烯二炔类抗肿瘤抗生素及其靶向药物研究近况

烯二炔类抗生素是一种结构新颖、作用机制独烯二炔结构是其活性中心。该类抗生素具有极强的抗肿瘤活性却因毒性较大难以直接用于临床。近年来,研究人员展开了烯二炔类抗生素靶向药物的研发工作,以提高其肿瘤靶向性并减少药物毒副作用。归纳总结了已报道的天然来源的烯二炔类抗肿瘤抗生素及其活性代谢物,并重点介绍烯二炔类抗生素相关靶向药物的研究进展,旨在为其深度开发提供参考。     

烯二炔类抗癌抗生素的前药研究

近年,在微生物代谢产物的探索研究中,发现了许多新抗癌抗生素,其中最引人注目的是1985年前后相继发现的具有环状烯二炔结构的新型抗生素,包括Calicheamicin、Esperamicin、Dyne-micin A、Neocarzinostatin、C-1027和Kedarcidin(图1),严格来讲,Neocarzinostatin的发色团不含(Z)-烯二炔结构,但由于其作用方式与前几种相同,故仍然被归人该类.由于这类抗生素(1)具有非常强的抗肿瘤活性,(2)其分子中的共轭环状烯二炔结构在天然化合物中是前所未见的,(3)具有经活化形成芳二游离基,迅速夺取两个来自DNA的氢原子,使DNA断裂的新颖抗癌作用机制(图2)等特住,引起世界关注,正在进行多方面的研究.其中,有关烯炔类模型化合物及有关前药的合成研究已有许多报道,并取得不小     

力达霉素抗肿瘤作用及其分子机制研究新进展

力达霉素属于烯二炔类抗肿瘤抗生素,由一个酸性蛋白和一个烯二炔发色团通过非共价键结合而成,通过多种作用机制在体内外对多种肿瘤产生强烈的抗肿瘤作用.目前,力达霉素已经进入Ⅱ期临床研究,本文介绍了力达霉素的抗肿瘤作用和分子作用机制方面的新进展,为进一步研究力达霉素提供参考.     

高通量分离纯化技术在天然产物化学中的应用

天然产物具有极大的化学多样性和复杂性。加快天然产物的纯化速度对快速建立天然产物库及新药研发具有重要意义。采用各类色谱技术快速制备天然产物库以满足高通量筛选的需要,利用色谱与光谱联用技术,将分离纯化及结构信息联系在一起,最终达到高效、快速地从天然产物资源中发现新型结构的活性天然产物的目的。本文对几种高通量技术做一综述。     

烯二炔类抗生素及其靶向药物研究新进展

烯二：炔类抗生素因强的抗肿瘤活性而受到重视。近年报道与单抗偶联的烯二炔类抗生素有力达霉素（Lidamycin LDM）、新制痛菌素（Neocarzinostatin,NCS）和卡利奇霉素（Calicheamicins,CLM）。本文突出阐明了其靶向药物的研究进展,同时也介绍了其辅基蛋白、新型筛选模型、产生菌发酵方面的最新动态。     

抗肿瘤抗生素的临床应用

抗肿瘤抗生素是由微生物产生的具有抗肿瘤活性的化学物质.我国对抗肿瘤抗生素的研究始于50年代,从最初更生霉素的分离到目前烯二炔类抗肿瘤抗生素的研究,50多年来,我国的抗肿瘤抗生素的临床应用得到了广泛的发展.     

世界最大激酶靶点细胞筛选库于中科院建成

从中国科学院获悉,中国科学院强磁场科学中心日前建成目前世界上规模最大的基于癌症激酶靶点的高通量细胞筛选库.该细胞库囊括了近70种癌症激酶靶点,细胞种类达150余种,几乎覆盖了目前已知的与肿瘤发生发展相关的全部激酶及激酶突变细胞.该细胞库的建成,填补了国内新药创制领域此类检测体系的空白,将为抗肿瘤新药研发提供有力支撑.     

天然源抗肿瘤药物研发的一些进展

天然产物在新药及新药先导化合物的发现中起着不可替代的作用,是结构新颖和作用独特的抗肿瘤化合物的重要来源。目前世界上被批准广泛使用的抗肿瘤药物中,一半以上来源于天然产物。本文综述了植物、海洋生物及微生物来源的抗肿瘤药物研发的一些进展。     

功能基因组学在微生物药物筛选中的应用进展

为了加快药物研发进展,解决日益严重的微生物耐药问题,新的微生物药物研究成为了近来研究的重点,其中药物的筛选已成为了新药开发的重要环节.随着分子生物学技术的深入发展,功能基因组学在微生物药物的筛选中得到了广泛的应用和发展.本文主要综述了近年来利用功能基因组学对微生物药物进行筛选的技术发展情况.     

