Attractive natural products with strained cyclopropane and/or cyclobutane ring systems

The strained cyclopropane and/or cyclobutane subunits occurred in many complex natural products including terpenoids, steroids and alkaloids. Natural products with cyclopropane and/or cyclobutane motifs not only furnished fascinating structures, but also exhibited versatile biological activities, such as cytotoxic, anti-HIV, antimicrobial, antiviral, and immunosuppressive effects. This review covered a large array of structurally unique natural products with strained cyclopropane and/or cyclobutane motifs and summarized their structural features, distributions, biological activities, as well as biogenetic considerations.     

Naturally occurring furofuran lignans: structural diversity and biological activities

Furofuran lignans containing the 2,6-diaryl-3,7-dioxabicyclo[3.3.0]octane skeleton, represent one of the major subclasses of the lignan family of natural products. Furofuran lignans feature a wide variety of structures due to different substituents at aryl groups and diverse configurations at furofuran ring. Moreover, they exhibit a wide range of significant biological activities, including antioxidant, anti-inflammatory, cytotoxic, and antimicrobial activities. This review summarizes source, phytochemistry, and biological activities of 137 natural furofuran lignans isolated from 53 species in 41 genera of 27 plant families for the last 20 years, which provides a comprehensive information for further research of these furofuran lignans as potential pharmaceutical agents.     

Directed biosynthesis of alkaloid analogs in the medicinal plant Catharanthus roseus

Terpene indole alkaloids are plant natural products with diverse structures and biological activities. A highly branched biosynthetic pathway is responsible for the production of approximately 130 different alkaloids in Madagascar periwinkle (C. roseus) from a common biosynthetic intermediate derived from tryptamine. Although numerous biosynthetic pathways can incorporate unnatural starting materials to yield novel natural products, it was not clear how efficiently the complex, eukaryotic TIA pathway could utilize unnatural substrates to make new alkaloids. This work demonstrates that the TIA biosynthetic machinery can be used to produce novel alkaloid structures and also highlights the potential of this pathway for future metabolic engineering efforts.     

Discovery and Reconstitution of the Cycloclavine Biosynthetic Pathway—Enzymatic Formation of a Cyclopropyl Group

The ergot alkaloids, a class of fungal‐derived natural products with important biological activities, are derived from a common intermediate, chanoclavine‐I, which is elaborated into a set of diverse structures. Herein we report the discovery of the biosynthetic pathway of cycloclavine, a complex ergot alkaloid containing a cyclopropyl moiety. We used a yeast‐based expression platform along with in vitro biochemical experiments to identify the enzyme that catalyzes a rearrangement of the chanoclavine‐I intermediate to form a cyclopropyl moiety. The resulting compound, cycloclavine, was produced in yeast at titers of >500 mg L^?1, thus demonstrating the feasibility of the heterologous expression of these complex alkaloids.     

Muscarine, imidazole, oxazole, and thiazole alkaloids

A great number of structurally diverse natural products containing five-membered heterocyclic subunits, such as imidazole, oxazole, thiazole, and their saturated congeners, are abundant in nature. These naturally occurring metabolites often exhibit extensive and pharmacologically important biological activities. The latest progress in the isolation, biological activities, chemical synthetic studies, and biosynthetic pathways on these natural products is summarized in this review.     

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.     

Natural‐Product Sugar Biosynthesis and Enzymatic Glycodiversification

Many biologically active small‐molecule natural products produced by microorganisms derive their activities from sugar substituents. Changing the structures of these sugars can have a profound impact on the biological properties of the parent compounds. This realization has inspired attempts to derivatize the sugar moieties of these natural products through exploitation of the sugar biosynthetic machinery. This approach requires an understanding of the biosynthetic pathway of each target sugar and detailed mechanistic knowledge of the key enzymes. Scientists have begun to unravel the biosynthetic logic behind the assembly of many glycosylated natural products and have found that a core set of enzyme activities is mixed and matched to synthesize the diverse sugar structures observed in nature. Remarkably, many of these sugar biosynthetic enzymes and glycosyltransferases also exhibit relaxed substrate specificity. The promiscuity of these enzymes has prompted efforts to modify the sugar structures and alter the glycosylation patterns of natural products through metabolic pathway engineering and enzymatic glycodiversification. In applied biomedical research, these studies will enable the development of new glycosylation tools and generate novel glycoforms of secondary metabolites with useful biological activity.     

