynamics -- MDA-MB-231 human breast cancer triple-negative cell line -- MeOH methanol -- MTT 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide -- NMR nuclear magnetic resonance -- NOE nuclear overhauser effect -- NOESY nuclear overhauser effect spectroscopy -- PBS phosphate-buffered saline -- PM physical mixture -- PMF potential of mean force -- Rg radius of gyration -- RMSD root-mean-square deviation -- ROESY rotating frame overhauser effect spectroscopy -- SD standard deviation -- TGA thermogravimetric analysis -- TMS tetramethylsilane -- US umbrella sampling -- WHAM weighted histogram analysis method; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Chemistry, Clinical -- Periodicals; Chemistry, Organic -- Periodicals; Chimie bio-organique -- Périodiques; Chimie pharmaceutique -- Périodiques; 615.19
• DOI: 10.1016/j.bmc.2020.115510
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: Highlights: Conformational analysis by 2D NMR and molecular dynamics of adamantane-doxorubicin prodrugs. Hydrazone-linker does not modify the solution conformation of the original drug. The inclusion complex with β-cyclodextrin generates a platform with high solubility in water. Adamantane-hydrazone-doxorubicin prodrug showed to be a reliable therapeutic load. Abstract: 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 9 H8, 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.