同步荧光光谱法结合分子对接研究金雀花碱与牛血清白蛋白间相互作用

金雀花碱(Cy)是一种生物碱,主要存在于豆科毒豆属植物种子中。Cy具有较强的生物活性,特别是作为戒烟药物已得到广泛应用。在模拟生理条件下,应用荧光光谱法研究了Cy同牛血清白蛋白(BSA)之间的相互作用以及Cy猝灭BSA荧光发射的机理。详细考查了水浴温度、水浴时间以及溶液pH等因素对荧光猝灭的影响,并且通过Stem-Volmer方程计算了Cy与BSA间的结合类型、结合位点数目以及结合常数。结果表明,Cy与BSA可形成摩尔比为1∶1的非共价复合物,其结合常数为5.6×103,其猝灭类型为静态猝灭。同步荧光光谱研究结果表明,Cy的结合主要影响BSA 的Trp残基的荧光发射。进一步应用分子对接研究表明,氢键与疏水作用是Cy与BSA形成复合物的主要推动力。Cy与BSA中Trp213及其周围的氨基酸残基间存在氢键与疏水作用,这种作用将改变Trp213所处微环境的疏水情况,从而导致BSA的荧光发生猝灭。     

Synthesis of a cytisine/epibatidine hybrid: a radical approach

With the aim of developing a new ligand of neuronal nicotinic receptors (nAChRs), ionic, and radical routes to the synthesis of a cytisine/epibatidine hybrid were studied. The key step of the convergent synthesis was an unprecedented intramolecular coupling between a primary radical and a pyridine heterocycle. The target compound ‘6,11-diaza’ was formed with its ‘4,11-diaza’ regioisomer (‘6,11″/’4,11″: 70/30). Both compounds exhibited a nanomolar affinity at the α₄β₂ nAChR subtype, slightly better for the unexpected regioisomer [K_i (nM) target compound and its regioisomer: 3.5 and 0.5 nM, respectively].     

1,3-Oxazole derivatives of cytisine as potential inhibitors of glutathione reductase of Candida spp.: QSAR modeling,docking analysis and experimental study of new anti-Candida agents

Natural products as well as their derivatives play a significant role in the discovery of new biologically active compounds in the different areas of our life especially in the field of medicine. The synthesis of compounds produced from natural products including cytisine is one approach for the wider use of natural substances in the development of new drugs. QSAR modeling was used to predict and select of biologically active cytisine-containing 1,3-oxazoles. The eleven most promising compounds were identified, synthesized and tested. The activity of the synthesized compounds was evaluated using the disc diffusion method against C. albicans M 885 (ATCC 10,231) strain and clinical fluconazole-resistant Candida krusei strain. Molecular docking of the most active compounds as potential inhibitors of the Candida spp. glutathione reductase was performed using the AutoDock Vina. The built classification models demonstrated good stability, robustness and predictive power. The eleven cytisine-containing 1,3-oxazoles were synthesized and their activity against Candida spp. was evaluated. Compounds 10, 11 as potential inhibitors of the Candida spp. glutathione reductase demonstrated the high activity against C. albicans M 885 (ATCC 10,231) strain and clinical fluconazole-resistant Candida krusei strain. The studied compounds 10, 11 present the interesting scaffold for further investigation as potential inhibitors of the Candida spp. glutathione reductase with the promising antifungal properties. The developed models are publicly available online at http://ochem.eu/article/120720 and could be used by scientists for design of new more effective drugs.     

Preparation and recognition performance of cytisine alkaloid‐imprinted material prepared using novel surface molecular imprinting technique

Methacrylic acid was first graft‐polymerized on the surfaces of micron‐sized silica gel particles in the manner of “grafting from” using 3‐methacryloxypropyl trimethoxysilane as an intermedia, obtaining the grafted particle polymethacrylic acid PMAA/SiO₂. By adopting the novel surface‐molecular imprinting technique put forward by us, cytisine molecule‐imprinted material MIP‐PMAA/SiO₂ was prepared with ethylene glycol diglycidyl ether as crosslinking agent. The binding characteristics of MIP‐PMAA/SiO₂ towards cytisine was investigated in depth with both batch and column methods and using matrine and oxymatrine as two contrast alkaloids, which with cytisine coexist in sophora alopecuroides and their chemical structure is similar to cytisine to a certain extent. The experimental results show that the surface‐imprinted material MIP‐PMAA/SiO₂ has excellent binding affinity for cytisine (20.1 g/100 g of binding capacity), and it is more important that MIP‐PMAA/SiO₂ has very high recognition selectivity for cytisine in relation to the two contrast alkaloids. The selectivity coefficients of the grafted particles PMAA/SiO₂ (non‐imprinted material) for cytosine in relation to matrine and oxymatrine are only 1.03 and 1.06, respectively, displaying no recognition selectivity for cytisine. However, after imprinting, the selectivity coefficient of MIP‐PMAA/SiO₂ for cytisine in respect to matrine and oxymatrine are remarkably enhanced to 12.08 and 15.05, respectively.     

Efficient synthesis of tetrazole derivatives of cytisine using the azido-Ugi reaction

The azido-Ugi reaction with natural alkaloid cytisine was investigated. It was demonstrated that the reaction could be performed with various carbonyls (both aldehydes and ketones) and isocyanides. The transformation proceeded under mild conditions in methanol using TMSN3 as a source of hydrazoic acid to give target tetrazole derivatives of cytisine in up to 98% yield. The diastereoselectivity of this reaction was studied using both aliphatic and aromatic aldehydes. A family of tetrazole derived cytisine compounds was prepared. Selective deprotection of tetrazoles was elaborated to synthesize the corresponding NH-tetrazoles.