环氧化物的生物不对称合成

手性环氧化物是有机化学合成中重要的中间体,与以往化学合成方法相比,手性环氧化物的生物合成有其独特之优点,本文从直接加氧、间接环氧和酶解拆分三个途径全面地介绍该领域的研究成果和最新进展,并对其未来的发展和方向进行了展望。     

手性苯基环氧乙烷的生物不对称合成

以苯乙烯为唯一碳源和能源,从不同来源的土壤样品中初筛分离出12株好氧细菌和2株真菌,经复筛,对液体培养物进行手性气相色谱分析,得到一株产生手性苯基环氧乙烷活力较高的菌种PS-1206,并对其发酵、产酶及苯乙烯的全细胞转化进行了研究,利用微生物细胞在30℃,pH 7.0,10mmol/L磷酸缓冲液中转化0.5%苯乙烯10h,获得?苯基环氧乙烷,e.e%值为80%,转化产率为35%。     

迅速发展中的不对称生物催化技术

本文概述了生物催化技术近年来迅速发展的背景、现状和前景,特别谈到酶在手性合成领域的广泛应用;结合国内外实例,分别介绍了生物催化的不对称氧化还原反应和水解酶催化的对映选择性合成两个主要方面的研究与开发动态.     

不对称生物还原制备手性药物

近年来手性药物的发展非常迅速,手性合成药物的出现不仅提高了药效,而且有利于克服现行消旋体药物在治疗上的副作用。本文介绍了用生物还原法制备高光学纯度手性醇前体的一些方法。     

高对映选择性环氧化物水解酶产生菌的筛选及特性研究

从土壤中分离的芽孢杆菌Bacillus megaterium ECU1001所产五氧化物水解酶能高对映选择性水解缩水甘油苯基醚（对映选择率E值可达47.8）,当转化率为55.9%时,剩余的（S）－缩水甘油苯基醚的光学纯度（对映体过量值,ee）可达99.5%;当底物浓度提高到60mmol/L时,光学纯（S）－缩水基油苯基醚的收率达到25.6%。     

高对映选择性环氧化物水解酶产生菌的筛选及特性研究*

从土壤中分离的芽孢杆菌BacillusmegateriumECU1 0 0 1所产环氧化物水解酶能高对映选择性水解缩水甘油苯基醚 (对映选择率E值可达 47 8) ,当转化率为 55.9%时 ,剩余的 (S) 缩水甘油苯基醚的光学纯度 (对映体过量值 ,ee)可达 99.5 % ;当底物浓度提高到 60mmol/L时 ,光学纯 (S) 缩水甘油苯基醚的收率达到 25.6%     

微生物环氧化物水解酶的研究进展

环氧化物水解酶(EH)是一类能催化外消旋环氧化物水解生成有光学活性的环氧化物和二醇的酶,应用前景广阔。自然界筛选到的微生物往往存在产酶活力低、对映体选择性不高等问题。近年来,基因工程技术的发展及其在微生物环氧化物水解酶中的应用,改善了酶的催化特性,为酶的工业化应用提供了条件。该文简单介绍了微生物环氧化物水解酶的催化反应机制和快速检测方法,详细介绍了环氧化物水解酶基因工程方面的研究进展。     

生物催化不对称还原制备氟代手性醇

由于氟原子的特殊性质，化合物中引入氟原子可显著改变其物理化学性质。因此，氟原子在药物中的应用越来越广。此外，80%药物分子结构属于手性分子。其中，氟代手性醇常见于手性药物结构中，该类结构的合成方法研究具有重要的意义。不对称还原含氟酮是合成此结构的常见方法。与化学还原方法相比，生物催化还原具有对映选择性强、产率高和易于分离纯化等优点。生物催化，特别是酶催化还原含氟酮类化合物成为手性药物合成领域的研究热点。本文从纯化酶催化和全细胞催化两个方面，综述了近年来含氟酮生物催化还原合成氟代手性醇的研究进展，并分析总结了氟代对酮生物催化还原的影响，最后对生物催化还原法未来的发展进行了展望。     

