海绵来源真菌天然产物的研究进展

随着海洋药物及其药物先导化合物研究的不断深入,海绵来源微生物,因其种类繁多、代谢产物复杂多样,引发了科研工作者的兴趣。许多化合结构新颖、具有强烈生物活性的化合物从海绵来源真菌中发现,包括多肽、生物碱、聚酮类、萜类等。本文仅就近几年来所报道的海绵来源真菌新天然产物的结构类型及其生物活性做简要介绍。     

南海海绵Pachychalinasp.化学成份的研究

从中国南海海绵Pachychalina sp.正丁醇可溶部分获得了5个化合物,通过UV,IR,~1H-NMR,~(13)C-NMR,MS,~1H-~1HDQFCOSY等实验确定了它们的结构分别是:对羟基苯醋酸甲酯(1),胸腺嘧啶(2),尿嘧啶(3),胸腺嘧啶脱氧核苷(4)和尿嘧啶脱氧核苷(5)。其中化合物(1)是首次从我国南海海洋生物中获得;化合物(5)则是首次从海绵中分离得到的天然产物。     

海洋药物的抗病毒研究

海洋由于其特殊的生态环境,包含着极其丰富的生物来源的天然产物。自本世纪七十年代以来,已经从海藻类、海绵类、海鞘类、海星类、腹足动物、棘皮动物、腔肠动物、软体动物、珊瑚及海洋微生物等海洋生物中分离出一系列有抗病毒作用的天然化合物,其中有些结构类型已成为抗病毒药物研究的导向化合物。基于现代分离和分析技术的发展、新的实验模型的建立和在病毒学方面分子生物学研究的进展,从海洋生物中寻找新的抗病毒药物已步入一个新的时代。     

海洋药物的抗病毒研究

海洋由于其特殊的生态环境,包含着极丰富的生物来源的天然产物。自本世纪七十年代以来,已经从海藻类、海绵类、海鞘类、海星类、腹足动物、棘皮动物、腔肠动物、软体动物、珊瑚及海洋微生物等海洋生物中分离出一系列有抗病毒作用的天然化合物,其中有些结构类型已成为抗病毒药物研究的导向化合物。基本现代分离和分析技术的发展、新的实验模型的建立和在病毒学方面分子生物学研究的进展,从海洋生物中寻找新的抗病毒药物已步入一个     

天然化合物抗真菌活性研究进展

近年来,真菌感染患者的发病率和死亡率持续上升,但现有抗真菌药物种类依然非常少,并且耐药现象的出现使临床可选择的抗真菌药物变得更加有限.因此,对新的抗真菌药物的开发迫在眉睫,从天然产物中寻找新型高效的抗真菌药物成为目前的研究热点之一.从天然产物中筛选出具有抗真菌活性的天然化合物,有助于扩大治疗真菌感染疾病的可选药物种类,减少耐药的发生.该文归纳现有报道的具有抗真菌活性的化合物,根据其不同来源及不同化学结构进行分类,阐明不同类别天然化合物的抗真菌作用机制,为开发新型高效抗真菌药物提供前体结构及抗真菌新靶点.     

海洋真菌代谢产物STb对垂体瘤GH3细胞的毒性作用及其机制探讨

垂体腺瘤是一种严重影响患者生活质量的良性肿瘤,从海洋天然产物筛选具有高效低毒的抗肿瘤药物是目前新药研究的趋势。本实验通过用大鼠垂体瘤GH3细胞系对中山大学化工学院提供的海洋化合物STb（我国南海红树林真菌代谢产物）进行抗垂体瘤活性的筛选,期望能够从海洋天然产物中寻找一种高效的抗垂体瘤药物。     

正青霉属真菌次生代谢产物的研究进展

<正>青霉属(Eupenicillium)真菌作为有性型青霉属的重要分支之一,种类多样,目前已收载了62种。研究发现,该属真菌的次生代谢产物种类多样,具有丰富的化学多样性。本文从菌株来源、化合物结构及其生物活性等方面,综述了自1974年第一个正青霉属真菌天然产物到2016年9月已报道的共66个正青霉属真菌来源的重要天然产物,且50%的化合物表现出细胞毒、抑菌、抗氧化和抗寄生虫等生物活性,为药物的研发提供了潜在的先导化合物,具有很好的研究及药用开发价值。     

