Synthesis And Electrochemistry Of Ubiquinone Analogue

Coenzyme Q, also known as ubiquinone. is a lipid-soluble compound, indispensable for optimal functioning of all living organisms. As the only nonprotein component of the mitochondrial electron-transport chain, CoQ is a central electron carrier, simultaneously transferring protons from the mitochondrial matrix to the intermembrane space. The concomitant proton gradient across the inner mitochondrial membrane is essential for ATP production. Apart from their main function. CoQ and several other CoQ family members have additional functions in the regulation of the cellular metabolism and antioxidant function as scavengers of free radicals. Some research indicates that systemic ubiquinone analogues (UQAs) studies for synthesis and biological application are generating interesting. Recently, biointerface fabrication and research on electrode and nano materials surface enjoys increasing interest in biosensing, bio-recognition, understanding molecule-biointerfaces interaction and biomimicking biological process, better than either solely organic or inorganic systems. From a biomimetic point of view, functionalized biointerfaces have played an important role in understanding of biomolecules behaviours in biological processes. On these account, the dissertation focuses on the Preparaiong of a series of UQAs. These unique compounds have been investigated to explore their electron-transfer processes and structure-activities relationships of UQAs were examined in this study. We construct the bio-interface using ubiquinone to represents a biomimetic electron-transfer system, modeling part of the mitochondrial respiratory chain the proton coupled electron transfer, and for Parkinson's disease diagnosis and progression. The details are summarized as follows:1. In situ spectroeletrochemistry and biological activities of natural UQAsQuinones are a group of potent antineoplastic agents. Here we described effective and facile routes to synthesize a series of UQAs. These unique compounds have been investigated by electrochemistry and in situ UV-Vis spectroelectrochemistry to explore their electron-transfer processes and radical properties in aprotic media. The structure-activities relationships of inhibiting cancer cell proliferation of UQAs were examined in murine melanoma B16F10 cells. Our results revealed that UQAs had improved antiproliferative activity and displayed better inhibitory effects than natural ubiquinone 10. The cytotoxic activities of UQAs were correlated to the semiubiquinone radicals, which were confirmed by in situ electron spin resonance. In the cytotoxicity test,6-vinyl ubiquinone 5 and 6-(4'-fluorophenyl) ubiquinone 7 that possess half maximal inhibitory concentration value (IC50) of 6.1μ.M and 6.2μM. This would make them as valuable candidates for future pharmacological studies2. Electrochemical study and hydrogen bond interaction of bis-coenzyme QoA methylene-bridged bis-coenzyme Qo (Bis-CoQo) that shows intramolecular electronic communications has been for the first time synthesized. By employing electrochemical, in-situ UV-vis and electron paramagnetic resonance spectroelectrochemical techniques, the unstable reduced intermediate species:mono-radicals, diamagnetic dianions and tetra-anions of Bis-CoQo have been observed. The electron-transfer process can be defined as a three-step reduction process with a total of four-electron in CH3CN solution. The chemical reaction in the third redox step process was confirmed by variable temperature cyclic voltammetry. In an aprotic CH3CN solution, the peak potential separation between electron-transfer steps diminished sequentially with increasing concentration of water. The hydrogen bonding interactions between water and the electrochemical reduced intermediates of Bis-CoQo can be estimated by peak potential shifts. The electronic communications of Bis-CoQo may be blocked when one reduction peak observed with proper quantities of water in CH3CN solution. Bis-CoQo protected cellular antioxidant defense capacity is also assessed.3. Reversible redox of NADH and NAD+ at a hybrid lipid bilayer membrane using ubiquinoneWe synthesized three ubiquinone-terminated disulfides with different alkyl spacers (QnS, n =1,5,10). QnS is the modified on the gold electrode surfac using self-assembled techniques. Biomimetic membrane model in which ubiquinone is embedded in lipid bilayer membranes that contains the NADH/NAD+redox couple (QnS-HBM-NADH/NAD+) were then formed on the QnS-SAMs. Importantly, we have shown that reversible interconversion between NADH and NAD+could occur at a low overpotential when both ubiquinone, as a redox mediator, and NADH/NAD+ were embedded in a lipid bilayer. Further evidence for the reversible interconversion NADH/NAD+ was obtained by in situ surface enhanced Raman scattering, and spectroelectrochemical UV-vis experiments confirmed that the electrochemical NADH oxidation at the ubiquinone HBM allows for the regeneration of biologically active NAD+ Furthermore, this system can be used as a platform to examine biologically relevant electroactive molecules embedded in a natural membrane environment and provide new insights into the mechanism of biological redox cycling.4. Ubiquinone/ubiquinol coupled quantum Dots as switchable redox-fluorescent biosensor for Parkinson's Disease diagnosisWe prepared surface-attached CdSe/ZnS QDs exploiting three ubiquinone-terminated disulphides (QnNS, n=2,5,10). The FL enhancement of reduced HQnNS and quenching of oxidized QnNS-modified QDs can be reversibly tuned with the redox potential of surface capping layer, following the transformation between QnNS and HQnNS state via electron transfer on the QDs surface. The FL and electrochemical properties are spacer dependent indicating the importance of the heterogeneous electron transfer kinetics from the surface capping layer to the QDs. Concerning synergy between ubiquinone and NADH in enzymatic reaction of electron transport chain, it enables us to follow the activities of complex I to mimic the initial electron-transfer process of respiratory chain and develop a unique optical sensor for the detection of complex I. We demonstrated the FL of QnNS-QDs light up with complex I in the presence of NADH arises from oxidized ubiquinone to reduced ubiquinol on the surface of QDs. Studies in human postmortem material indicate that impaired complex I activity of mitochondria are important in the pathogenesis of sporadic PD. Others have also demonstrated that complex I deficiency is a potential index for PD diagnosis. Importantly, the utility of the system is demonstrated by monitoring the FL change to trace complex I levels in human neuroblastoma SH-SY5Y cells. Our results demonstrated that our constructed QnNS-QDs sensor could be used for early detection of PD and monitoring disease progression. If our results are confirmed in other cohorts, there is no doubt that this biosensing approach is a significant step forward toward molecular diagnosis of PD.