Chemodiversity in freshwater and terrestrial cyanobacteria - a source for drug discovery

Cyanobacteria are considered a promising source for new pharmaceutical lead compounds and a large number of chemically diverse and bioactive metabolites have been obtained from cyanobacteria over the last few decades. This review highlights the structural diversity of natural products from freshwater and terrestrial cyanobacteria. The review is divided into three areas: cytotoxic metabolites, protease inhibitors, and antimicrobial metabolites. The first section discusses the potent cytotoxins cryptophycin and tolytoxin. The second section covers protease inhibitors from freshwater and terrestrial cyanobacteria and is divided in five subsections according to structural class: aeruginosins, cyanopeptolins, microviridins, anabaenopeptins, and microginins. Structure activity relationships are discussed within each protease inhibitor class. The third section, antimicrobial metabolites from freshwater and terrestrial cyanobacteria, is divided by chemical class in three subsections: alkaloids, peptides and terpenoids. These examples emphasize the structural diversity and drug development potential of natural products from freshwater and terrestrial cyanobacteria.     

Biomolecules produced by mangrove-associated microbes

This review summarizes the sources and characteristics of various natural products that can be extracted from mangrove-associated microbes with a focus on bioactivity, highlighting the unique chemical diversity of these metabolic products.     

南海海绵的结构多样性和生物活性

海绵是重要的海洋生物资源,由于其生态条件特殊,产生的天然产物结构多样、生物活性显著。本文就作者近年对我国南海海绵代谢产物及其生物活性研究的部分结果进行总结,以阐明我国海绵生物资源的结构多样性,为我国海绵作为药用资源的深入研究提供参考依据。     

Mining the microbial metabolome: a new frontier for natural product lead discovery

Traditionally, natural products have been important sources of new leads for the pharmaceutical industry, but with discovery rates of novel structural classes in decline, the need to bioprospect alternate sources of chemical diversity is evident. Microbial genome sequencing projects have revealed the presence of 'silent' biosynthetic gene clusters where there is no current detectable product. Likewise, culture-independent techniques have provided access to the collective genomes of environmental microflora. Both sources of molecular diversity could encode potentially valuable metabolites. The ability to measure the entire complement of metabolites within microorganisms that are used as surrogate hosts to express such gene clusters will be crucial to the exploitation of these yet untapped reservoirs of metabolic diversity for future natural product drug discovery.     

表观遗传修饰法增加真菌次级代谢产物化学多样性的应用

真菌次级代谢产物结构新颖、活性显著,是药物先导化合物的重要来源.然而,大量已知化合物的重复分离限制了传统真菌天然产物研究的快速发展.化学表观遗传修饰法是1种真菌代谢调控的简便、有效方法,其通过在培养基中添加化学表观遗传修饰剂激活真菌的沉默代谢途径获得隐蔽天然产物.本文综述了 2016年至2020年间采用化学表观遗传修饰...     

双联苄类化合物结构多样性的研究进展

目的对双联苄类化合物结构多样性进行综述。方法查阅国内外相关文献29篇,从生源合成、旋阻异构和化学合成三方面介绍双联苄类化合物的结构多样性。结果与结论双联苄化合物是光学活性奇特的天然产物,其结构类型多样,深入研究其结构特征,对理解这类天然产物的构效关系的研究和生物合成都具有指导性作用。     

Natural products as a source of protein kinase activators and inhibitors

Many of the protein kinase activators and inhibitors presently under investigation are natural products or are derivatives of natural products. Since over 500 kinases are encoded by the human genome, the task is to discover modulatory compounds which have high specificity for a single enzyme. Many different low molecular weight compounds have been studied for activity. These come from various sources, such as plants, marine organisms, microorganisms and cyanobacteria. The search for specific inhibitors is mainly performed in cell-based assays.     

Chemistry and biology of fascaplysin, a potent marine-derived CDK-4 inhibitor

Marine natural products offer an abundant source of pharmacologically active agents with great diversity and complexity, and the potential to produce valuable therapeutic entities. Indole alkaloids is one of the important class of marine-derived secondary metabolites, with wide occurrence amongst variety of marine sources such as sponges, tunicates, algae, worms and microorganisms and have been extensively studied for their biological activities. Among this chemical family, a sponge-derived bis-indole alkaloid fascaplysin (1) exhibited broad range of bioactivities including antibacterial, antifungal, antiviral, anti-HIV-1-RTase, p56 tyrosine kinase inhibition, antimalarial, anti-angiogenic, antiproliferative activity against numerous cancer cell lines, specific inhibition of cyclin-dependent kinase-4 (IC(50) 350 nM) and action as a DNA intercalator. In the present review, the chemical diversity of natural as well as synthetic analogues of fascaplysin has been reviewed with a detailed account on synthetic reports and pharmacological studies. Our analysis of the structure-activity relationships of this family of compounds highlights the existence of various potential leads for the development of novel anticancer agents.     