植物来源药用天然产物的合成生物学研究进展

大多数药用天然产物在植物中含量低微,提取分离困难;而且这些化合物一般结构复杂,化学合成难度大,还容易造成环境污染。基于合成生物学技术获得药用天然产物具有绿色环保和可持续发展等优点。文中以药用萜类化合物人参皂苷、紫杉醇、青蒿素、丹参酮,生物碱类化合物长春新碱、吗啡以及黄酮类化合物灯盏花素为例,总结了植物来源药用萜类、生物碱类和黄酮类化合物的生物合成途径及合成生物学研究进展,介绍了药用天然产物合成生物学研究的关键技术与方法,并展望了合成生物学技术在药用天然产物研究与开发方面的应用前景。     

海绵来源链霉菌S52-B中氨酰胺天然产物的分离与鉴定

【背景】海洋微生物是复杂海洋生态环境中重要的生物资源之一。海洋微生物所产生的活性天然产物极为丰富,是药物或药物先导化合物的重要来源。【目的】探索海洋中海绵来源链霉菌Streptomycessp.S52-B的优势生长条件,挖掘其次级代谢产物,以期分离具有良好生物活性的天然产物。【方法】根据"One Strain Many Compounds"(OSMAC)策略,寻找利于Streptomyces sp. S52-B生长和次级代谢产物产生的优势培养基,结合质谱及特征性的紫外吸收谱图,选择培养基进行大量发酵。利用正相硅胶柱色谱、葡聚糖凝胶柱色谱和制备型高效液相色谱等进行分离纯化,并应用高分辨质谱和核磁共振光谱进行化合物结构解析。【结果】确定培养基A–D为海洋链霉菌S52-B的优势培养基,基于紫外吸收光谱与质谱分析,从培养基A的大量发酵物中分离鉴定3个具有吡咯并[4,3,2-de]喹啉核心结构的含氯化合物,属于氨酰胺类天然产物,其中Ammosalic acid为新结构化合物。【结论】已知含有吡咯并喹啉母核的氨酰胺类家族化合物具有优良的抗癌活性。本研究从海绵来源链霉菌S52-B中分离鉴定了3个氨酰胺类化合物,其中一个是新结构化合物,不仅丰富了此类化合物家族的结构类型,也为研究其生物合成途径中的未知机理奠定了基础,还有利于结合培养条件和基因组信息从这株海绵来源链霉菌中挖掘新结构的活性天然产物。     

新书介绍

中华海洋本草：海洋天然产物 本书为国家海洋局908专项研究成果之一,是在搜集、提取、整理庞大的国内外海洋天然产物研究数据信息基础上,整编而成的海洋天然产物大型图书。本书主编为我国著名海洋专家,院士,编委包括国内药学界十几位院士及海洋药物研究方面的权威专家．收录了现代海洋天然产物研究获得的2万余个化合物的数据信息,堪称海洋天然产物大全。     

Questioning the evidence of organic compounds called sponge biomarkers

Elevated concentrations of an organic compound, 24‐isopropylcholestane, found in the Precambrian Huqf Supergroup of Oman may provide the oldest known sponge ‘fossil’. This evidence is of critical importance for a properly balanced understanding of the origin of animals. Several different pelagophyte (Class Pelagophyceae part of the Stramenopiles within the Chromaveolata) algae are also capable of producing these exact compounds, and may similarly have done so in deep time. Modern marine algae are also reported to produce structural isomers that are compositionally identical to the sponge marker; they do this in copious quantities. Further, 24‐isopropylcholestane can be produced by diagenetic alteration of compounds produced in large quantities by algae. It is also possible that contamination by petroleum derived lubricating oil used when coring while extracting these compounds from subsurface layers, has affected the data. All extinct organisms that may have produced this compounds are unavailable for analysis by the modern organic chemist and cannot be eliminated from the list of possible producers of the sponge marker. There are also significant uncertainties regarding the dating of the strata from which these ancient compounds are found. Although the compounds are widely reported as c. 751 Ma, they are younger than 645 Ma. It seems more likely that these compounds represent algal biochemical evolution at a time when algal burial occurred in great quantity with well known coeval algal fossils but no sponge fossils. The macroalgal biomass may have declined during the agronomic revolution at the base of the Cambrian Period owing to processing by metazoans, accounting for the comparative scarcity of these sponge markers in Phanerozoic sediments, after which time sponge spicules and body fossils become evident.     

