Cellular targets of natural products

Natural products have evolved, at least in part, to bind to biological macromolecules, particularly proteins. As a result, natural products are able to interact with many specific targets within the cell. Indeed for many years this has been central in the drug development process. Today, however, natural products are finding increasing use as probes to interrogate biological systems as part of chemical genomics and related research. In order to demonstrate the utility of natural products in these efforts, the biological activities of many of the major classes of natural products is discussed, according to the cellular organelle and localisation of their specific molecular targets. Emphasis is given to newly discovered compounds and activities that either provide interesting insights into a specific biological function, or that form the basis for potentially new therapeutic approaches.     

Quality, not quantity: the role of natural products and chemical proteomics in modern drug discovery

Chemical genetics and reverse chemical genetics parallel classical genetics but target genes at the protein level and have proven useful in recent years for screening combinatorial libraries for compounds of biological interest. However, the performance of combinatorial chemistry in filling pharmaceutical pipelines has been lower than anticipated and the tide may be turning back to Nature in the search for new drug candidates. Even though diversity oriented synthesis is now producing molecules that are natural product-like in terms of size and complexity, these molecules have not evolved to interact with biomolecules. Natural products, on the other hand, have evolved to interact with biomolecules, which is why so many can be found in pharmacopoeias. However, the cellular targets and modes of action of these fascinating compounds are seldom known, hindering the drug development process. This review focuses on the emergence of chemical proteomics and reverse chemical proteomics as tools for the discovery of cellular receptors for natural products, thereby generating protein/ligand pairs that will prove useful in identifying new drug targets and new biologically active small molecule scaffolds. Such a system-wide approach to identifying new drugable targets and their small molecule ligands will help unblock the pharmaceutical product pipelines by speeding the process of target and lead identification.     

In silico carborane docking to proteins and potential drug targets

The presence of boron atoms has made carboranes, C(2)B(10)H(12), attractive candidates for boron neutron capture therapy. Because of their chemistry and possible conjugation with proteins, they can also be used to enhance interactions between pharmaceuticals and their targets and to increase the in vivo stability and bioavailability of compounds that are normally metabolized rapidly. Carboranes are isosteric to a rotating phenyl group, which they can substitute successfully in biologically active systems. A reverse ligand-protein docking approach was used in this work to identify binding proteins for carboranes. The screening was carried out on the drug target database PDTD that contains 1207 entries covering 841 known potential drug targets with structures taken from the Protein Data Bank. First, for validation, the protocol was applied to three crystal structures of proteins in which carborane derivatives are present. Then, the model was applied to systems for which the protein structure is available, but the binding site of carborane has not been reported. These systems were used for further validation of the protocol, while simultaneously providing new insight into the interactions between cage and protein. Finally, the screening was carried out on the database to reveal potential carborane binding targets of interest for biological and pharmacological activity. Carboranes are predicted to bind well to protease and metalloprotease enzymes. Other carborane pharmaceutical targets are also discussed, together with possible protein carriers.     

Magnetic nanomaterials catalyzed synthesis of tetrazoles

Abstract

Tetrazoles are valuable molecules in pharmaceutical and agriculture chemistry, because they are excited in many drugs, natural products and biologically active molecules. During the last decade, magnetic nanomaterials have appeared as highly efficient catalysts in chemical science in general organic chemistry, because of their simple preparation, modification, and large surface area ratio. In this paper, we provide an overview of the utilization of magnetic nanomaterials as attractive and efficient catalytic systems in synthesis of biologically active tetrazoles.     

Investigation of innovative synthesis of biologically active compounds on the basis of newly developed reactions

Synthesis of biologically active compounds, including natural products and pharmaceutical agents, is an important and interesting research area since the large structural diversity and complexity of bioactive compounds make them an important source of leads and scaffolds in drug discovery and development. Many structurally and also biologically interesting compounds, including marine natural products, have been isolated from nature and have also been prepared on the basis of a computational design for the purpose of developing medicinal chemistry. In order to obtain a wide variety of derivatives of biologically active compounds from the viewpoint of medicinal chemistry, it is essential to establish efficient synthetic procedures for desired targets. Newly developed reactions should also be used for efficient synthesis of desired compounds. Thus, recent progress in the synthesis of biologically active compounds by focusing on the development of new reactions is summarized in this review article.     