转氨酶催化不对称合成芳香族L-氨基酸

芳香族L-氨基酸是合成许多药物、农药、精细化学品和食品添加剂的重要手性砌块(Chiral buildingblocks)。利用酶催化具有高活性和高立体选择性的特点合成手性砌块是目前不对称合成领域重要的研究方向。通过对不同来源转氨酶的进化分析,选择分别源自原核生物大肠杆菌Escherichia coli和真核生物酿酒酵母Saccharomyces cerevisia中的两种具有代表性Ⅰ型芳香族转氨酶TyrB和Aro8,比较研究了两种转氨酶通过平衡逆转不对称氨化催化合成芳香族L-氨基酸的反应过程和催化效率。重组转氨酶TyrB和Aro8都能有效地合成天然芳香族氨基酸苯丙氨酸和酪氨酸以及非天然氨基酸苯甘氨酸。手性HPLC分析表明,合成的氨基酸都是L-构型的,e.e值等于100%。L-丙氨酸是适宜的氨基供体,转氨酶TyrB和Aro8都不能利用D-型氨基酸作为氨基供体。反应体系中氨基供体L-丙氨酸和氨基受体芳香族α-酮酸的最适摩尔比为4∶1。底物芳香族α-酮酸分子结构中芳香环上的取代基以及脂肪酸碳链部分的长度都对酶催化的转氨效率有显著的影响。在制备规模试验中,TyrB催化不对称转氨反应合成L-苯甘氨酸、L-苯丙氨酸和L-酪氨酸的比生产速率为0.28 g/(g.h)、0.31 g/(g.h)和0.60 g/(g.h),Aro8催化上述反应的比生产速率分别为0.61 g/(g.h)、0.48 g/(g.h)和0.59 g/(g.h)。研究结果对利用转氨酶通过平衡逆转不对称催化合成芳香族L-氨基酸的工业化应用具有指导意义。     

生物催化剂在手性药物合成中的应用

基因表达及功能分析需要高通量的表达系统,因而简单、经济且高效地将PCR产物或其他来源的目的基因片段构建到质粒载体中就成为了亟需解决的问题.传统克隆方法使用限制性内切酶和连接酶,其缺点是受到基因序列中原有的酶切位点的限制以及依赖连接酶导致的较低的连接转化率.为了克服这些缺点,一些不需要限制酶和连接酶的克隆方法被开发出来并运用到基因克隆中,获得了更佳的实验结果.该文就LIC、UDG克隆和Gateway重组克隆这三种不依赖连接反应的高通量克隆方法的原理及特性进行介绍.     

Chiral porphyrin imine manganese complex as catalyst for asymmetric epoxidation of styrene derivatives

New chiral porphyrin imine was synthesized from (S)‐3‐benzyl‐2‐methyl‐4‐phenylbutanal according to dipyrromethane method using trifluoroacetic acid, BF₃ etherate, and p‐chloranil. Manganese complex of this chiral porphyrin imine ligand was used as catalyst in the asymmetric epoxidation of styrene derivatives possessing different substituents. Styrene derivatives possessing electron withdrawing groups gave the corresponding chiral epoxides in high yield up to 98% and ee up to 99%. The mechanism for the catalytic asymmetric epoxidation was also discussed based on transfer of oxygen.     

火山岩滤料固定化恶臭假单胞菌条件的优化及其吸附铜离子的研究

利用生物催化方法生产药物的组分已经得到了广泛的认同.由于酶具有高的化学、区域和对映选择性,生物酶催化合成路线已经逐渐取代传统的化学合成路线.水解酶、氧化还原酶是制药行业中最常用的酶,本文主要对这两种酶在制药工业中的应用进行综述.     

天然产物黄檀内酯的研究进展

本文概述了目前已发表的天然产物黄檀内酯在植物中分布、生物合成、全合成及生物活性的研究进展。     

Enantiopure encaged Verkade's superbases: Synthesis,chiroptical properties,and use as chiral derivatizing agent

Verkade's superbases, entrapped in the cavity of enantiopure hemicryptophane cages, have been synthesized with enantiomeric excess (ee) superior to 98%. Their absolute configuration has been determined by using electronic circular dichroism (ECD) spectroscopy. These enantiopure encaged superbases turned out to be efficient chiral derivatizing agents for chiral azides, underlining that the chirality of the cycloveratrylene (CTV) macrocycle induces different magnetic and chemical environments around the phosphazide functions.     

