新型氮杂多肽酰肼类衍生物的设计、合成和抗肿瘤活性研究

目的:新型氮杂多肽酰肼类衍生物的设计和合成及其抗肿瘤活性研究。方法:以脯氨酸甲酯盐酸盐为原料,通过与苄氧羰基丙氨酸反应,在肼中肼解,得到所需中间体,进而与富马酸单酯反应得到目标化合物;和溴乙酸叔丁酯反应,三氟乙酸中脱去叔丁氧基,再与取代胺或氨水反应得到目标化合物。用MTT法测试合成的氮杂多肽酰肼类衍生物对肿瘤细胞的抑制活性。结果:合成了10个氮杂多肽酰肼类衍生物,其中有6个化合物对肿瘤细胞表现出抑制活性。结论:初步建立了氮杂多肽酰肼类衍生物的合成方法及其对肿瘤细胞抑制活性的构效关系。     

沙雷氏杆菌(Serratia marcescens)红素缩合酶的提取与稳定性的研究

 <正> 红素(Prodigiosin)是某些沙雷氏杆菌(Serratia marcescens)菌株所合成的一种三吡咯衍生物的红色色素,它对某些细菌,真菌和原虫具有抗生作用,因而引起人们的注意。在活菌体内,它由两个中间前体:2-甲基-3-戊基吡咯(MAP)和4-甲氧基-2,2’-双吡咯-5-甲醛(MBC)缩合而成。催化这一反应的酶,我们称之为红素缩合酶。除MAP外,某些人     

神经营养因子功能的“阴/阳”特性

神经营养因子是一类对神经元的营养、支持、分化及突触可塑性等具有重要作用的蛋白质。近年来研究发现神经营养因子合成中的前体分子产生相反的诱导神经元凋亡作用,并在中枢退行性疾病发生中扮演着重要的角色。本文综述了神经营养因子及其前体蛋白在合成代谢、受体调控和功能上的"阴/阳"特性,并讨论其在疾病过程中的可能作用,为进一步探索认识神经营养因子的功能、病理意义、疾病治疗价值提供新的视角。     

白藜芦醇及其水溶性衍生物的合成

目的:合成白藜芦醇及其水溶性衍生物。方法:以3,5-二甲氧基苯甲醛和4-甲氧基碘苯为原料,经Wittig反应,Heck偶联,脱甲基反应,连接侧链等合成白藜芦醇及其衍生物,并使用紫外法测定其在水中的溶解度大小。结果:目标化合物经核磁共振氢谱,质谱等确证为白藜芦醇及其水溶性衍生物,且水溶性提高3倍。结论:该方法的反应路线步骤短,操作简便,对反式产物选择性高。     

计算预测天然产物生物合成

正植物天然产物(Plant natural products,PNPs)及其衍生物是重要的但未被充分开发的药物分子来源。为了利用这种未开发的潜力,在工程微生物中重组植物天然产物及其衍生物生物合成途径可以用于探索和生产新的PNP衍生物。2021年3月19日Nature Communications报道,斯坦福大学研究者开发了一个计算工作流,用于系统地筛选生物分子合成的衍生途径,该工作流在预测代谢工程中的反应、途径和酶上具有很高的价值。     

二硫吡咯酮类抗生素的生物合成与代谢工程应用北大核心CSCD

二硫吡咯酮类抗生素是一类具有独特的吡咯酮二硫杂环戊二烯(4H-[1,2]二硫[4,3-b]吡咯-5-酮)骨架的化合物的总称。基于N-7位酰基侧链的不同以及N-4位是否含有甲基,可分为N-methyl-Nacylpyrrothine、N-acylpyrrothine和thiomarinols等类别。迄今为止,已有27种该类化合物被报道,重要代表包括全霉素(holomycin)、硫藤黄菌素(thiolutin)、金霉素(aureothricin)以及最近发现的thiomarinols。就生物活性而言,二硫吡咯酮类抗生素具有广谱的抗细菌活性,对多种微生物,包括革兰氏阴性菌、革兰氏阳性菌以及寄生虫都有较好的杀灭活性。甚至一些二硫吡咯酮衍生物表现出较强的抗肿瘤活性。近几年来,多个二硫吡咯酮类抗生素的生物合成基因簇相继被报道,其生物合成机理也逐步被阐明。本文将针对目前国内外二硫吡咯酮类抗生素的生物合成研究进展,以及在组合生物合成与代谢工程领域所取得的成果进行综述,旨在为通过合成生物学的方法创造结构新颖、高效低毒的"非天然"二硫吡咯酮类化合物提供理论借鉴。     