中国创新微生物药物研发获进展

过去5年中国创新微生物药物筛选与发现研究获进展,目前已拥有12万株,40万份的药用微生物菌株和20万个微生物发酵提取品,微生物产物高通量筛选模型150多个,获得了一批微生物药物先导化合物或候选物,为创新微生物药物研发奠定了良好基础。中国医学科学院医药生物技术研究所所长蒋建东今天披透露这一信息时称,中国是拥有生物多样性最多的国家,具有研究开     

PTP-Shp2抑制剂flavoglaucin的发现与研究

目的 以蛋白酪氨酸磷酸酶Shp2(PTP-Shp2)为靶点发现其小分子抑制剂。方法 高通量筛选小分子PTP-Shp2抑制剂并进行动力学分析,利用计算机分子对接分析抑制剂在PTP-Shp2上的结合位点。结果 从本实验室微生物代谢产物化合物库中发现了PTP-Shp2蛋白抑制剂flavoglaucin,其IC50值为5.08μmol/L。米氏方程的双倒数分析证明flavoglaucin是非竞争的PTP-Shp2蛋白抑制剂。计算机分子对接结果显示flavoglaucin结合在PTP-Shp2蛋白的WDP loop上并形成3个氢键。结论 Flavoglaucin是微生物来源的新型小分子PTP-Shp2抑制剂。     

睾酮转化菌的诱变育种

从雄甾二酮的转化产生菌偶发分枝杆菌MF2出发,经紫外诱变结合平板筛选,获得一株主要转化生产睾酮的突变株TS-N-121。该菌株可以胆固醇等单一或混合甾醇作为原料,经一步培养转化生产睾酮,其含量占总转化产物的90%以上,转化率大于80%。     

以人载脂蛋白B为靶点的基因表达下调剂筛选模型的建立与应用

摘要：目的 构建以人ApoB为靶点的基因表达调节剂的高通量筛选模型,筛选apoB基因表达下调剂。方法 以人基因组 DNA为模板,通过PCR扩增apoB基因上游的启动子序列,将扩增的DNA片段克隆至荧光素酶报告基因质粒pGL4.17,采用脂质 体介导的方法将重组质粒转染人肝癌细胞HepG2,经G418抗性筛选,获得稳定转染细胞株。应用槲皮素对筛选模型进行评价, 进而基于检测荧光素酶的表达活性变化筛选人apoB基因表达下调剂。结果 PCR扩增得到人apoB基因上游的启动子序列,构建 完成相应的重组荧光素酶报告基因质粒pGL4-apoB-P,建立了稳定转染细胞株ApoB-Luc HepG2。以槲皮素为阳性化合物进行模 型评价,Z'因子为0.77,符合高通量筛选的要求。应用该模型对5688个微生物发酵液粗提物进行筛选,获得了2株阳性菌株。 结 论 建立了人apoB基因表达下调剂筛选模型,并应用于微生物来源样品的筛选。     

The historical delivery of antibiotics from microbial natural products--can history repeat?

Microbial natural products are the origin of most of the antibiotics on the market today. However, research in antibiotics and natural products has declined significantly during the last decade as a consequence of diverse factors, among which the lack of interest of industry in the field and the strong competition from collections of synthetic compounds as source of drug leads. As a consequence, there is an alarming scarcity of new antibiotic classes in the pipelines of the pharmaceutical industry. Still, microbial natural products remain the most promising source of novel antibiotics, although new approaches are required to improve the efficiency of the discovery process. The impact of microbial biodiversity, the influence of growth conditions on the production of secondary metabolites, the choice of the best approach at the screening step and the challenges faced during the isolation and identification of the active compounds are examined in this review as the critical factors contributing to success in the effort of antibiotic discovery from microbial natural products.     

FR177391, a new anti-hyperlipidemic agent from Serratia. I. Taxonomy, fermentation, isolation, physico-chemical properties, structure elucidation and biological activities

In the course of screening for a new anti-hyperlipidemic agent from microbial products, we found that FR177391, produced by Serratia liquefaciens No. 1821, alleviated the decrease in lipid droplet formation in differentiated 3T3-L1 adipocyte cells, induced by the addition of tumor necrosis factor-alpha. Structural elucidation by spectroscopic methods and X-ray crystallographic analysis of its propylamide derivative revealed that FR177391 was a chlorinated macrocyclic lactone.     

