天然药物化学研究与新药开发

自从有人类历史以来,天然药物一直是人类防病治病的主要来源。天然产物是自然界的生物历经千百万年的进化过程通过自然选择保留下来的二次代谢产物,具有化学多样性、生物多样性和类药性。临床上应用的许多药物都直接或间接来源于天然产物,如天然产物可作为药物半合成的前体物、药物化学合成的模板以及为药物设计提供了新的思路。但是在20世纪80~90年代,由于受高通量筛选和组合化学的影响,天然药物的研究一度进入低谷。近10年来天然药物化学在新药研发中的作用又重新受到科学家的重视,天然产物已成为发现治疗重大疾病的药物或重要先导化合物的主要源泉之一。现就天然药物化学在新药开发中的作用进行了回顾与总结,并对其前景进行了展望。     

Developing a drug-like natural product library

Addressing drug-like/lead-like properties of biologically active small molecules early in a lead generation program is the current paradigm within the drug discovery community. Lipinski's "rule of five" has become the most commonly used tool to assess the relationship between structures and drug-like properties. Sixty percent of the 126 140 unique compounds in The Dictionary of Natural Products had no violations of Lipinski's "rule of five". We have isolated 814 natural products based on their expected drug-like/lead-like properties to generate a natural product library (NPL) in which 85% of the isolated compounds had no Lipinski violations. The library demonstrates the feasibility of obtaining natural products known for rich chemical diversity with the required physicochemical properties for drug discovery. The knowledge generated in creation of the library of structurally characterized pure natural products may provide opportunities to front-load lead-like property space in natural product drug discovery programs.     

新型结构活性天然产物的识别与获取新方法

天然产物与人类健康关系密切。从天然产物中筛选发现新型结构的活性化合物是天然产物化学研究的重点领域。新型结构的活性天然化合物仍是创新药物先导化合物的主要来源之一。天然产物研究者们正在努力寻找有效的新方法，对天然资源样品进行快速分析，在微克级水平高效、快速地鉴定具有结构多样性的天然化合物结构。LC／MS（LC／MS^n）、LC／NMR、LC／NMR／MS、LC／SPE／NMR／MS等色谱-波谱联用技术，在天然产物研究中显示了巨大的威力，是对天然产物进行化学筛选的有效手段，能够达到快速识别和锁定并有针对性地分离获取新型结构化合物的目的。将亲和色谱法与色谱-波谱联用技术结合起来，即将活性筛选与化学筛选在线集成应用，可以大大提高活性天然产物发现的效率和几率，加快药物先导化合物和创新药物的研制速度。     

Challenges and rewards of research in marine natural products chemistry in Brazil

Brazil is blessed with a great biodiversity, which constitutes one of the most important sources of biologically active compounds, even if it has been largely underexplored. As is the case of the Amazon and Atlantic rainforests, the Brazilian marine fauna remains practically unexplored in the search for new biologically active natural products. Considering that marine organisms have been shown to be one of the most promising sources of new bioactive compounds for the treatment of different human diseases, the 8000 km of the Brazilian coastline represents a great potential for finding new pharmacologically active secondary metabolites. This review presents the status of marine natural products chemistry in Brazil, including results reported by different research groups with emphasis on the isolation, structure elucidation, and evaluation of biological activities of natural products isolated from sponges, ascidians, octocorals, and Opistobranch mollusks. A brief overview of the first Brazilian program on the isolation of marine bacteria and fungi, directed toward the production of biologically active compounds, is also discussed. The current multidisciplinary collaborative program under development at the Universidade de S?o Paulo proposes to establish a new paradigm toward the management of the Brazilian marine biodiversity, integrating research on the species diversity, ecology, taxonomy, and biogeography of marine invertebrates and microorganisms. This program also includes a broad screening program of Brazilian marine bioresources, to search for active compounds that may be of interest for the development of new drug leads.     

Biologically active sesquiterpene coumarins from Ferula species

Extracts from different species of the genus Ferula (Apiaceae) have had various biomedical applications for many centuries. Many biological features of this genus such as cytotoxicity, antibacterial, antiviral, P-glycoprotein (P-gp) inhibitory and antiinflammatory activity have been attributed to sesquiterpene coumarins; structures containing a common coumarin group and a sesquiterpene moiety. This both highlights the importance of sesquiterpene coumarins as biologically active natural products and necessitates further studies on these compounds. Taking into account the versatile biological properties of compounds isolated from Ferula and the unprecedented interest in the application of natural products as a new generation of therapeutics, the present review will discuss reports on biological activities of sesquiterpene coumarins of the genus Ferula, from 1990 onwards.     