丹参酮IIA衍生物的合成

目的:丹参酮IIA是中药丹参的脂溶性成分,具有抗肿瘤、抗氧化、抗心脑血管疾病等多种生理活性。本文拟对其进行结构改造以获得活性更好的丹参酮IIA衍生物。方法:首先,以丹参酮IIA为原料,通过Vilsmeier反应在其16-位引入醛基,再与醋酸胺进行还原胺化反应,以较高收率得到16-位胺甲基取代的丹参酮IIA衍生物。接着,对其氨基进行修饰,得到10个不同N-取代的丹参酮IIA衍生物。同时考察反应温度、反应溶剂和反应时间等条件对还原胺化反应的影响,确定最佳反应条件。结果:通过1H-NMR、13C-NMR以及LC-MS对所有产物结构进行了确认。还原胺化反应的最佳反应条件为:以1,2-二氯乙烷为溶剂,温度保持40℃,反应时间为2h。结论:反应步骤简单、条件温和、产率较高,是合成16-位取代的丹参酮IIA衍生物的理想方法。     

L-酪氨酸苄酯的合成及其影响因素研究

以L-酪氨酸和苯甲醇为原料合成一种新型的L-酪氨酸衍生物——L-酪氨酸苄酯。首先用苯甲醇与氯化亚砜反应生成氯化亚硫酸酯,合成物再与L-酪氨酸发生酯化反应得到L-酪氨酸苄酯,其结构经质谱(MS)分析法确证。在此基础上研究了影响该合成工艺的主要因素,即原料配比、反应温度、反应时间、pH值。结果显示合成L-酪氨酸苄酯的较佳工艺条件为:物料摩尔比mol(SOCl2)∶mol(L-酪氨酸)=1.3∶1.0,室温下反应3h,120℃下反应2h,后处理溶液pH为7.5。本工艺适宜于工业化大规模生产。     

用溴甲基五氟苯衍生气相色谱法测定葡萄浆果中的脱落酸和吲哚-3-乙酸

ＡＢＡ和ＩＡＡ是葡萄浆果中的两个重要激素,用溴甲基五氟苯对其衍生、酯化成各具有５个氟的两种衍生物,这两种酯在气相色谱柱上分离效果良好,对电子检测器反应敏感。该方法操作简单,精确度高     

四种药用异黄酮的全合成北大核心CSCD

研究了以2,4-二羟基苯乙酮(1a)、2,4,6-三羟基苯乙酮(1c)和对溴苯酚(8)、对甲氧基溴苯(9a)为起始原料,利用Negishi交叉偶联反应合成芒柄花素(7a)、大豆苷元(7b)和鹰嘴豆芽素A(7c)、染料木素(7d)四种药用异黄酮化合物的新方法。反应中使用的芳基锌试剂易于制备,镍催化剂NiCl2(PPh3)2廉价易得;与其它合成方法相比,芳基锌试剂的制备、取代3-碘色原酮的制备和Negishi交叉偶联反应都是在室温下进行的,全合成反应不涉及高温,不需要惰性气体保护,操作简便、后处理简单,反应条件温和,对环境友好,产品产率高,具有潜在的应用价值。     

MCR III1. Multicomponent Reactions and Their Libraries,a New Type of Organic Chemistry of the Isocyanides and Phosphorus Derivatives.

Abstract

Various new one-pot multicomponent reactions (MCRs) of C^II and P^III derivatives and their libraries are described here. The preparation of some nucleobase- and phospholipid compound libraries by MCRs have been carried out.