Developing new antibacterials through natural product research

Introduction: Natural products have long been instrumental for discovering antibiotics, but many pharmaceutical companies abandoned this field and new antibiotics declined. In contrast, microbial resistance to current antibiotics has approached critical levels.

Areas covered: This article gives historical perspectives by providing background about present-day economic realities and medical needs for antibiotic research, whose pipeline is mostly focused toward older known agents and newer semi-synthetic derivatives. Future research trends and projected technological developments open many innovative opportunities to discover novel antibacterials and find ways to control pathogenic bacteria without conventional antibiotics that provoke resistance.

Expert opinion: The successful registration of daptomycin, retapamulin and fidaxomicin indicate the re-emergence of natural products has already begun. Semi-synthetic derivatives from other under-explored classes are progressing. More effort is being put into approaches such as total synthesis, discovery of new structural scaffolds for synthesis, alterations of biosynthetic pathways, combinatorial biosynthesis, new screening targets and new resources from which to isolate natural products. A return to successful screening of actinomycetes depends on solving the rate-limiting dereplication obstacle. Long-term solutions need to come from greater exploration of the massive numbers of uncultured microbes. An ultimate solution to the antibiotic-promoted microbial resistance cycle may lie in finding ways to control bacteria by non-lethal means.     

Toxicological considerations for protein components of biological pesticide products.

The toxicity of protein components of microbial pesticide products is evaluated at EPA by requiring that pesticide manufacturers conduct a thorough taxonomic evaluation of the active microbial ingredient. The requirement for acute toxicity testing by dosing laboratory animals with the active microbial ingredient and with fermentation growth medium materials provides additional information on the toxicity of protein components of microbial pesticides. The potential for toxicity from proteins associated with contaminating organisms is addressed by use of appropriate quality control procedures to minimize or prevent growth of contaminants and by screening of fermentation batches for known human/mammalian pathogens. These considerations also would apply to any biochemical pesticide that is formed via the growth of a microorganism. If a protein itself is intended for commercial use as an active pesticide ingredient, acute exposure studies and in vitro digestibility studies could be done to answer potential concerns regarding toxicity.     

Eupenicillum sp.UN88胞内活性物质的分离纯化与结构鉴定

在筛选微生物来源代谢产物的过程中,分离到一株抗真菌活性强的正青霉Eupenicillum sp.UN88,采用溶媒浸提与结晶进行分离和纯化Eupenicillum sp.UN88的发酵产物,得到一个大环内酯类化合物UN88A。经理化性质研究和UV、MS、IR、1HNRM、13CNMR及DEPT及HSBC和HMQC等波谱分析,确定由Eupenicillum sp.UN88产生具有活性的次级代谢产物UN88A的化学结构与布雷菲尔德菌素A相同。     

Investigations into the stability of 17 psychoactive drugs in a “simulated postmortem blood” model

In the postmortem environment, some drugs and metabolites may degrade due to microbial activity, even forming degradation products that are not produced in humans. Consequently, underestimation or overestimation of perimortem drug concentrations or even false negatives are possible when analyzing postmortem specimens. Therefore, understanding whether medications may be susceptible to microbial degradation is critical in order to ensure that reliable detection and quantitation of drugs and their degradation products is achieved in toxicology screening methods. In this study, a “simulated postmortem blood” model constructed of antemortem human whole blood inoculated with a broad population of human fecal microorganisms was used to investigate the stability of 17 antidepressant and antipsychotic drugs. Microbial communities present in the experiments were determined to be relevant to postmortem blood microorganisms by 16S rRNA sequencing analyses. After 7 days of exposure to the community at 37°C, drug stability was evaluated using liquid chromatography coupled with diode array detection (LC-DAD) and with quadrupole time-of-flight mass spectrometry (LC-QTOF-MS). Most of the investigated drugs were found to be stable in inoculated samples and noninoculated controls. However, the 1,2-benzisothiazole antipsychotics, ziprasidone and lurasidone, were found to degrade at a rate comparable with the known labile control, risperidone. In longer experiments (7 to 12 months), where specimens were stored at −20°C, 4°C, and ambient temperature, N-dealkylation degradation products were detected for many of the drugs, with greater formation in specimens stored at −20°C than at 4°C.