Metagenomic approaches to exploit the biotechnological potential of the microbial consortia of marine sponges

Natural products isolated from sponges are an important source of new biologically active compounds. However, the development of these compounds into drugs has been held back by the difficulties in achieving a sustainable supply of these often-complex molecules for pre-clinical and clinical development. Increasing evidence implicates microbial symbionts as the source of many of these biologically active compounds, but the vast majority of the sponge microbial community remain uncultured. Metagenomics offers a biotechnological solution to this supply problem. Metagenomes of sponge microbial communities have been shown to contain genes and gene clusters typical for the biosynthesis of biologically active natural products. Heterologous expression approaches have also led to the isolation of secondary metabolism gene clusters from uncultured microbial symbionts of marine invertebrates and from soil metagenomic libraries. Combining a metagenomic approach with heterologous expression holds much promise for the sustainable exploitation of the chemical diversity present in the sponge microbial community.     

Chemical Composition during Maturing and Spawning of the Sponge Dysidea herbacea (Porifera: Demospongiae)

Mycosporine-like amino acids (MAAs) have been implicated in many biochemical processes in marine organisms, but the major emphasis has been directed to their role as UV protectant compounds. The quantitation of MAAs, mycosporine-glu-gly, mycosporine-gly, usujirene and palythene in the sponge Dysidea herbacea [34] suggests that whereas some mycosporine amino acids may serve in this capacity, others are intrinsically involved in the reproductive process. The role of other compounds, such as homarine, gadusol and arachidonic acid, in reproduction of this sponge is also discussed.     

Efforts to develop a cultured sponge cell line: revisiting an intractable problem

Residents of the marine environment, sponges (Porifera) have the ability to produce organic compounds known as secondary metabolites, which are not directly involved in the normal growth, development, or reproduction of an organism. Because of their sessile nature, the production of these bioactive compounds has been interpreted as a functional adaptation to serve in an important survival role as a means to counter various environmental stress factors such as predation, overgrowth by fouling organisms, or competition for limited space. Regardless of the reasons for this adaptation, a variety of isolated compounds have already proven to demonstrate remarkable anticancer, fungicidal, and antibiotic properties. A major obstacle to the isolation and production of novel compounds from sponges is the lack of a large, reliable source of sponge material. Sponge collection from the sea would be environmentally detrimental to the already stressed and sparse sponge populations. Sponge production in an aquaculture setting might appear to be an ideal alternative but would also be cost-ineffective and sponge growth is extremely slow. A third approach involves the development of a sponge cell culture system capable of producing the necessary cell numbers to harvest for research purposes as well as for the eventual commercial-scale production of promising bioactive compounds. Unfortunately, little progress has been made in this direction other than the establishment of temporary cultures containing aggregates and fragments of cells. One impediment toward successful sponge cell culture might be ascribed to a lack of published knowledge of failed methodologies, and thus, time and effort is wasted on continued reinvention of the same methods and procedures. Consequently, we have undertaken here to chart some of our unsuccessful research efforts, our methodology, and results to provide the sponge research community with knowledge to assist them to better avoid taking the same failed pathways.     

Novel cytotoxic polyoxygenated steroids from an Okinawan sponge Dysidea sp

A library of extracts established from hundreds of marine organisms was screened by a cytotoxicity test. The active organic extract of an Okinawan marine sponge of the genus Dysidea was subjected to bioassay-guided fractionation to give three new polyoxygenated steroids dysideasterols F-H (1-3), together with two known related compounds (4 and 5). Their structures were confirmed by NMR and mass spectroscopic analyses. A characteristic structural feature of 2, 4 and 5 is an allylic epoxide, whereas this epoxide undergoes ring-opening by a neighbouring hydroxyl group to give a tetrahydrofuran ring in 1 and 3. All compounds 1-5 exhibited a similar cytotoxic effect with IC50 values of 0.15-0.3 μM against human epidermoid carcinoma A431 cells, demonstrating that the allylic epoxide moiety was not responsible for this cytotoxic effect.     

