Połączenia krzyżowe pochodnych cysteiny z aldehydowymi adduktami nukleozydów adeninowych
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Date
2016
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Cross-links of cysteine derivatives with aldehydic adducts of adenine nucleosides
Abstract
Addukty aldehydu malonowego i glioksalu oraz odpowiednio metyloglioksalu z nukleozydami adeninowymi zawierają w swojej strukturze α,β-nienasycone ugrupowanie karbonylowe, które może ulegać reakcjom z grupami nukleofilowymi biocząsteczek tworząc wiązania krzyżowe. Celem rozprawy było zbadanie możliwości tworzenia modelowych połączeń krzyżowych typu DNA-białko oraz RNA-białko w wyniku reakcji wspomnianych adduktów z grupami tiolowymi N-acetylocysteiny (NAC) i glutationu (GSH). Zsyntezowane addukty adenozyny i 2’-deoksyadenozyny z aldehydem malonowym i glioksalem (M1Gx-A) oraz metyloglioksalem (M1MGx-dA) poddano szczegółowym badaniom strukturalnym (NMR i DFT-GIAO). W wyniku przeprowadzonych badań reaktywności M1Gx-A, M1MGx-dA, M1MGx-Ade i M1MGx-A wobec NAC otrzymano i scharakteryzowano strukturalnie (1D i 2D NMR) szereg produktów stanowiących modelowe połączenia krzyżowe. Związki te okazały się stosunkowo trwałe w warunkach fizjologicznych, jednak w obecności Nα-acetylolizyny ulegały szybkiej przemianie w pochodne tego aminokwasu. Przedstawiono również rezultaty badań reaktywności M1Gx-A i M1MGx-A wobec GSH. Szereg produktów powstających w tych reakcjach scharakteryzowano na podstawie analiz LC-MS, wskazując, że zarówno grupa tiolowa, jak i aminowa glutationu biorą udział w tworzeniu połączeń krzyżowych typu DNA-białko i RNA-białko.
The aim of the doctoral dissertation was synthesis, structural characterization and stability studies of malonaldehyde-glyoxal and malonaldehyde-methylglyoxal adducts of adenine nucleosides with cysteine derivatives: N-acetylcysteine (NAC) and glutathione (GSH). The structural studies were performed using spectroscopic methods (1D and 2D NMR) and quantum chemical calculations (DFT). The reactivity and stability studies of the synthesized compounds were performed using HPLC-DAD and HPLC-MS. The adducts formed in reactions of malonaldehyde and glyoxal with adenosine (M1Gx-A), and malonaldehyde and methylglyoxal with 2’-deoxyadenosine (M1MGx-dA) were studied structurally using 1D and 2D NMR and DFT-GIAO methods. The studied adducts comprise units derived from malonaldehyde-glyoxal and malonaldehyde-methylglyoxal conjugates (M1Gx-A and M1MGx-A) and possess two electrophilic centers. In a consequence, they exhibit potential capacity to interact with nucleophilic biomolecules. The aim of the study was to examine cross-linking activity of these adducts in reactions with NAC and GSH. NAC and GSH were found to be highly reactive towards these adducts and formed a range of modifications. The identified products can represent models for DNA-protein cross-links that could be formed between the DNA adducts of endogenous electrophiles and proteins containing the thiol groups.
The aim of the doctoral dissertation was synthesis, structural characterization and stability studies of malonaldehyde-glyoxal and malonaldehyde-methylglyoxal adducts of adenine nucleosides with cysteine derivatives: N-acetylcysteine (NAC) and glutathione (GSH). The structural studies were performed using spectroscopic methods (1D and 2D NMR) and quantum chemical calculations (DFT). The reactivity and stability studies of the synthesized compounds were performed using HPLC-DAD and HPLC-MS. The adducts formed in reactions of malonaldehyde and glyoxal with adenosine (M1Gx-A), and malonaldehyde and methylglyoxal with 2’-deoxyadenosine (M1MGx-dA) were studied structurally using 1D and 2D NMR and DFT-GIAO methods. The studied adducts comprise units derived from malonaldehyde-glyoxal and malonaldehyde-methylglyoxal conjugates (M1Gx-A and M1MGx-A) and possess two electrophilic centers. In a consequence, they exhibit potential capacity to interact with nucleophilic biomolecules. The aim of the study was to examine cross-linking activity of these adducts in reactions with NAC and GSH. NAC and GSH were found to be highly reactive towards these adducts and formed a range of modifications. The identified products can represent models for DNA-protein cross-links that could be formed between the DNA adducts of endogenous electrophiles and proteins containing the thiol groups.
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Wydział Chemii
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Keywords
addukty DNA, DNA adducts, połączenia krzyżowe DNA-białko, DNA-protein cross-links, etenoaddukty, ethenoadducts, NMR, DFT