Recent developments in the field of arrow and dart poisons

Arrow and dart poisons, considered as conventional natural sources for future drug discovery, have already provided numerous biologically active molecules used as drugs in therapeutic applications or in pharmacological research. Plants containing alkaloids or cardiotonic glycosides have generally been the main ingredients responsible for the efficacy of these poisons, although some animals, such as frogs, have also been employed. This paper, without being exhaustive, reports the greater strides made during the past 15 years in the understanding of the chemical nature and biological properties of arrow and dart poison constituents. Examples both of promising biological properties shown by these molecules and of crucial discoveries achieved by their use as pharmacological tools are given. Further studies of these toxic principles are likely to enable scientists to find new valuable lead compounds, useful in many fields of research, like oncology, inflammation and infectious diseases.     

The 2,11-cyclized cembranoids: cladiellins, asbestinins, and briarellins (period 1998-2010)

The 2,11-cyclized cembranoids are isolated from marine invertebrates of Octocorallia species. They are a very interesting class of natural products sharing a common oxatricyclo[6.6.1.0(2,7)]pentadecane core and carrying a varied substituent pattern. This review presents their structural diversity along with the reported biological activities. The 2,11-cyclized cembranoids were comprehensively reviewed previously in 1998, and this contribution will serve as an update of that work. Since 1998 a number of structural assignments of the isolated products have been revised, some as a result of total synthesis efforts. The chemical reactivity of several of the natural compounds has been studied, and the relevance of these findings to the biosynthesis or the generation of isolation artifacts is discussed. The wide range of biological activities displayed by the 2,11-cyclized cembranoids justifies the interest shown within the synthetic chemistry community and suggests that this class of natural products remains a fruitful area for future synthetic and biological research.     

生物碱类化合物抗结核病的研究进展

结核病是全球发病率和死亡率较高的疾病之一,面对越来越严峻的挑战,寻找新途径、新思路研发抗结核病新药是战胜结核病的关键。生物碱类化合物在天然产物中分布广泛,具有生物来源多样性、化学结构多样性和生物活性多样性等特点,大多生物碱类化合物具有抗结核病的活性。综述近年来生物碱类化合物抗结核病作用及其相关机制的研究进展,以期总结不同类型生物碱抗结核病的特点,为该类化合物抗结核病的进一步深入研究与开发利用提供参考。     

达玛烷型三萜皂苷结构修饰研究进展

对达玛烷型三萜皂苷的结构修饰及其构效关系等方面研究成果进行了文献整理和介绍。在中国知识网(CNKI)学术文献总库和Medline数据库中,对近20年达玛烷型三萜皂苷的结构修饰进行检索,针对化学法﹑生物转化法﹑组合化学法等3种修饰方法及构效关系进行了综述,通过对玛烷型三萜皂苷进行结构修饰、结构优化,改善了玛烷型三萜皂苷的理化性质,提高了生物活性,提高了生物利用度,降低了毒副作用。不仅扩大了其临床应用的范围,还可以获得众多新化合物,供生物活性筛选,为充分利用玛烷型三萜皂苷类化合物提供理论依据,玛烷型三萜皂苷类化合物及其衍生物将发挥着更加重要的作用。     

Biosynthesis of unusual aminocyclitol-containing natural products

The aminocyclitol family of natural products is a class of sugar-derived microbial secondary metabolites that demonstrate significant biological activities. Within this class of natural products are the C7N-aminocyclitol-containing compounds, which were originally associated with potent sugar-hydrolase inhibition. However, recent discoveries indicate a broader array of chemical structures and biological activities of this class of compounds. Using both conventional feeding experiments and contemporary molecular genetic approaches, some progress has been made in understanding the biosynthesis of this class of natural products. Results of in silico investigation also suggest a wide distribution of this class of natural products or closely related compounds across different classes of microorganisms, including cyanobacteria and fungi. This review describes our recent progress in the biosynthetic studies of a number of C7N-aminocyclitol-containing compounds and the potential use of bioinformatic approaches to search for novel aminocyclitol-containing natural products.     

