抗溃疡性结肠炎新药IPSALAZIDE的合成

以对硝基苯甲酸为原料,经氯化后,被氨基乙酸取代,得到对硝基苯甲酰氨基乙酸,再经还原,重氮化后,与水杨酸偶合,合成了抗溃疡性结肠炎新药－５［［４－［（羧甲基）甲酰氨］苯］偶氮基］水杨酸（Ｉｐｓａｌａｚｉｄｅ）。并做了红外光谱鉴定。     

抗溃疡性结肠炎新药—Balsalazide的合成

以对硝基苯甲酸为原料,经氯化后,被β—氨基丙酸取代,得到对硝基苯甲酰—β—氨基丙酸,再经还原、重氮化后,与水杨酸偶合,合成了抗溃疡性结肠炎新药—５—〔［４［（β－羧乙基）甲酰氨］苯］偶氮基〕水杨酸（Ｂａｌｓａｌａｚｉｄｅ）,并做了红外光谱鉴定。     

花旗松素衍生物的设计、合成及抗炎活性构效关系研究北大核心CSCD

以邻羟基苯乙酮衍生物和苯甲醛衍生物为原料,经缩合、氧化、水解生成A环和/或B环取代的花旗松素衍生物4a^4o。以邻氨基苯乙酮衍生物和苯甲醛衍生物为原料,经同样的方法得到C环改变的花旗松素衍生物4p^4r。共设计合成19个化合物,其结构经核磁共振氢谱、碳谱分析确证。测定所合成化合物对小鼠巨噬细胞RAW264. 7的体外抗炎活性。结果表明:A环上的5,7位酚羟基是其发挥活性的关键性基团; B环4/位的卤素取代基对于活性影响极大,特别是氟原子的取代效果尤其显著;改变C环的结构都会使其炎症因子的抑制作用降低。     

花旗松素衍生物的设计、合成及抗炎活性构效关系研究

以邻羟基苯乙酮衍生物和苯甲醛衍生物为原料,经缩合、氧化、水解生成A环和/或B环取代的花旗松素衍生物4a~4o。以邻氨基苯乙酮衍生物和苯甲醛衍生物为原料,经同样的方法得到C环改变的花旗松素衍生物4p~4r。共设计合成19个化合物,其结构经核磁共振氢谱、碳谱分析确证。测定所合成化合物对小鼠巨噬细胞RAW264. 7的体外抗炎活性。结果表明:A环上的5,7位酚羟基是其发挥活性的关键性基团; B环4/位的卤素取代基对于活性影响极大,特别是氟原子的取代效果尤其显著;改变C环的结构都会使其炎症因子的抑制作用降低。     

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。     

内消旋-二氨基庚二酸脱氢酶不对称合成非天然手性D-氨基酸的研究进展

内消旋-二氨基庚二酸脱氢酶不对称合成非天然的手性D-氨基酸是目前生物催化领域的研究热点。内消旋-二氨基庚二酸脱氢酶具有优良的立体选择性,利用其进行酶催化不对称合成光学纯的手性D-氨基酸,被广泛用于医药、食品、化妆品、精细化学品等领域。为了促进生物催化法在合成手性D-氨基酸方向的进一步发展,本文对内消旋-二氨基庚二酸脱氢酶催化合成D-氨基酸的现状进行了综述。重点介绍了Corynebacterium glutamicum、Ureibacillus thermosphaericus、Symbiobacterium thermophilum来源的内消旋-二氨基庚二酸脱氢酶在新酶的挖掘、催化性能、晶体结构解析、分子改造、功能与催化机制、合成D-氨基酸新途径等方面的研究进展,并对内消旋-二氨基庚二酸脱氢酶的未来研究方向及策略进行了展望。本综述将进一步加深人们对内消旋-二氨基庚二酸脱氢酶的认识,也为具有挑战性的生物合成任务提供信息借鉴。     

β-N-乙酰氨基己糖苷酶及其合成寡糖的研究进展

β-N-乙酰氨基己糖苷酶(EC.3.2.1.52)是一类重要的糖苷水解酶,在自然界中催化简单的β-N-乙酰氨基己糖苷或复杂的寡糖链、多糖链中末端N-乙酰己糖苷键的水解,在微生物、植物和动物中广泛分布,具有重要的生物学功能。某些种类的β-N-乙酰氨基己糖苷酶在一定的人为条件下水解β-N-乙酰氨基己糖苷键的同时还具有转糖基作用,能将β-N-乙酰氨基己糖基转移到不同的羟基化合物上,合成β-N-乙酰氨基己糖苷化合物,在糖链合成上具有应用的潜力。本文综述了β-N-乙酰氨基己糖苷酶的结构和催化机制、酶的生物学功能以及酶在β-N-乙酰氨基己糖苷化合物合成中的应用,以促进β-N-乙酰氨基己糖苷酶的进一步研究和开发应用。     