Approaches to target profiling of natural products

Natural products have long been regarded as excellent sources for drug discovery given their structural diversity and wide variety of biological activities. Accordingly, the identification of the molecular targets of natural products is an important aspect of current drug discovery, as knowledge regarding a compound's molecular targets will greatly aid drug development and design. In this review, we will explore genomic, proteomic, and computational approaches to the elucidation of these mechanisms and the implications of these approaches for the target profiling of natural products. The recent applications of target profiling of natural products will also be reviewed.     

Discovery of tryptamine derivatives from Bacillus sp. PKU-TA00001

Tryptamine-derived natural products have been discovered from different sources including animals, plants and bacteria,and they show various biological activities. However, they are not discovered widely compared with the large amounts of tryptaminederivatives generated by chemical synthesis. We here report the discovery of five tryptamine-derived natural products (1–5) and one known polyketide 6 from Bacillus sp. PKU-TA00001. Compounds 1 and 2are new compounds featuring methyl-hexanamide moieties, compound 4is first discovered as a natural product, and 3 and 4’s NMR data are first provided. All compounds showed MIC (minimum inhibitory concentration) values higher than 50 µM against several Gram-positive and negative strains, and showed no cytotoxicity at the concentration of 100 µM against the human cancer cell lines A549, HCT-8 and MCF-7. The discovery of 1–4expands the structural diversity of tryptamine-derived natural products, and sets the stage for revealing their biosynthetic mechanisms and biological activities in the future.     

Rapid assembly of molecular diversity via exploitation of isocyanide-based multi-component reactions

Molecular diversity is the variability of physical properties between molecules, viewed in terms of molecular shape, polarity/charge, lipophilicity, polarizability and flexibility. Due to their widespread medicinal properties, natural products were one of the original sources of molecular diversity; however, new developments in the search for novel pharmacological agents over the last decade have focused on the preparation of chemical libraries as the source of new leads for drug discovery. A plethora of personal synthesizers and new automation technologies have emerged to help fuel the lead discovery engines of drug discovery organizations. Multistep solid-phase syntheses of diverse libraries in excess of 10,000 products can now be prepared via split-and-mix techniques. Simultaneously, a multitude of more efficient, diversity- or target-oriented solution-phase chemical methodologies have appeared in the chemical literature, enabling the relatively facile construction of successful lead generation libraries with low full-time equivalent input and little capital expenditure. Isocyanide-related multi-component reactions hold a pre-eminent position in this regard, and are finding increasing applications in the discovery process of new drugs and agrochemicals. This review is the authors' personal assessment of advances in the field over the last two years (2002 to 2003), with little emphasis placed on highly mechanistic details.     

Thoughts and facts about antibiotics: Where we are now and where we are heading

The declining trends in microbial metabolite and natural products research and the refocusing of this research area are discussed. Renewing natural products research requires inexhaustible natural resources, as well as new genetic techniques and microbial sources, including endophytic microbes. The numbers of known bioactive metabolites are summarized according to their microbiological origin, biological activities and chemical structures. Synthetic and natural product-based libraries are also compared. Importantly, the wide range of microbial metabolite bioactivities, future trends and the importance of prioritizing natural products over synthetic compounds are emphasized.     

The role of pharmacognosy in modern medicine and pharmacy

This review details the contribution to modern medicine and pharmacy made by natural products and drugs derived from natural products, with an emphasis on essential medicines and new introductions to the market. Areas covered include recent advances in the development of drugs derived from marine organisms, microbes, terrestrial animals, and vascular plants, and current issues regarding botanical medicines. The role of natural products in drug discovery and development is evaluated, particularly with regard to their value as sources of drug leads with "drug-like" properties. A rationale for the success of natural products research in providing new drugs and drug prototypes is presented, drawing on lines of evidence from chemical informatics and chemical ecology. Several innovative strategies for natural products drug discovery and evaluation of botanical medicines are also reviewed.     

海洋来源的放线菌次级代谢产物及其生物活性

放线菌是迄今最重要和最大的药用微生物种群。海洋放线茵生存于苛刻特殊的海洋环境，使其具备了复杂独特的代谢途径，其次级代谢产物在结构类型以及在生物活性等方面都呈现出与陆生放线茵不同的特点和多样性。多年来，诸多结构新颖、生物活性显著的天然活性产物持续从海洋来源放线茵代谢产物中被发现，这些活性化合物为新药研究提供了丰富的先导化合物，有些已进入研发阶段。近年，海洋放线茵活性产物的研究仍然是海洋微生物产物研究中值得关注的一个热点。本文按化舍物结构类型简要介绍了海洋来源放线茵代谢产物及其生物活性的研究概况。     

Molecular Scaffold Analysis of Natural Products Databases in the Public Domain

Natural products represent important sources of bioactive compounds in drug discovery efforts. In this work, we compiled five natural products databases available in the public domain and performed a comprehensive chemoinformatic analysis focused on the content and diversity of the scaffolds with an overview of the diversity based on molecular fingerprints. The natural products databases were compared with each other and with a set of molecules obtained from in‐house combinatorial libraries, and with a general screening commercial library. It was found that publicly available natural products databases have different scaffold diversity. In contrast to the common concept that larger libraries have the largest scaffold diversity, the largest natural products collection analyzed in this work was not the most diverse. The general screening library showed, overall, the highest scaffold diversity. However, considering the most frequent scaffolds, the general reference library was the least diverse. In general, natural products databases in the public domain showed low molecule overlap. In addition to benzene and acyclic compounds, flavones, coumarins, and flavanones were identified as the most frequent molecular scaffolds across the different natural products collections. The results of this work have direct implications in the computational and experimental screening of natural product databases for drug discovery.     