Sphaeropsidones, phytotoxic dimedone methyl ethers produced by Diplodia cupressi: a structure-activity relationship study

Sphaeropsidone and episphaeropsidone are two phytotoxic dimedone methyl ethers produced by Diplodia cupressi, the causal agent of a canker disease of cypress in the Mediterranean area. In this study, eight derivatives obtained by chemical modifications and two natural analogues were assayed for phytotoxic and antifungal activities, and a structure-activity relationship was examined. Each compound was tested on nonhost plants and on five fungal pathogenic species belonging to the genus Phytophthora. The results provide insights into structure-activity relationships within these compounds. It was found that the hydroxy group at C-5, the absolute C-5 configuration, the epoxy group, and the C-2 carbonyl group appear to be structural features important in conferring biological activity. The conversion of sphaeropsidone into the corresponding 1,4-dione derivative led to a compound showing greater antifungal activity than its precursor. This finding could be useful in devising new natural fungicides for practical application in agriculture.     

海洋天然产物研究概述

近年来海洋天然产物越来越引起科学家们的注意,在浩瀚的海洋中存在着大量令人激动、活性独特、结构新颖的次生代谢产物。海洋天然产物已成为发现重要先导药物和新的生物作用机制的主要源泉。对目前海洋天然产物研究概况进行综述,其中重点介绍大环内酯类和聚醚类等化合物。     

海绵中活性化学成分的研究进展

海洋生物海绵的活性化学成分研究一直都是海洋药物研究的焦点。目前,从海绵中发现了大量的具有抗微生物、抗炎、抗肿瘤、抗病毒和免疫调节等活性的化学成分,其按照化学结构类型可分为脂类、大环内酯类、肽类、生物碱类、甾醇类和萜类等,并且有很多化合物已经进入临床研究。对近年来从海绵中发现的活性化学成分进行综述。     

Expanding the ChemGPS chemical space with natural products

Recently various attempts have been made to increase the efficacy and precision of chemical libraries used in high-throughput screening (HTS) drug discovery approaches. One such approach is ChemGPS, which provides a defined chemical space for prescreening evaluation of chemical compound properties or virtual dereplication. In the present study, ChemGPS has been applied to a set of natural products shown to exhibit cyclooxygenase-1 and/or -2 (COX-1/2) inhibition. With the purpose of defining chemical properties and linking these to the observed mode of enzyme inhibition, this resulted in two lines of reasoning. On one hand several specific features of these compounds have been identified and discussed. Overall COX inhibition was frequently correlated with the presence of at least one ring in the structure, fragments exhibiting structural rigidity, and a relatively large molecular size. The concept "size" includes several parameters, e.g., molecular volume, weight, and number of bonds. On the other hand, and possibly even more important, was the unexpected finding that the natural products studied to a large extent fell outside the defined ChemGPS chemical space. Therefore, we also propose an expanded space for natural products: ChemGPS-NP.     

海绵药物的研究进展:化学和生物活性

近年来国际上对海洋天然产物的研究日益深入，依托现代大规模药理筛选，目前已有多种结构新颖、药理活性显著且作用机制特殊的海洋天然产物进入临床试验阶段或正在进行临床前研究。海绵种类繁多，代谢途径独特，生存环境多样，共生现象复杂而普遍，多年来一直是海洋天然产物领域最富成果的研究领域之一。本文简要介绍近几年海绵化学成份及其药理活性的研究进展，以供国内同行参考。     

Plant-derived products as antimutagens

Higher plants synthesize a myriad of structurally varied biologically active secondary metabolites. These compounds have been subjected to wide experimental scrutiny for various therapeutic potentials. In this review, the promise of these secondary phytochemicals as natural antimutagens has been focused upon. The compounds belonging to various chemical classes which have until now, been isolated and characterized with potential antimutagenicity are described. Besides making an extensive survey of structurally well characterized antimutagenic agents of the plant kingdom, antimutagenicity screening results of extracts of edible plants such as cereals, pulses, vegetables, oil-seeds and other health and tonic herbs reported up to date are reviewed. © 1998 John Wiley & Sons, Ltd.     