抗肿瘤药物帕玛度胺类似物的合成

目的：设计并合成抗肿瘤药物帕玛度胺的3位N取代的新型类似物。方法：从3-硝基邻苯二甲酸（2）和N-（叔丁氧羰基）．L-谷氨酰胺（4）出发,经过六步反应得到目标化合物。3-硝基邻苯二甲酸（2）经脱水制得3-硝基邻苯二甲酸酐（3）。用N-（叔丁氧羰基）-L-谷氨酰胺（4）经闭环、脱保护制得3-氨基-2,6-哌啶二酮三氟乙酸盐（6）。4与6经缩合、钯碳催化氢化制得免疫调节剂Pomalidomide（8）,（8）经过酰化得到3-乙酰氨基-N-（2,6-二氧代-3-哌啶基）邻苯二甲酰亚胺（1）。以（4）计总收率约34．9％。结果：得到3-乙酰氨基-N-（2,6-二氧代-3-哌啶基）-邻苯二甲酰亚胺（1）,应用于细胞活性测试。结论：改进了帕玛度胺的合成工艺,得到了3位N乙酰化的新型帕玛度胺类似物（1）,初步研究显示（1）的生物活性与帕玛度胺接近。     

葡萄糖氨基醌类的合成

由于一般小分子醌属于脂溶性化合物,常不溶于水,不能直接静脉给药,限制了其临床应用。为此在各类醌母环上设法引入亲水性葡萄糖氨基,增强醌分子极性和溶解性,改善母体结构的生物活性。本文探讨了氨基葡萄糖对含不同结构类型芳环的对、邻醌亲核加成合成反应的影响。以四氯苯醌、2,3-二氯-1,4-萘醌、1,4-萘醌、茜素、茜素红等醌类和氨基葡萄糖盐酸盐为主要原料,吗啡啉和糠胺等为辅料。氨基葡萄糖与等物质的量四氯苯醌反应后,主要生成一元葡萄糖氨基取代三氯苯醌(b),(b)再与等物质的量糠胺或吗啡啉反应,得到具有杂环结构的葡萄糖氨基苯醌(d)和(e)。氨糖与等物质的量2,3-二氯-1,4-萘醌反应可生成一元葡萄糖氨基取代萘醌(i)。而氨糖与等物质的量的1,4-萘醌、茜素及茜素红通过加成-氧化法可分别生成相应氨基醌(h)、(k)、(m)和(n)。加成-氧化法收率高于卤代醌取代法,分离操作相对简单。通过红外、紫外、质谱、核磁等检测手段对产物进行表征。     

胰岛素B_(29)-赖氨酸侧链修饰对其与胰岛素抗体结合的影响

本文报道了若干胰岛素B_(29)-赖氨酸侧链氨基修饰的胰岛素衍生物与胰岛素抗体的结合能力。结果表明B_(29)的侧链氨基用各种不同类型的基团取代后其与胰岛素抗血清的结合能力没有明显变化或有所下降。当两个胰岛素分子的B_(29)-赖氨酸的侧链氨基通过己二酰交联形成二聚体后,其与胰岛素抗体结合力约为胰岛素的38.5±4.9%。     

STUDIES OF THE INTER-RELATIONSHIP BETWEEN CEREBROSPINAL FLUID AND PLASMA AMINO ACID CONCENTRATIONS IN NORMAL INDIVIDUALS

Abstract— —The concentration of free amino acids has been determined in lumbar CSF in 37 fasting normal subjects. The values obtained have been compared with the concentration of the same amino acids measured in venous plasma collected simultaneously and with ventricular CSF amino acid concentrations. Twenty-three amino acids have been identified and quantitated in CSF and plasma. Trace quantities of eight other amino acids have been also detected.
The concentration of 13 amino acids in CSF has been shown to be directly related to the plasma concentration. No such relationship was noted for the other 7 amino acids. Significant variations in the concentration of individual amino acids relating to both age and sex have been noted. A large number of unidentified ninhydrin positive compounds have been found in CSF. Preliminary studies have identified one of these as ɛ-aminobutyric acid (GABA).     