Synthesis of novel C2-symmetrical chiral sulfides and their utility in asymmetric epoxidation of aldehydes

Novel C(2)-symmetrical chiral sulfides were synthesized from (R,R)-tartaric acid and their utility in the asymmetric epoxidation of aldehydes with benzyl bromide was examined. Among the sulfides used, silyl ether-type sulfides were found to be superior to diol- and benzyl ether-type sulfides. Also, the presence of an aromatic group on the sulfide was proven to be an important factor for increasing enantioselectivity.     

乙醛酸的生物合成法研究进展

简要介绍了乙醛酸的用途及生物合成法的原理,概述了国内外生物合成法生产乙醛酸的研究动态.     

Production of chiral epoxides: Epoxide hydrolase-catalyzed enantioselective hydrolysis

Chiral epoxides are highly valuable intermediates, used for the synthesis of pharmaceutical drugs and agrochemicals. They have broad scope of market demand because of their applications. A major challenge in modern organic chemistry is to generate such compounds in high yields, with high stereo- and regio-selectivities. Epoxide hydrolases (EH) are promising biocatalysts for the preparation of chiral epoxides and vicinal diols. They exhibit high enantioselectivity for their substrates, and can be effectively used in the resolution of racemic epoxides through enantioselective hydrolysis. The selective hydrolysis of a racemic epoxide can produce both the corresponding diols and the unreacted epoxides and vicinal diol has prompted researchers to explore their use in the synthesis of epoxides and diols with high ee values.     

Investigation of the Effects of Squalene and Squalene Epoxides on the Homeostasis of Coenzyme Q10 in Rats by UPLC‐Orbitrap MS

Squalene has been used as a dietary supplement for a long history due to its potential cancer‐preventive function. However, the mechanism has not been investigated in detail yet. Therefore, the aim of this study is to see if the plasma coenzyme Q10 (CoQ10) level will be altered by gavage of squalene and oxidosqualenes to rats. In the present work, a sensitive and simple high‐performance analytical method based on ultra‐high‐performance liquid chromatography coupled with an Orbitrap mass spectrometry (UPLC‐Orbitrap‐MS) was developed for the quantification of CoQ10 in rat plasma. Coenzyme Q9 (CoQ9) was employed as the internal standard. CoQ10 was determined after acetonitrile‐mediated plasma protein precipitation using UPLC‐Orbitrap‐MS in negative ion mode. Intragastric administration of squalene and the two squalene epoxides into rats once daily for several days elevated the level of CoQ10 in their plasma, but there was no significant difference between high‐dose (286 mg/kg) and low‐dose (143 mg/kg) groups. Intragastric administration of squalene once a day for 5 consecutive days and oxidosqualenes once a day for 3 consecutive days is necessary for reaching the steady‐state level of CoQ10. Our present findings indicate that squalene and oxidosqualenes may be useful for stimulating the synthesis of CoQ10 in rats.     

Synthesis,Molecular Modeling,and Biological Evaluation of Novel Chiral Thiosemicarbazone Derivatives as Potent Anticancer Agents

A series of new chiral thiosemicarbazones derived from homochiral amines in both enantiomeric forms were synthesized and evaluated for their in vitro antiproliferative activity against A549 (human alveolar adenocarcinoma), MCF‐7 (human breast adenocarcinoma), HeLa (human cervical adenocarcinoma), and HGC‐27 (human stomach carcinoma) cell lines. Some of compounds showed inhibitory activities on the growth of cancer cell lines. Especially, compound 17b exhibited the most potent activity (IC₅₀ 4.6 μM) against HGC‐27 as compared with the reference compound, sindaxel (IC₅₀ 10.3 μM), and could be used as a lead compound to search new chiral thiosemicarbazone derivatives as antiproliferative agents. Chirality 27:177–188, 2015. © 2014 Wiley Periodicals, Inc.     

Enantiopure building blocks for chiral drugs from racemic mixtures of secondary alcohols by combination of lipase catalysis and Mitsunobu esterification.

The racemic alcohols 3-chloro-1-(2-thienyl)-1-propanol, 3-chloro-1-phenylpropanol, and 1-chloro-3-(3,4-difluorophenoxy)-2-propanol were converted into a mixture of one enantiomer as butanoate and the other as alcohol by lipase catalysis. Subsequent Mitsunobu esterification without separation proceeded with inversion of the unreacted alcohols to give high yield and ee of the three enantiopure butanoates. The butanoates of opposite configuration were produced in a similar manner, but starting with lipase-catalyzed hydrolysis of the racemic butanoates.