Synthesis and biological characterization of arylomycin B antibiotics

Antibiotics are virtually always isolated as families of related compounds, but the evolutionary forces underlying the observed diversity are generally poorly understood, and it is not even clear whether they are all expected to be biologically active. The arylomycin class of antibiotics is comprised of three related families that are differentiated by nitration, glycosylation, and hydroxylation of a conserved core scaffold. Previously, we reported the total synthesis of an A series member, arylomycin A2, as well as the A series derivative arylomycin C16 and showed that both are active against a broader spectrum of bacteria than previously appreciated. We now report the total synthesis of a B series analogue, arylomycin B-C16, and its aromatic amine derivative. While the aromatic amine loses activity against all bacteria tested, the B series compound shows activities that are similar to the A series compounds, except that it also gains activity against the important pathogen Streptococcus agalactiae.     

Selected Secondary Plant Metabolites for Cancer Therapy

Secondary plant metabolites reveal numerous biological activities making them attractive as resource for drug development of human diseases. As the majority of cancer drugs clinically established during the past half century is derived from nature, cancer researchers worldwide try to identify novel natural products as lead compounds for cancer therapy. Natural products are considered as promising cancer therapeutics, either as single agents or in combination protocols, to enhance the antitumor activity of additional therapeutic modalities. Most natural compounds exert pleotrophic effects and modulate various signal transduction pathways. A better understanding of the complex mechanisms of action of natural products is expected to open new perspectives in coming years for their use alone or in combination therapies in oncology. Two major strategies to identify novel drug candidates from nature are the bioactivity-guided fractionation of medicinal plant extracts to isolate cytotoxic chemicals and the identification of small molecules inhibiting specific targets in cancer cells. In the present review, we report on our own efforts to unravel the molecular modes of action of phytochemicals in cancer cells and focus on resveratrol, betulinic acid, artesunate, dicentrine and camptothecin derivatives.     

糖谱及其在中药多糖质量控制中的应用

多糖是生命四大基础物质之一,兼具有多方面药理活性,是中药主要功效成分之一。近年来,随着分析技术的进步和分子生物学的发展,糖的研究也取得巨大进展,多糖类药物和保健品的研究正成为生命科学研究中又一新的前沿和热点。然而,多糖质量控制是多糖类新药研发中的瓶颈,提高中药多糖质量控制研究至关重要。由于中药多糖化学结构复杂、多样性大,其质量控制一直是难点并极具挑战性。实际上,中药多糖的生物活性与其结构特征密切相关,建立基于结构特征的中药多糖质量控制方法,对于保证中药多糖的安全有效至关重要。因此,该文首先对中药多糖生物活性与其化学结构关系进行归纳总结,提出中药多糖5种作用机制,阐明中药多糖质量控制的必要性和重要性;在此基础上,介绍基于糖谱法的中药多糖质量控制策略和应用,旨在为中药多糖质量研究提供新思路。     

小花鬼针草中咖啡酰奎宁酸类成分及其抑制组胺释放活性

目的研究小花鬼针草B id ens p arv if lora全株的化学成分,并通过抑制组胺释放活性方法寻找生物活性化合物。方法采用硅胶、Sephadex LH-20和ODS柱色谱分离化合物,运用1D NM R,2D NM R等波谱法鉴定了化学结构,通过组胺抑制实验探讨抗炎活性。结果分离鉴定6种咖啡酰奎宁酸类化合物及其甲酯,分别是3,5-二氧咖啡酰奎宁酸(3,5-d i-O-caffeoy lqu in ic ac id,Ⅰ)、3,4-二氧咖啡酰奎宁酸(3,4-d i-O-caffeoy lqu in ic ac id,Ⅱ)、4,5-二氧咖啡酰奎宁酸(4,5-d i-O-caffeoy lqu in ic ac id,Ⅲ)、4-氧-咖啡酰奎宁酸(4-O-caffeoy lqu in ic ac id,Ⅳ)、5-氧-咖啡酰奎宁酸(5-O-caffeoy lqu in ic ac id,Ⅴ)、4-[3-(3,4-二羟基苯基)-丙烯酰氧基]-2,3-二羟基-2-甲基-丁酸{4-[3-(3,4-d ihydroxy-pheny l)-acry loy loxy]-2,3-d ihydroxy-2-m ethy l-bu tyric ac id,Ⅵ}。结论所有化合物均为首次从该植物中分得,化合物Ⅵ为新化合物。这些化合物显示一定的抑制组织胺释放活性。