Non-protein amino acids in plant defense against insect herbivores: representative cases and opportunities for further functional analysis

Chemical defense against herbivores is of utmost importance for plants. Primary and secondary metabolites, including non-protein amino acids, have been implicated in plant defense against insect pests. High levels of non-protein amino acids have been identified in certain plant families, including legumes and grasses, where they have been associated with resistance to insect herbivory. Non-protein amino acids can have direct toxic effects via several mechanisms, including misincorporation into proteins, obstruction of primary metabolism, and mimicking and interfering with insect neurological processes. Additionally, certain non-protein amino acids allow nitrogen to be stored in a form that is metabolically inaccessible to herbivores and, in some cases, may act as signals for further plant defense responses. Specialized insect herbivores often possess specific mechanisms to avoid or detoxify non-protein amino acids from their host plants. Although hundreds of non-protein amino acids have been found in nature, biosynthetic pathways and defensive functions have been elucidated in only a few cases. Next-generation sequencing technologies and the development of additional plant and insect model species will facilitate further research on the production of non-protein amino acids, a widespread but relatively uninvestigated plant defense mechanism.     

A review of adsorption of amino acids on minerals: Was it important for origin of life?

Minerals more readily adsorb amino acids with charged R groups than uncharged R groups, so that the incorporation of amino acids with charged R groups into peptides would be more frequent than for amino acids with uncharged R groups. However, 74% of the amino acids in the proteins of modern organisms contain uncharged R groups. Thus, what could have been the mechanisms that produced peptides/proteins with more amino acids with uncharged R groups than precursors with charged R groups? Should we expect the composition of amino acids adsorbed on minerals to be similar to those of present proteins? Was the adsorption of amino acids on minerals important for the origin of life? The lipid world offers an alternative view of origin of life. Liposomes contributed to elongation of peptides as well as select hydrophobic amino acids and peptides. These experiments could be showing the mechanism, which hydrophobic amino acids have been selected. However, liposomes have no influence on the stereoselectivity in the oligomerization of amino acids. In the present paper, several other mechanisms are also discussed that could produce peptides with a greater proportion of amino acids with uncharged R groups.     

The atmosphere of the primitive Earth and the prebiotic synthesis of amino acids

The atmosphere of the Earth at the time of its formation is now generally believed to have been reducing, an idea proposed by Oparin and extensively discussed by Urey. This atmosphere would have contained CH₄, N₂ with traces of NH₃, water and hydrogen. Only traces of NH₃ would have been present because of its solubility in water. UV light and electric discharges were the major sources of energy for amino acid synthesis, with electric discharges being the most efficient, although most other sources of energy also give amino acids.The first prebiotic electric discharge synthesis of amino acids showed that surprisingly high yields of amino acids were synthesized. Eleven amino acids were identified, four of which occur in proteins. Hydroxy acids, simple aliphatic acids and urea were also identified. These experiments have been repeated recently, and 33 amino acids were identified, ten of which occur in proteins, including all of the hydrophobic amino acids.Methionine can be synthesized by electric discharges if H₂S or CH₃SH is added to the reduced gases. The prebiotic synthesis of phenylalanine, tyrosine and trytophan involves pyrolysis reactions combined with plausible solution reactions.Eighteen amino acids have been identified in the Murchison meteorite, a type II carbonaceous chondrite, of which six occur in proteins. All of the amino acids found in the Murchison meteorite have been found among the electric discharge products. Furthermore, the ratios of amino acids in the meteorite show a close correspondence to the ratios from the electric discharge synthesis, indicating that the amino acids on the parent body of the carbonaceous chondrites were synthesized by electric discharges or by an analogous process.     

alpha,alpha'-disubstituted amino acids with silylated side chains as lipophilic building blocks for the synthesis of peptaibol analogues

New alpha,alpha'-disubstituted amino acids with silylated side chains have been synthesized in racemic form. Starting from a Schiff base of glycine tert-butyl ester, a large variety of alpha,alpha'-dialkylated amino acids has been obtained, depending on the alkylating reagents. The application of a hydrosilylation methodology enabled the synthesis of the same unnatural amino acids in an enantiomerically pure form. The ability of these bulky amino acids to be incorporated into peptides by solution-phase methodology has also been demonstrated, since constrained silylated dipeptides have been synthesized. These new lipophilic building blocks could be useful and innovative in the design of peptaibol analogues.     