Potential of sponges and microalgae for marine biotechnology

Marine organisms can be used to produce several novel products that have applications in new medical technologies, in food and feed ingredients and as biofuels. In this paper two examples are described: the development of marine drugs from sponges and the use of microalgae to produce bulk chemicals and biofuels. Many sponges produce bioactive compounds with important potential applications as medical drugs. Recent developments in metagenomics, in the culturing of associated microorganisms from sponges and in the development of sponge cell-lines have the potential to solve the issue of supply, which is the main limitation for sponge exploitation. For the production of microalgal products at larger scales and the production of biofuels, major technological breakthroughs need to be realized to increase the product yield.     

Quorum Sensing Antagonism from Marine Organisms

With the global emergence of multiresistant bacteria there is an increasing demand for development of new treatments to combat pathogens. Bacterial cell–cell communication [quorum sensing (QS)] regulates expression of virulence factors in a number of bacterial pathogens and is a new promising target for the control of infectious bacteria. We present the results of screening of 284 extracts of marine organisms from the Great Barrier Reef, Australia, for their inhibition of QS. Of the 284 extracts, 64 (23%) were active in a general, LuxR-derived QS screen, and of these 36 (56%) were also active in a specific Pseudomonas aeruginosa QS screen. Extracts of the marine sponge Luffariella variabilis proved active in both systems. The secondary metabolites manoalide, manoalide monoacetate, and secomanoalide isolated from the sponge showed strong QS inhibition of a lasB::gfp(ASV) fusion, demonstrating the potential for further identification of specific QS antagonists from marine organisms.     

Strongylophorine-8, a pro-electrophilic compound from the marine sponge Petrosia (Strongylophora) corticata, provides neuroprotection through Nrf2/ARE pathway

Green plant-origin electrophilic compounds are a newly-recognized class of neuroprotective compounds that provide neuroprotection through activation of the Nrf2/ARE pathway. Electrophilic hydroquinones are of particular interest due to their ability to become electrophilic quinones upon auto-oxidation. Although marine organisms frequently produce a variety of electrophilic compounds, the detailed mechanisms of action of these compounds remain unknown. Here, we focused on the neuroprotective effects of strongylophorine-8 (STR8), a para-hydroquinone-type pro-electrophilic compound from the sponge Petrosia (Strongylophora) corticata. STR8 activated the Nrf2/ARE pathway, induced phase 2 enzymes, and increased glutathione, thus protecting neuronal cells from oxidative stress. Microarray analysis indicated that STR8 induced a large number of phase 2 genes, the regulation of which is controlled by the Nrf2/ARE pathway. STR8 is the first example of a neuroprotective pro-electrophilic compound from marine organisms.     

Influence of size and spatial competition on the bioactivity of coral reef sponges

Sponges biosynthesize a wealth of secondary metabolites, many with novel structures and strong biological activity. Such compounds may serve multiple ecological roles including anti-predation, anti-fouling functionalities and are implicated in border defense or attack during spatial competition. Relative size of benthic organisms may also play an important role in competitive interactions. To determine if a relationship exists between individual size and bioactive metabolite production in the context of spatial competition, we examined three sponge species with different morphologies: the massive Coscinoderma matthewsi, the club-shaped branching Hyrtios erecta, and the fan-shaped Ianthella basta. Extracts from sponges of various sizes and competitive environments were examined using a cell based bioassay as a proxy of bioactivity. For I. basta, sponge size was correlated with bioactivity; the largest individuals generally being the most bioactive. In contrast, there was no correlation between size and bioactivity for either C. matthewsi or H. erecta. Bioactivity of sponges in this study were however highly variable among individuals, regardless of levels of competition. The prevalence of encroaching organisms was not correlated with sponge size for any of the three sponge species, suggesting that potential bioactivity is not influenced by surrounding competition.