Importance of Baylis-Hillman adducts in modern drug discovery

The Baylis-Hillman (BH) reaction plays a fascinating role in the field of synthetic and medicinal chemistry. BH adducts and their derivatives have been used as crucial synthons for the synthesis of various pharmaceutically useful natural products and compounds with carbocyclic or heterocyclic frameworks. This digest letter aims to discuss some key ideas for the synthesis of biologically active scaffolds using BH reaction and raise the awareness of this emerging research domain in modern drug discovery. In this review, we will present and discuss recent reports of various biologically active scaffolds derived from BH reaction, and their reported biological activities.     

Target identification strategies in chemical genetics

Chemical inhibitors have had a profound impact on many diverse fields of biology. The goal of chemical genetics is to use small molecules to perturb biological systems in a manner conceptually similar to traditional genetics. Key to the advancement of the chemical genetic paradigm is the further development of tools and approaches for the identification of the protein targets of active compounds identified in chemical genetic screens. This review will address historic examples in which forward chemical genetics yielded new insight into a biological problem through successful identification of the target of an active molecule. The approaches covered have been grouped into two broad classes: target identification by affinity-based methods and target identification by deduction. Strengths and shortcomings of each approach as it pertains to their application to modern chemical genetics will be discussed. Finally, a series of new genomic and proteomic-based techniques for target identification will be described. Although a truly general approach to target identification has yet to be developed, these examples illustrate that there are many effective strategies for successfully elucidating the biological targets of active small molecules.     

Natural products: chemical instruments to apprehend biological symphony

As a striking variety of biological activities are elicited by natural products, these chemicals have been used for decades to study biological phenomena. Understanding how these products interfere with normal cell functions at a molecular level led to a wide range of discoveries including new signaling pathways and proteins. Moreover, as natural products often act as chemical inhibitors, such studies often allow the identification of their binding partners as relevant targets for drug design. This article aims to emphasize how natural products or engineered analogs can be used as chemical tools to apprehend some biological problems from the point of view of a chemical biologist.     

Inverse-Electron-Demand Diels–Alder Reactions of 2-Pyrones: Bridged Lactones and Beyond

Inverse-electron-demand Diels–Alder (IEDDA) reactions of electron-poor 2-pyrones as electrophilic dienes have been extensively studied in the past fifty years. These reactions provide an efficient access to bridged bicyclic lactones and their derivatives, such as densely functionalized 1,3-cyclohexadienes after CO₂ extrusion and polysubstituted aromatic compounds through elimination. This reaction has been used for the synthesis of many biologically active natural products and drug candidates. In this review, the developments of these IEDDA reactions including non-catalytic, Lewis acid-catalyzed and organocatalytic IEDDA reactions, and their applications in total synthesis are discussed in detail.     

Mimicking/Extracting Structure and Functions of Natural Products: Synthetic Approaches that Address Unexplored Needs in Chemical Biology

Natural products are often attractive and challenging targets for synthetic chemists, and many have interesting biological activities. However, synthetic chemists need to be more than simply suppliers of compounds to biologists. Therefore, we have been seeking ways to actively apply organic synthetic methods to chemical biology studies of natural products and their activities. In this personal review, I would like to introduce our work on the development of new biologically active compounds inspired by, or extracted from, the structures of natural products, focusing on enhancement of functional activity and specificity and overcoming various drawbacks of the parent natural products.     

Synthesis and properties of allenic natural products and pharmaceuticals

Nowadays, about 150 natural products comprising an allenic or cumulenic structure are known. The chemistry of these compounds has turned out to be a very attractive and prolific area of interest: advances in the isolation and characterization of new allenic natural products have led to the establishment of efficient synthetic procedures which in many cases also open up an access to enantiomerically pure target molecules. Inspired by the intriguing biological activities of many allenic natural products, allene moieties are now systematically introduced in pharmacologically active classes of compounds (steroids, prostaglandins, amino acids, nucleosides). The functionalized allenes thus obtained often exhibit impressive activities as mechanism-based enzyme inhibitors, cytotoxic, or antiviral agents. A prerequisite for further developments in this field is the efficient stereoselective synthesis of allene derivatives.     