大杯香菇辐射新株系各类氨基酸的遗传主成分分析

对大杯香菇辐射选育新株系的各类氨基酸总量进行了遗传主成分分析。结果表明,变异系数最大的为硫氨基酸总量,达到13．39％;其次为儿童氨基酸总量,变异系数为7．00％;其它变异系数较小分别为甜味氨基酸总量、芳香族氨基酸总量、必需氨基酸总量、支链氨基酸总量和鲜味氨基酸总量为5．69％、5．64％、5．19％、5．24％和5．06％;在相关性上,鲜味氨基酸总量与甜味氨基酸总量、支链氨基酸总量、芳香族氨基酸总量、儿童氨基酸总量和必需氨基酸总量是呈极显著和显著的正相关,甜味氨基酸总量与支链氨基酸总量、儿童氨基酸总量和芳香族氨基酸总量呈极显著和显著的正相关,硫氨基酸总量与儿童氨基酸总量呈极显著负相关,与必需氨基酸总量是呈极显著正相关;支链氨基酸总量与芳香族氨基酸总量、必需氨基酸总量是呈极显著,与儿童氨基酸总量呈显著正相关;芳香族氨基酸总量与儿童氨基酸总量和必需氨基酸总量是呈极显著和显著的正相关;主成分分析结果表明,前4个特征根在7个特征根中累计贡献率达97．14％,也就是前4个主成分对变异的贡献率达96．07％。在各类氨基酸总量指标选择上,首先对变异大的各类氨基酸总量进行选择是及其重要的。在辐射选育新株系选择时,应注意选择大杯香菇中硫氨基酸总量高的新株系。     

The use of mutants and transgenic plants to study amino acid metabolism

Mutants of higher plants with alterations in amino acid metabolism have now been available for 20 years. Following the realization that at least four distinct classes of herbicides (phosphinothricins, glyphosates, imidazolinones and sulphonylureas) act by the inhibition of amino acid biosynthesis, mutants resistant to the herbicides have also been obtained. More recently, transgenic plants containing altered levels of enzymes of amino acid biosynthesis have been constructed. In this article, we have attempted to review several areas of amino acid biosynthesis including ammonia assimilation, the aspartate pathway, branched chain amino acids, aromatic amino acids and proline.     

The interaction of amino acids with o-phthaldialdehyde: A kinetic study and spectrophotometric assay of the reaction product

A detailed study has been made of the kinetics of interaction between amino acids and esters of amino acids and o-phthaldialdehyde in the presence of mercaptoethanol. The reaction products have been characterized. A spectrophotometric method for quantitative analysis of all amino acids, except proline and hydroxyproline, has been developed. The possibility of determination of amino acid esters in mixtures containing free amino acids has been demonstrated. It is noted that determination of glycine and histidine with the help of o-phthaldialdehyde has certain specificities associated with faster, compared to other amino acids, degradation of their derivatives. Optimal conditions for quantitative analysis of amino acids in solutions of higher than 10^?5m concentration are recommended. The reproducibility of the determination was ±2%.     

Genetic code correlations: Differential rates of non-enzymatic activation of hydrophobic amino acids by ATP

The relative rates of non-enzymatic activation of several hydrophobic amino acids by ATP have been found to bear an interesting relationship to the ordering of these amino acids in the genetic anticode. All of these hydrophobic amino acids (phe, leu, val, ile and met) have adenylic acid, the most hydrophobic nucleotide, as the central and most important member of their anticodons, and the ordering of their relative rates of nonenzymatic activation by ATP has been found not to correlate with the ordering of the hydrophobicities of the amino acids themselves, but rather with the ordering of the average estimates of the hydrophobicities of their respective anticodonic dinucleotides. These data suggest that the genetic code is based not just on hydrophobic relationships or affinities between amino acids and nucleotides, but perhaps more importantly, on the total reaction chemistry between amino acids and nucleotides.     

Comparative characterization of random‐sequence proteins consisting of 5, 12, and 20 kinds of amino acids

Screening of functional proteins from a random‐sequence library has been used to evolve novel proteins in the field of evolutionary protein engineering. However, random‐sequence proteins consisting of the 20 natural amino acids tend to aggregate, and the occurrence rate of functional proteins in a random‐sequence library is low. From the viewpoint of the origin of life, it has been proposed that primordial proteins consisted of a limited set of amino acids that could have been abundantly formed early during chemical evolution. We have previously found that members of a random‐sequence protein library constructed with five primitive amino acids show high solubility (Doi et al., Protein Eng Des Sel 2005;18:279–284). Although such a library is expected to be appropriate for finding functional proteins, the functionality may be limited, because they have no positively charged amino acid. Here, we constructed three libraries of 120‐amino acid, random‐sequence proteins using alphabets of 5, 12, and 20 amino acids by preselection using mRNA display (to eliminate sequences containing stop codons and frameshifts) and characterized and compared the structural properties of random‐sequence proteins arbitrarily chosen from these libraries. We found that random‐sequence proteins constructed with the 12‐member alphabet (including five primitive amino acids and positively charged amino acids) have higher solubility than those constructed with the 20‐member alphabet, though other biophysical properties are very similar in the two libraries. Thus, a library of moderate complexity constructed from 12 amino acids may be a more appropriate resource for functional screening than one constructed from 20 amino acids.