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ABSTRACT: Differential scanning calorimetry (DSC) and electron paramagnetic resonance spectroscopy (EPR) were applied to investigate effects of cholesterol component on molecular interactions between paclitaxel, which is one of the best antineoplastic agents found from nature, and dipalmitoylphosphatidylcholine (DPPC) within lipid bilayer vesicles (liposomes), which could also be used as a model cell membrane. DSC analysis showed that incorporation of paclitaxel into the DPPC bilayer causes a reduction in the cooperativity of bilayer phase transition, leading to a looser and more flexible bilayer structure. Including cholesterol component in the DPPC/paclitaxel mixed bilayer can facilitate the molecular interaction between paclitaxel and lipid and make the tertiary system more stable. EPR analysis demonstrated that both of paclitaxel and cholesterol have fluidization effect on the DPPC bilayer membranes although cholesterol has more significant effect than paclitaxel does. The reduction kinetics of nitroxides by ascorbic acid showed that paclitaxel can inhibit the reaction by blocking the diffusion of either the ascorbic acid or nitroxide molecules since the reaction is tested to be a first order one. Cholesterol can remarkably increase the reduction reaction speed. This research may provide useful information for optimizing liposomal formulation of the drug as well as for understanding the pharmacology of paclitaxel.
International Journal of Pharmaceutics 07/2007; 338(1-2):258-66. · 3.35 Impact Factor
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ABSTRACT: A series of ferrocenyl chalcones were synthesized and evaluated in vitro against Plasmodium falciparum (K1) in a [3H] hypoxanthine uptake assay. Appropriate size, electronic, lipophilic and electrochemical parameters were determined for QSAR analysis. The results showed that the location of ferrocene influenced the ease of oxidation of Fe2+ in ferrocene and the polarity of the carbonyl linkage. These parameters were found to influence antiplasmodial activity. A general trend was noted in which compounds with ferrocene adjacent to the carbonyl linkage (series A) were associated with more selective and potent antiplasmodial activities. These compounds had polarized carbonyl linkages, lower lipophilicities and ferrocene rings that were less readily oxidized. The most active analogue was 1-ferrocenyl-3-(4-nitrophenyl)prop-2-en-1-one (28) (IC50 4.6 microM, selectivity index 37 against KB3-1 cells). To understand how the redox properties of ferrocene might influence antiplasmodial activity, the oxidant properties of selected compounds were investigated in antioxidant (ABTS+) and EPR experiments. The incorporation of ferrocene in the chalcone template was found to enhance its role in processes that involved the quenching and generation of free radicals. Thus, ferrocene may participate in redox cycling and this process may contribute to the antiplasmodial activity of ferrocenyl chalcones. However, the extent to which this property is manifested is also influenced by other physicochemical properties (lipophilicity, polarity, and planarity) of the compound.
European Journal of Pharmaceutical Sciences 03/2006; 27(2-3):175-87. · 3.21 Impact Factor
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Zakaria A Almsherqi,
Craig S McLachlan,
Malgorzata B Slocinska,
Francis E Sluse,
Rachel Navet, Nikolai Kocherginsky,
Iouri Kostetski,
Dong-Yun Shi,
Shan-Lin Liu,
Peter Mossop,
Yuru Deng
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ABSTRACT: Cardiogenic shock is the leading cause of death among patients hospitalized with acute myocardial infarction (MI). Understanding the mechanisms for acute pump failure is therefore important. The aim of this study is to examine in an acute MI dog model whether mitochondrial bio-energetic function within non-ischemic wall regions are associated with pump failure. Anterior MI was produced in dogs via ligation of left anterior descending (LAD) coronary artery, that resulted in an infract size of about 30% of the left ventricular wall. Measurements of hemodynamic status, mitochondrial function, free radical production and mitochondrial uncoupling protein 3 (UCP3) expression were determined over 24 h period. Hemodynamic measurements revealed a > 50% reduction in cardiac output at 24 h post infarction when compared to baseline. Biopsy samples were obtained from the posterior non-ischemic wall during acute infarction. ADP/O ratios for isolated mitochondria from non-ischemic myocardium at 6 h and 24 h were decreased when compared to the ADP/O ratios within the same samples with and without palmitic acid (PA). GTP inhibition of (PA)-stimulated state 4 respiration in isolated mitochondria from the non-ischemic wall increased by 7% and 33% at 6 h and 24 h post-infarction respectively when compared to sham and pre-infarction samples. This would suggest that the mitochondria are uncoupled and this is supported by an associated increase in UCP3 expression observed on western blots from these same biopsy samples. Blood samples from the coronary sinus measured by electron paramagnetic resonance (EPR) methods showed an increase in reactive oxygen species (ROS) over baseline at 6 h and 24 h post-infarction. In conclusion, mitochondrial bio-energetic ADP/O ratios as a result of acute infarction are abnormal within the non-ischemic wall. Mitochondria appear to be energetically uncoupled and this is associated with declining pump function. Free radical production may be associated with the induction of uncoupling proteins in the mitochondria.
Cell Research 03/2006; 16(3):297-305. · 8.19 Impact Factor
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ABSTRACT: A series of ferrocenyl chalcones were synthesized and evaluated in vitro against Plasmodium falciparum (K1) in a [3H] hypoxanthine uptake assay. Appropriate size, electronic, lipophilic and electrochemical parameters were determined for QSAR analysis. The results showed that the location of ferrocene influenced the ease of oxidation of Fe2+ in ferrocene and the polarity of the carbonyl linkage. These parameters were found to influence antiplasmodial activity. A general trend was noted in which compounds with ferrocene adjacent to the carbonyl linkage (series A) were associated with more selective and potent antiplasmodial activities. These compounds had polarized carbonyl linkages, lower lipophilicities and ferrocene rings that were less readily oxidized. The most active analogue was 1-ferrocenyl-3-(4-nitrophenyl)prop-2-en-1-one (28) (IC50 4.6 μM, selectivity index 37 against KB3-1 cells). To understand how the redox properties of ferrocene might influence antiplasmodial activity, the oxidant properties of selected compounds were investigated in antioxidant (ABTS+) and EPR experiments. The incorporation of ferrocene in the chalcone template was found to enhance its role in processes that involved the quenching and generation of free radicals. Thus, ferrocene may participate in redox cycling and this process may contribute to the antiplasmodial activity of ferrocenyl chalcones. However, the extent to which this property is manifested is also influenced by other physicochemical properties (lipophilicity, polarity, and planarity) of the compound.
European Journal of Pharmaceutical Sciences.