Highly efficient biomimetic total synthesis and structural verification of bistratamides E and J from Lissoclinum bistratum

The interesting biological activities of heterocycle-containing cyclic peptide-derived natural products, isolated from marine organisms over the past twenty years, have attracted the interest of many synthetic and natural products chemists. Bistratamides E-J, members of this class of natural products that were isolated very recently from Lissoclinum bistratum, exhibited cytotoxic activity against a human colon tumor (HCT-116) cell line. Here we report the first total syntheses of bistratamides E (1) and J (2) in overall yields of 19 and 34 %, respectively. The thiazole substructures have been synthesized by oxidation of their corresponding thiazoline substructures, which were obtained from cysteine containing peptides using a novel biomimetic approach wherein Val-Cys dipeptide units were converted to thiazolines by a bisphosphonium salt. The final macrocyclization was promoted efficiently using the combination of PyBOP and DMAP. This approach allows the use of readily available Fmoc-protected amino acids to make complex thiazole and oxazoline-containing natural products.     

Function‐Oriented Synthesis: How to Design Simplified Analogues of Antibacterial Nucleoside Natural Products?

It is important to pursue function‐oriented synthesis (FOS), a strategy for the design of less structurally complex targets with comparable or superior activity that can be made in a practical manner, because compared to synthetic drugs, many biologically relevant natural products possess large and complex chemical structures that may restrict chemical modifications in a structure–activity relationship study. In this account, we describe recent efforts to simplify complex nucleoside natural products including caprazamycins. Considering the structure–activity relationship study with several truncated analogues, three types of simplified derivatives, namely, oxazolidine, isoxazolidine, and lactam‐fused isoxazolidine‐containing uridine derivatives, were designed and efficiently synthesized. These simplified derivatives have exhibited promising antibacterial activities. A significant feature of our studies is the rational and drastic simplification of the molecular architecture of caprazamycins. This study provides a novel strategy for the development of a new type of antibacterial agent effective against drug‐resistant bacteria.     

Asymmetric Synthesis of Chiral Flavan-3-Ols

Flavan-3-ols are a series of natural products widely present in plants and show versatile biological activities. The structures of such compounds are characterized by owing two adjacent chiral centers and three rings. Their interesting structures and promising biological activities have driven increasing research developments toward the preparation of enantioenriched flavan-3-ols. This review summarizes the recent approaches for the asymmetric synthesis of chiral flavan-3-ols from two strategies in the construction of chiral centers. The key steps in the synthetic protocol involve Sharpless asymmetric dihydroxylation, Shi asymmetric epoxidation and Sharpless asymmetric epoxidation.     

多环型Xanthone类天然产物的合成研究进展

多环型xanthone类天然产物是一类具有高度氧化态和六环骨架结构的天然产物.目前分离得到的此类化合物主要来源于放线菌.由于这类化合物具有结构特独、广泛的抗细菌活性、一定程度的抗真菌活性以及良好的抗肿瘤活性,吸引了大量有机合成和药物化学等领域学者的关注.近十年来,相关的生物和化学合成以及药物化学研究报道明显增多,主要总结了多环型xanthone类天然产物的合成研究进展.     

Piperazic acid-containing natural products: isolation, biological relevance and total synthesis

Since their first discovery in 1959, natural products containing the piperazic acid motif have been isolated from a variety of sources and exhibit diverse biological activity profiles. This review provides information about their isolation and biological activities, and presents an overview of recent total syntheses of these molecules.     

Development of new synthetic methods and its application to total synthesis of nitrogen-containing bioactive natural products

A group of naturally occurring substances containing nitrogen is widely distributed in plants as well as in fungi, animal, marine organisms, and insects, and many exhibit significant biological activity. These natural products with a huge variety of chemical structures include antibiotics, antitumor agents, immunostimulants, drugs affecting the cardiovascular and central nervous systems, analgesics etc. The diverse activities and low natural abundance of this group of natural products when coupled with their molecular complexity warrant development of new and efficient synthetic methods and strategy for the total synthesis of these products, in particular alkaloids. The purpose of this review is to describe some of our achievements in the total synthesis of the naturally-occurring bases including the Dendrobatid alkaloids pumiliotoxin B and allopumiliotoxin A, the anitibiotic streptazolin, the tricyclic marine alkaloids isolated from the ascidians such as fasicularin, lepadiformine, and cylindricine C, and the dimeric monoterpene alkaloid incarvillateine as well as the formal total synthesis of the spirocyclic marine alkaloids halichlorine and pinnaic acid, which are isolated from the Japanese marine sponge and the Okinawan bivalve, respectively.     