Antibacterial Natural Products in Medicinal Chemistry—Exodus or Revival?

To create a drug, nature's blueprints often have to be improved through semisynthesis or total synthesis (chemical postevolution). Selected contributions from industrial and academic groups highlight the arduous but rewarding path from natural products to drugs. Principle modification types for natural products are discussed herein, such as decoration, substitution, and degradation. The biological, chemical, and socioeconomic environments of antibacterial research are dealt with in context. Natural products, many from soil organisms, have provided the majority of lead structures for marketed anti-infectives. Surprisingly, numerous "old" classes of antibacterial natural products have never been intensively explored by medicinal chemists. Nevertheless, research on antibacterial natural products is flagging. Apparently, the "old fashioned" natural products no longer fit into modern drug discovery. The handling of natural products is cumbersome, requiring nonstandardized workflows and extended timelines. Revisiting natural products with modern chemistry and target-finding tools from biology (reversed genomics) is one option for their revival.     

Chemomics and drug innovation

Chemomics is an interdisciplinary study using approaches from chemoinformatics,bioinformatics,synthetic chemistry,and other related disciplines.Biological systems make natural products from endogenous small molecules (natural product building blocks) through a sequence of enzyme catalytic reactions.For each reaction,the natural product building blocks may contribute a group of atoms to the target natural product.We describe this group of atoms as a chemoyl.A chemome is the complete set of chemoyls in an organism.Chemomics studies chemomes and the principles of natural product syntheses and evolutions.Driven by survival and reproductive demands,biological systems have developed effective protocols to synthesize natural products in order to respond to environmental changes;this results in biological and chemical diversity.In recent years,it has been realized that one of the bottlenecks in drug discovery is the lack of chemical resources for drug screening.Chemomics may solve this problem by revealing the rules governing the creation of chemical diversity in biological systems,and by developing biomimetic synthesis approaches to make quasi natural product libraries for drug screening.This treatise introduces chemomics and outlines its contents and potential applications in the fields of drug innovation.     

化学基元组学与药物创新

化学基元组学（chemomics）是与化学信息学、生物信息学、合成化学等学科相关的交叉学科．生物系统从内源性小分子（天然砌块）出发,通过酶催化的化学反应序列制造天然产物．生物系统通过化学反应和天然砌块向目标天然产物“砌入”一组原子,这样的一组原子称为化学基元（chemoyl）．化学基元组（chemome）是生物组织中所含有的化学基元的全体．化学基元组学研究各种化学基元的结构、组装与演化的基本规律．在生存压力和繁衍需求的驱动下,生物系统已经进化出有效手段来合成天然产物以应付环境的变化,并产生了丰富多彩的生物和化学多样性．近年来,人们意识到药物创新的瓶颈之一是药物筛选资源的日益枯竭．化学基元组学可以解决这个瓶颈问题,它通过揭示生物系统制备化学多样性的规律,发展仿生合成方法制备类天然化合物库（quasi natural product libraries）以供药物筛选．本文综述了化学基元组学的主要研究内容及其在药物创新各领域中的潜在应用．     

Dendrimer as a versatile platform for biomedical application: A review

Modern chemistry is vastly fascinated by dendrimer chemistry, an area that is rapidly expanding and brimming with potential applications. Dendrimers are highly branched polymers that have multiple peripheral groups, interior cavities and they have many structural properties therefore Dendrimers play a crucial role in the fields of nanotechnology, pharmaceuticals, and medicinal chemistry. The terminal functional groups of dendrimers may be chemically linked to other moieties in order to adjust surface properties for applications such as biomimetic nanodevices. A variety of biologically active agents can be incorporated into dendrimers to create biologically active conjugates, including novel drug carriers, by utilizing the homogeneity of their three-dimensional architecture. The purpose of this review is to provide a brief overview of bio-inspired dendrimer applications, highlighting their use as drug and gene delivery agents, and biomedical diagnostic agents. In addition, the review mentions briefly some dendrimer applications in cosmetics, agrochemicals, and catalyst.     