     

Relation of structural features to pyrrolic metabolites in livers of rats given pyrrolizidine alkaloids and derivatives

Levels of pyrrolic metabolites have been measured in the livers of rats given some pyrrolizidine alkaloids and semisynthetic derivatives. Structural and chemical features favouring the formation of such metabolites have been defined. The most important of these were: steric hindrance or chemical properties giving resistance to ester hydrolysis; lipophilic character, allowing access to hepatic microsomal enzymes; a conformation favoring microsomal oxidation of the pyrroline ring in preference to N-oxidation. In addition, the presence of ester groups gave the resulting pyrroles high chemical reactivity, leading to tissue binding.Amounts of pyrroles bound to liver were very low when animals were given either highly water soluble pyrrolizidine derivatives, including non-esterified bases or more-lipophilic esters if these were easily hydrolysed. Compounds prone to hydrolysis gave increased pyrrole levels in rats pretreated to deplete their esterase activity. Whereas heliotridine-based alkaloids usually give more pyrrole than similar retronecine esters, heliotridine ditiglate gave less pyrrole than retronecine ditiglate because the former was more open to hydrolytic attack.Among the carboxylic diesters, the cyclic retronecine diesters, in which the pyrrolizidine nucleus is more exposed to oxidative metabolism, gave the highest pyrrole levels in rats.Liver pyrrole measurements are useful for studying relationships between molecular structure, metabolism and toxicity of pyrrolizidine derivatives. They can be used for screening alkaloids for potential toxicity and for assessing dose levels suitable for toxicity tests when limited material is available.     

POSSIBLE ORIGIN FOR PORPHIN DERIVATIVES IN PREBIOTIC CHEMISTRY – A COMPUTATIONAL STUDY

A set of chemical reactions is postulated to account for the formation of the macrocyclic porphin structure, basic to the pyrrole derivatives chlorophyll, protoporphyrin, heme and bilirubin, important in photosynthesis, respiration and digestion. A set of equations is given for the prebiotic synthesis of porphin derivatives from the simple molecules; cyanoacetylene, diacetylene, carbon monoxide and ammonia that have been detected in space. A number of isomers of hydrogenated porphin arise which may lose hydrogen to give ultimately porphin and its dehydrogenated derivative. The reactions, while not unique, provide a pathway which has been shown to be feasible from the overall enthalpy changes in the ZKE approximation at the HF and MP2/6-31G* level     

Antimycobacterial compounds. New pyrrole derivatives of BM212

We have identified BM212 as a lead compound among a series of pyrrole derivatives with good in vitro activity against mycobacteria and candidae. First studies led us to synthesize some pyrrole compounds in which the thiomorpholine fragment was present. Some compounds revealed very active and these findings prompted us to prepare new pyrrole derivatives 2-15 in the hope of increasing the activity. The microbiological data showed interesting in vitro activity against Mycobacterium tuberculosis and atypical mycobacteria.     

A theoretical study of the sequence specificity in binding of lexitropsins to B-DNA

A theoretical study is presented on the binding to B-DNA of a series of lexitropsins, these ligands being netropsin derivatives in which one or both of the pyrrole rings have been replaced by imidazoles. The best complexes have been located by energy minimisation taking into account nucleic acid flexibility, ligand flexibility, explicit, mobile counterions and solvent dielectric effects. Calculations have been performed for two homopolymeric DNA receptor sequences, AT base sequence, which only decreases in the imidazole derivatives. These results emphasize the decisive role of the molecular electrostatic potential of the nucleic acid in determining the sequence selectivity of these ligands, as opposed to the postulated role of adenine C2 - pyrrole beta hydrogen contacts.     

