Structures of the N-Terminal Domain of PqsA in Complex with Anthraniloyl- and 6-Fluoroanthraniloyl-AMP: Substrate Activation in Pseudomonas Quinolone Signal (PQS) Biosynthesis

Pseudomonas aeruginosa, a prevalent pathogen in nosocomial infections and a major burden in cystic fibrosis, uses three interconnected quorum-sensing systems to coordinate virulence processes. At variance with other Gram-negative bacteria, one of these systems relies on 2-alkyl-4(1H)-quinolones (Pseudomonas quinolone signal, PQS) and might hence be an attractive target for new anti-infective agents. Here we report crystal structures of the N-terminal domain of anthranilate-CoA ligase PqsA, the first enzyme of PQS biosynthesis, in complex with anthraniloyl-AMP and with 6-fluoroanthraniloyl-AMP (6FABA-AMP) at 1.4 and 1.7 Å resolution. We find that PqsA belongs to an unrecognized subfamily of anthranilate-CoA ligases that recognize the amino group of anthranilate through a water-mediated hydrogen bond. The complex with 6FABA-AMP explains why 6FABA, an inhibitor of PQS biosynthesis, is a good substrate of PqsA. Together, our data might pave a way to new pathoblockers in P. aeruginosa infections.     

诺氟沙星合成方法的改进

1-乙基-6-氟-7-氯-1,4-二氢-4-氧代喹啉-3-羧酸与哌嗪在聚乙二醇催化下反应,以高收率得到诺氟沙星。     

过滤精度对煤焦油QI的组成和结构的影响

采用精度为2~5μm和20~40μm的滤芯分别对煤焦油进行热过滤,从得到的滤渣中提取出喹啉不溶物(QI)。然后利用元素分析(EA)、激光粒度仪(LPSA)、扫描电子显微镜/X射线能量色散光谱(SEM/EDS)、傅里叶红外光谱(FT-IR)、X射线衍射仪(XRD)、X射线光电子能谱(XPS)等对所得煤焦油QI组分进行对比分析。结果表明:煤焦油QI组分芳构化程度高,有机物多为稠环类物质并带有很多侧链或杂质原子,同时存在少量石英石、方解石以及煤灰等无机物;当煤焦油热过滤时采用的滤芯精度较低时,最终提取出的QI组分缩聚度相对较高,并且稠环结构中所含侧链和杂原子也相对较少。经精度较低的滤芯热过滤后提取的QI组分中金属杂原子含量相对较高,这些金属杂原子主要存在于大颗粒无机物中,部分存在于小颗粒有机物中。当滤芯精度较高时所得QI组分中主要含酚类、醚类和羧酸类有机物,酮类含量相对较少;反之,QI中则主要含酚类、醚类和酮类有机物。因此,煤焦油热过滤所选的滤芯精度不宜过高,尤其不宜选精度在5μm以下的滤芯。     

2-氨基丙醇的合成研究

以环氧丙烷为原料,开环生成α-氯丙醇和β-氯丙醇,β-氯丙醇再经氨解制得目标产物2-氨基丙醇;α-氯丙醇经皂化反应生成起始原料环氧丙烷进入循环反应。本合成工艺反应简单,操作方便,成本低;副产物可回收套用,原子经济性高,工业化前景良好。     

喹诺酮类抗菌化合物的环合反应研究

以环丙氨、乙胺、叔丁胺、氨基吡啶、氨基嘧啶等6种不同的α-(2,4-二氯-5-氟苯甲酰)-β-取代氨基丙烯酸酯作为环化底物来进行分子内亲核取代反应形成喹诺酮母环,合成得到了不同的N-取代的喹诺酮环中间体,并对它们的反应条件和分子内亲核取代反应性能进行了研究。     

Facile Fabrication of Luminescent Eu(III) Functionalized HOF Hydrogel Film with Multifunctionailities: Quinolones Fluorescent Sensor and Anticounterfeiting Platform

The luminescent hydrogen-bonded organic framework (HOF) based films have become one of the most remarkable materials for optical application, thus, developing facile synthesis methods and establishing multifunctional applications for HOF-based luminescent materials are essential. Herein, a dual-emitting Eu³⁺-functionalized HOF hydrogel film ( 1 ) is fabricated successfully. 1 emits a blue-green long afterglow when turning off the UV lamp, and the long afterglow lifetime gets to 1.99 s. 1 performs great selectivity, high sensitivity, and low detection limit toward ofloxacin and flumequine, and the sensing toward ofloxacin and flumequine is in accord with the chroma and ratio modes. The fluorescent response mechanisms of 1  toward ofloxacin and flumequine are investigated in depth, which are further utilized to build an anticounterfeiting platform with high-level security. The film-based anticounterfeiting platform can conduct information encryption on demand inline with different fluorescent responses and can also fetch specific information by controlling the long afterglow intensity and excited light. This study not only provides a representative case of the fabrication of dual-emitting Eu³⁺-functionalized HOF-based hydrogel film but also opens the possibility of HOF-based film as intelligent luminescent materials with multifunctionalities.     

同时含氟、氯元素的重要医药中间体

介绍了近年来对同时含氟、氯元素化合物医药中间体的合成研究进展，如：3-氯-4-氟硝基苯，5-氯-2-氟硝基苯，2，4-二氯氟苯，2，6-二氯氟苯，3-氯-4-氟苯胺，氟氯苯乙酮，2-氯-5-三氟甲基吡啶等十几种化合物。其中对2，4-二氯氟苯、2，4-二氯-5-氟苯甲酸的合成路线作了较详细介绍。另外，对它们的制备、应用、需求和发展趋势也作了论述并展望了我国医药产业的发展前景。     

离心分离技术在焦油脱渣脱水工艺中的应用

采用离心分离技术对攀钢焦油进行预处理,分析不同转速离心、不同离心时间对煤焦油原料脱渣的效果,同时分析不同转速离心对煤焦油原料脱水的影响,结果表明,采用离心分离处理后煤焦油除渣率≥90%,得到焦油含渣量≤0.3%,含水≤2.0%。     

喹诺酮类药物的溶解度模型

采用Glew-Hildebrand饱和技术,应用高效液相色谱法和人工神经网络技术,实验测得氧氟沙星、诺氟沙星和吡哌酸在不同温度水溶液中的溶解度,应用化工热力学理论,提出溶解度模型,用实验和文献数据作了检验．通过扩展增广距离矩阵,提出能表征杂原子、多重键和复杂环的化合物分子结构的新的分子拓扑指数,由实测3种喹诺酮类药物的溶解度数据,得到分子结构-溶解度定量相关模型．据此模型预报氟罗沙星（Fleroxacin)等9种喹诺酮类新药在25℃和37℃时的溶解度,与实验值符合良好．     

N，N-二甲氨基丙烯酸乙酯的合成

介绍了制备N,N-二甲氨基丙烯酸乙酯的亚胺络合法、一氧化碳高压合成法和羟醛缩合法及其优缺点。采用羟醛缩合法,即以甲酸乙酯与乙政乙酯为原料。在金属钠或氢化钠存在下,经羟醛缩合生成甲酰基乙酸乙酯钠盐,再与二甲胺盐酸盐反应．合成目标产物。反应最佳温度25-30℃,较理想的溶剂为甲苯和二甲苯,总收率为60％。该方法反应条件温和、操作简单、原予经济性高、污染少,适合工业化生产。