Muscarine, imidazole, oxazole and thiazole alkaloids

Novel and structurally diverse natural products containing imidazol-, oxazole-, or thiazole-unit(s) display a wide variety of biological activities. The isolation, biological activity and total synthesis of naturally occurring muscarine, imidazole, oxazole and thiazole alkaloids have been reviewed. The literature covers from January 2003 to June 2004.     

Natural products and their derivatives as G-quadruplex binding ligands

G-quadruplexes comprise a class of secondary structures that are formed in guanine-rich sequences in eukaryotic genomes and play a crucial role in the regulation of many biological events. G-quadruplexes have become targets for anticancer drugs with high selectivity vs. duplex DNA and low cytotoxicity against normal cells. Natural products and their derivatives display polymorphism, structural complexity, and potent activity. It is, therefore, reasonable to seek ligands targeting G-quadruplexes from natural products. Recently, many successful examples have been reported, showing ligands with excellent anticancer activities. In this review, we summarized the development of research on natural products and derivatives that target G-quadruplex structures in an effort to guide future studies.     

Biosynthesis-based artificial evolution of microbial natural products

Natural products are often secondary metabolites in living organisms with a wide variety of biological activities. The diversification of their structures, aiming to the search for biologically active small molecules by expanding chemical and functional spaces, is a major area of current interest in synthetic chemistry. However, developing synthetic accessibility and efficiency often faces challenges associated with structural complexity. Synthetic biology has recently emerged and is promising to accomplish complex molecules; by contrast, the application to structural diversification of natural products relies on the understanding, development and utilization of compatible biosynthetic machinery. Here, we review the strategies primarily concerning the artificial evolution of microbial natural products whose biosynthesis features template enzymology, including ribosomally synthesized and post-translationally modified peptides as well as the assembly line-resultant polyketides, non-ribosomal peptides and hybrids. The establishment of these approaches largely facilitates the expansion of the molecular diversity and utility through bioengineering at different stages/levels of biosynthetic pathways.     

Symbionts,a promising source of bioactive natural products

Symbionts are microorganisms residing in multicellular hosts(e.g., plants and animals), and they have been witnessed to be a rich source of diverse functional molecules. This review describes structures and biological activities of symbiont-derived secondary metabolites commonly referred to as "natural products", and highlights that symbiotic microbes represent an underexplored reservoir of natural products with unique scaffolds and promising significance in managing human healthcare and agricultural production.     

The structural biology of enzymes involved in natural product glycosylation

Covering: up to 2012The glycosylation of microbial natural products often dramatically influences the biological and/or pharmacological activities of the parental metabolite. Over the past decade, crystal structures of several enzymes involved in the biosynthesis and attachment of novel sugars found appended to natural products have emerged. In many cases, these studies have paved the way to a better understanding of the corresponding enzyme mechanism of action and have served as a starting point for engineering variant enzymes to facilitate to production of differentially-glycosylated natural products. This review specifically summarizes the structural studies of bacterial enzymes involved in biosynthesis of novel sugar nucleotides.     

Chemoproteomic Evaluation of the Polyacetylene Callyspongynic Acid

Polyacetylenes are a class of alkyne‐containing natural products. Although potent bioactivities and thus possible applications as chemical probes have already been reported for some polyacetylenes, insights into the biological activities or molecular mode of action are still rather limited in most cases. To overcome this limitation, we describe the application of the polyacetylene callyspongynic acid in the development of an experimental roadmap for characterizing potential protein targets of alkyne‐containing natural products. To this end, we undertook the first chemical synthesis of callyspongynic acid. We then used in situ chemical proteomics methods to demonstrate extensive callyspongynic acid‐mediated chemical tagging of endoplasmic reticulum‐associated lipid‐metabolizing and modifying enzymes. We anticipate that an elucidation of protein targets of natural products may serve as an effective guide to the development of subsequent biological assays that aim to identify chemical phenotypes and bioactivities.     

Synthetic Strategies toward Natural Products Containing Contiguous Stereogenic Quaternary Carbon Atoms

Strategies for the total synthesis of complex natural products that contain two or more contiguous stereogenic quaternary carbon atoms in their intricate structures are reviewed with 12 representative examples. Emphasis has been put on methods to create quaternary carbon stereocenters, including syntheses of the same natural product by different groups, thereby showcasing the diversity of thought and individual creativity. A compendium of selected natural products containing two or more contiguous stereogenic quaternary carbon atoms and key reactions in their total or partial syntheses is provided in the Supporting Information.