A novel and one-pot synthesis of new 1-tosyl pyrrol-2-one derivatives and analysis of carbonic anhydrase inhibitory potencies

Here we propose a novel one-pot synthesis of new tosyl-pyrrole derivatives. By means of the new developed method, pyrrole derivatives were synthesized at room temperature in a single step, and a useful method is proposed for the synthesis of similar compounds. Moreover, inhibitions of two human cytosolic carbonic anhydrase (hCA, EC 4.2.1.1) isozymes I and II by 1-tosyl-pyrrole and 1-tosyl-pyrrol-2-on derivatives were investigated. 1-Tosyl-pyrrole, 1-tosyl-1H-pyrrol-2(5H)-one, 5-hydroxy-1-tosyl-1H-pyrrol-2(5H)-one and 5-oxo-1-tosyl-2,5-dihydro-1H-pyrrol-2-yl acetate showed inhibitory action with K_i values in the range of 14.6–42.4 μM for hCA I and 0.53–37.5 μM for hCA II, respectively. All pyrrole derivatives were competitive inhibitors with 4-nitrophenylacetate as substrate. Some new synthesized pyrrole derivatives showed very effective hCA II inhibitory effects, in the same range as the clinically used sulfonamide acetazolamide, and might be used as leads for generating enzyme inhibitors targeting other CA isoforms.     

Polymers of malic acid and 3-alkylmalic acid as synthetic PHAs in the design of biocompatible hydrolyzable devices.

Poly(beta-malic acid) and poly(beta-3-alkylmalic acid) derivatives, as synthetic polyhydroxyalkanoates (PHAs), present several advantages as macromolecular materials for temporary biomedical applications. Indeed, such polymers, which can be synthesized through different chemical and biological routes, have cleavable ester bonds in their backbone for hydrolytic degradation, stereogenic centres in the monomers units for controlling the macromolecular structure. bioassimilable or non-toxic repeating units and lateral chemical functions which can be adapted to specific requirements. The strategy for building such complex architectures, with one or several specific pendant groups, is based on the anionic ring-opening polymerization or copolymerization of the large family of malolactonic and 3-alkylmalolactonic acid esters. Because we are able to control the monomer synthesis and the polymerization step, we have been able to prepare different degradable materials for the biomedical field, such as: degradable associating networks made up by the association of random copolyesters containing a small percentage of hydrophobic moieties and beta-cyclodextrin copolymers; degradable macromolecular micelles constituted by degradable amphiphilic block copolymers of poly(beta-malic acid) as hydrophilic segments and poly(beta-alkylmalic acid alkyl esters) as hydrophobic blocks; and degradable nanoparticles made up by hydrophobic poly(beta-malic acid alkyl esters) derivatives. We have also prepared a terpolymer which exhibits growth factor-like properties in vivo. Finally, poly(beta-malic acid) has been used as an additive in the preparation of peritoneal dialysis bags.     

Novel benzoyl nitrogen mustard derivatives of pyrazole analogues of distamycin A: synthesis and antileukemic activity

The design and synthesis of novel benzoic acid mustard (BAM) derivatives of distamycin A bearing one or more pyrazole rings replacing the pyrrole rings of the latter are described. In vitro and in vivo activities against L1210 leukemia are reported and discussed. Some of these compounds show an activity profile comparable to tallimustine 1. All the compounds bearing the pyrazole ring close to the BAM moiety show reduced cytotoxicity in comparison to derivatives characterized by the BAM linked to a pyrrole: the same effect has not been observed when occurring at the amidine terminus of the oligopeptidic frame.     

Recent advances in isocyanide-based multicomponent chemistry

Multicomponent reactions (MCRs) provide a powerful tool towards the one-pot synthesis of diverse and complex compounds on the one hand and small and 'drug-like' heterocycles on the other hand. No other single synthesis technology enables chemists to search such large chemical spaces as provided by MCRs. MCRs that involve isocyanides are by far the most versatile reactions in terms of scaffolds and number of accessible compounds.     

锂离子电池层状正极材料的研究进展

从结构、性能、合成工艺及其应用等方面,综述了锂离子电池正极材料LiCoO2、LiNiO2及其衍生物的研究进展。着重介绍了LiNi1-xCoxO2材料的合成方法、电化学性能及其改性的最新成果。