Natural Products as a Resource for New Drugs

Natural products have served as a major source of drugs for centuries, and about half of the pharmaceuticals in use today are derived from natural products. The aim of this review is to provide an overview of the continuing central role of natural products in the discovery and development of new pharmaceuticals. In this context, selected examples of important natural product-derived drugs are cited, focusing on some of the most recent introductions to the clinical setting, and a brief overview of some of the important recent developments and remaining challenges in the process of discovering and developing bioactive natural products is provided. Interest in natural products research is strong and can be attributed to several factors, including unmet therapeutic needs, the remarkable diversity of both chemical structures and biological activities of naturally occurring secondary metabolites, the utility of bioactive natural products as biochemical and molecular probes, the development of novel and sensitive techniques to detect biologically active natural products, improved techniques to isolate, purify, and structurally characterize these active constituents, and advances in solving the demand for supply of complex natural products. Opportunities for multidisciplinary research that joins the forces of natural products chemistry, molecular and cellular biology, synthetic and analytical chemistry, biochemistry, and pharmacology to exploit the vast diversity of chemical structures and biological activities of natural products are discussed.     

Strategies for discovering drugs from previously unexplored natural products

Natural products are the most consistently successful source of drug leads. Despite this, their use in drug discovery has fallen out of favour. Natural products continue to provide greater structural diversity than standard combinatorial chemistry and so they offer major opportunities for finding novel low molecular weight lead structures that are active against a wide range of assay targets. As less than 10% of the world's biodiversity has been tested for biological activity, many more useful natural lead compounds are awaiting discovery. The challenge is how to access this natural chemical diversity.     

Discovery of antibacterials and other bioactive compounds from microorganisms-evaluating methodologies for discovery and generation of non-ribosomal peptide antibiotics

After decades of neglect in industrial research the comeback of natural products is due since improved screening approaches are at disposal, yielding a multitude of new compounds from natural sources. Besides traditional compound libraries peptides are characterized by an enormous structural complexity, thus increasing the chance of finding a hit in a screening. Emphasizing antibacterial compounds structural complexity is a prerequisite for their success. This review focuses on the screening approaches employed for the discovery of mostly antibacterial, non-ribosomal peptides derived from natural sources. Traditional screening methodologies as well as genetic approaches are discussed in this context. Utilizing genetic engineering methods e.g., precursor-directed biosynthesis, mutasynthesis, combinatorial biosynthesis, as well as chemoenzymatics to achieve greater structural diversity is thoroughly discussed and exemplified by recent discoveries.     

烯烃关环复分解反应及其在海洋来源抗肿瘤活性大环内酯类化合物全合成中的应用

烯烃关环复分解（Ring-closing olefin metathesis, RCM）反应在天然来源大环内酯的全合成中一般作为关键的一步反应,一直是合成化学家关注的焦点。高活性、结构新颖的海洋来源大环内酯类化合物往往含量低微,从海洋生物中难以大量,这就阻碍了该类化合物后续的生物活性研究。利用有机合成方法全合成该类化合物是解决药源的有效途径。该类化合物全合成中最大的挑战就是如何构建其大环母核骨架。因此,本文主要介绍RCM反应及其近年在海洋来源抗肿瘤活性大环内酯类化合物全合成中的应用。     

Nutraceuticals for protection and healing of gastrointestinal mucosa

Natural medicinal products have been used for millennia for the treatment of several ailments. Although many have been superseded by conventional pharmaceutical approaches, there is currently a resurgence in the interest in natural products by the general public and the use of complementary and alternative medicine is increasing rapidly in developed countries. Also, pharmaceutical industries are more and more interested in examining their potential as sources of novel medicinal compounds which may act as growth factor or show immunomodulatory or anti-microbial activity. The subgroup of natural bioactive compounds that bridge the gap between food products and drugs are termed nutraceuticals or functional foods. In contrast with most standard medicinal compounds, nutraceuticals are generally used to prevent rather than to treat disease. Many of the claims for such products are supported by very limited scientific evidence. However, there has recently been a great interest at evaluating the mechanism by which natural products exert their beneficial effects in the gastrointestinal tract. In particular, a major area of interest is for the use of biologically active chemical components of plants, i.e. phytochemicals, in a number of gastrointestinal disorders. While the major focus of phytochemical research has been on cancer prevention, several products of plant origin are being used and/or under study for a variety of other gastrointestinal problems. In this review we discuss the scientific evidence supporting the potential use of nutraceuticals as agents capable to prevent or accelerate healing of gastrointestinal mucosal damage, with a focus on polyphenol extracts obtained from apple.