Biology-oriented synthesis

Which compound classes are best suited as probes and tools for chemical biology research and as inspiration for medicinal chemistry programs? Chemical space is enormously large and cannot be exploited conclusively by means of synthesis efforts. Methods are required that allow one to identify and map the biologically relevant subspaces of vast chemical space, and serve as hypothesis‐generating tools for inspiring synthesis programs. Biology‐oriented synthesis builds on structural conservatism in the evolution of proteins and natural products. It employs a hierarchical classification of bioactive compounds according to structural relationships and type of bioactivity, and selects the scaffolds of bioactive molecule classes as starting points for the synthesis of compound collections with focused diversity. Navigation in chemical space is facilitated by Scaffold Hunter, an intuitively accessible and highly interactive software. Small molecules synthesized according to BIOS are enriched in bioactivity. They facilitate the analysis of complex biological phenomena by means of acute perturbation and may serve as novel starting points to inspire drug discovery programs.     

Review on asymmetric synthetic methodologies for chiral isoquinuclidines; 2008 to date

Isoquinuclidines constitute the central structural nucleus of numerous biologically active natural products, for example, iboga alkaloids such as ibogamine and catharanthine as well as non-indole-containing alkaloids such as the dioscorine and the cannivonines. Furthermore, in medicinal and pharmaceutical chemistry, the isoquinuclidine core is commonly employed as a rigid azabicyclic scaffold, thus providing significant precursors in the synthesis of numerous valuable alkaloids. Summarizing well-organized approaches to access the chiral isoquinuclidine structural centerpiece signifies a significant endeavor not only for developing biologically active natural products but also enhancing biological researches that can lead to possible drug discovery. Over time, the values and methodologies for the asymmetric synthesis of chiral isoquinuclidines are increasing; hence to advance asymmetric synthesis, this review combines and discusses the pros and cons of each synthesis techniques from 2008. This review should be helpful for promoting further developments of asymmetric synthetic methodologies and for medicinal chemistry.     

Natural products as an inspiration in the diversity-oriented synthesis of bioactive compound libraries

The purpose of diversity-oriented synthesis is to drive the discovery of small molecules with previously unknown biological functions. Natural products necessarily populate biologically relevant chemical space, since they bind both their biosynthetic enzymes and their target macromolecules. Natural product families are, therefore, libraries of pre-validated, functionally diverse structures in which individual compounds selectively modulate unrelated macromolecular targets. This review describes examples of diversity-oriented syntheses which have, to some extent, been inspired by the structures of natural products. Particular emphasis is placed on innovations that allow the synthesis of compound libraries that, like natural products, are skeletally diverse. Mimicking the broad structural features of natural products may allow the discovery of compounds that modulate the functions of macromolecules for which ligands are not known. The ability of innovations in diversity-oriented synthesis to deliver such compounds is critically assessed.     

Rapid Assembly of Saturated Nitrogen Heterocycles in One‐Pot: Diazo‐Heterocycle “Stitching” by N–H Insertion and Cyclization

Methods that provide rapid access to new heterocyclic structures in biologically relevant chemical space provide important opportunities in drug discovery. Here, a strategy is described for the preparation of 2,2‐disubstituted azetidines, pyrrolidines, piperidines, and azepanes bearing ester and diverse aryl substituents. A one‐pot rhodium catalyzed N–H insertion and cyclization sequence uses diazo compounds to stitch together linear 1,m‐haloamines (m=2–5) to rapidly assemble 4 ‐, 5 ‐, 6 ‐, and 7 ‐membered saturated nitrogen heterocycles in excellent yields. Over fifty examples are demonstrated, including examples with diazo compounds derived from biologically active compounds. The products can be functionalized to afford α,α‐disubstituted amino acids and applied to fragment synthesis.     

Stereoselective Synthesis of Enantiomerically Pure Natural Products—Estrone as Example

Natural products have been synthesized for billions of years in animals, plants, and microorganisms. As a rule they occur enantiomerically pure. Their chiral character corroborates their use in metabolism or as biologically active agents. Natural products may be insufficient in quality or quantity. They have recently begun to become accessible, either unchanged or modified, by biological synthesis; here, too, they are obtained enantiomerically pure. In the last twenty years chemical synthesis has become a major concern of organic chemists. Their target compounds are primarily enantiomerically pure natural products or biologically active variants thereof.