Epipolythiodiketopiperazine Alkaloids: Total Syntheses and Biological Activities

Epipolythiodiketopiperazine (ETP) alkaloids are structurally characterized by the presence of diketopiperazine rings having sensitive (poly)sulfide bridges, and most of them are classified as fungal secondary metabolites. Various biological activities have been reported for members of this family, including cytotoxic, antibacterial, antimicrobial, antiviral, antitumor, antiallergic, and antimalarial activities. Notably, some of the molecules were reported to show specific inhibitory activities against certain critical enzymes. Since the supply of these compounds from natural sources is quite limited, efficient chemical syntheses of ETP alkaloids would be useful for biological studies. However, total syntheses of ETP alkaloids remain a formidable challenge in current synthetic organic chemistry because of their structural complexity. In this review article, we present an overview of synthetic approaches to the ETP alkaloids during the past 50 years, and discuss significant milestones. We also summarize the biological activities of these compounds, focusing on the molecular mechanisms.     

生物碱类化合物的研究进展

生物碱作为一类广泛存在于自然界中的碱性含氮有机化合物,数目众多,结构类型复杂。依据化学结构不同可分为异喹啉类、喹啉类、咪唑类、哌啶类、莨菪烷类、吲哚类、咔唑类、海洋多环胍类、萜类、manzamine型生物碱等。文章就部分生物碱类化合物结构研究进展进行综述。     

吲哚类衍生物理论研究进展综述

简要介绍了吲哚类衍生物密度泛函理论研究进展,重点评述理论化学方法在吲哚类衍生物的理化性质、计算方法以及化合物结构和性质的主要影响,并介绍了目前这类化合物最常出现的部分理论化学方法。     

风吹楠属植物化学成分及活性研究进展

为了全面了解和综合利用风吹楠属植物,本文对风吹楠属植物的化学成分和药理活性研究进展进行了综述。目前风吹楠属植物研究所涉及的种类仅5种,从中共分离到40个化学成分,包括黄酮、色原酮、木脂素、生物碱、芳基酮等结构类型。活性研究表明,一些化学成分具有明显的细胞毒活性和抗疟疾活性。开展风吹楠属植物的研究,对发现新的药用活性成分及资源保护具有重要的意义。     

Pityriarubins, novel highly selective inhibitors of respiratory burst from cultures of the yeast Malassezia furfur: comparison with the bisindolylmaleimide arcyriarubin A

Pityriasis versicolor is the most common skin mycosis in humans worldwide. Yeasts of the genus Malassezia, particularly M. furfur, a saprophyte occurring widely on human skin, are generally regarded as the causative agents. M. furfur is able to convert tryptophan into a variety of indole alkaloids, some of them showing biological properties that correlate well with certain clinical features of pityriasis versicolor. This suggests a possible role for these compounds in the pathophysiology of the disease. We here report that the novel pityriarubins A, B and C, isolated from cultures of the yeast, inhibit respiratory burst in human neutrophils, activated by various agents, in a highly selective, unexpected manner. The release of 5-lipoxygenase products after challenge of neutrophils with the calcium ionophore A23187 is also inhibited in a dose-dependent manner. These activities reflect the close structural relationship of pityriarubins to bisindolylmaleimides, which have recently gained great interest as protein kinase inhibitors.     

Astonishing diversity of natural surfactants: 6. Biologically active marine and terrestrial alkaloid glycosides

This review article presents 209 alkaloid glycosides isolated and identified from plants, microorganisms, and marine invertebrates that demonstrate different biological activities. They are of great interest, especially for the medicinal and/or pharmaceutical industries. These biologically active glycosides have good potential for future chemical preparation of compounds useful as antioxidants, anticancer, antimicrobial, and antibacterial agents. These glycosidic compounds have been subdivided into several groups, including: acridone; aporphine; benzoxazinoid; ergot; indole; enediyne alkaloidal antibiotics; glycosidic lupine alkaloids; piperidine, pyridine, pyrrolidine, and pyrrolizidine alkaloid glycosides; glycosidic quinoline and isoquinoline alkaloids; steroidal glycoalkaloids; and miscellaneous alkaloid glycosides. For the previous article in this series, see Reference 1.     

Total synthesis of zoanthamine alkaloids

Zoanthamine alkaloids, isolated from organisms in the Zoanthus genus, constitute a distinctive family of marine metabolites. These molecules exhibit a broad spectrum of unique biological properties. For example, norzoanthamine inhibits interleukin-6, the key mediator of bone resorption in osteoporosis, providing a promising drug candidate for a disease that affects more than 10 million people over age 50 in the United States. In addition, these natural products are characterized by a densely functionalized heptacyclic framework, as exemplified by the structures of zoanthamine, norzoanthamine, and zoanthenol, which makes them extremely attractive targets for chemical synthesis. Prior to our first total synthesis of norzoanthamine in 2004, the densely functionalized and complex stereostructures of the zoanthamine alkaloids had impeded synthetic studies of these molecules. In this Account, we describe our synthetic approach toward the total synthesis of zoanthamine alkaloids, focusing on how we overcame various synthetic challenges. At the beginning of our synthetic studies, we aimed to develop an efficient route that was flexible enough to provide access to several members of the family while allowing the synthesis of various analogues for biological testing. Our first project was the total synthesis of norzoanthamine, and we established an efficient synthetic route based on a novel strategy involving the following key features. First, we used a sequential three-component coupling reactions and subsequent photosensitized oxidation of a furan moiety to synthesize the precursor for the key intramolecular Diels-Alder reaction. Second, the key intramolecular Diels-Alder reaction constructed the ABC-ring carbon framework bearing two adjacent quaternary asymmetric carbon atoms at the C12 and C22 positions in a single stereoselective step. Third, we installed the third quaternary asymmetric carbon center at the C9 position by an intramolecular acylation of a keto alcohol followed by successive O-methylation and C-methylation reactions with complete stereoselectivity. Through the exploitation of a deuterium kinetic isoptope effect, we then efficiently synthesized the alkyne segment. Next, a coupling reaction between the alkyne segment and the amino alcohol segment and several subsequent synthetic transformations afforded the bis-aminoacetalization precursor. Finally, bis-aminoacetalization reactions carried out in one-pot constructed the DEFG-ring system and culminated in the total synthesis of norzoanthamine. Our synthetic route to norzoanthamine also allowed access to other zoanthamine alkaloids from a common synthetic intermediate, by way of stereoselective introduction of the C19 methyl group for zoanthamine, and isoaromatization for construction of the aromatic A-ring in zoanthenol. The chemistry described here not only allowed us to overcome formidable synthetic challenges but also opened a completely chemical avenue to naturally occurring zoanthamine alkaloids and their synthetic derivatives.     

Using Chemistry to Investigate the Molecular Consequences of Protein Ubiquitylation

Chemistry has long played an indispensable role in biological discovery through the synthesis of homogeneous, structurally defined material. With continuing advances in the area of synthetic protein chemistry, chemists are able to prepare increasingly large and complex proteins that have enabled key biochemical experiments. Here, we describe some of the chemical methods that have been applied to the synthesis of ubiquitylated proteins, as ubiquitylation is a crucial post‐translational modification that mediates a variety of important biological effects on substrate proteins.     

Synthetic Approaches of Epoxysuccinate Chemical Probes

Synthetic chemical probes are powerful tools for investigating biological processes. They are particularly useful for proteomic studies such as activity-based protein profiling (ABPP). These chemical methods initially used mimics of natural substrates. As the techniques gained prominence, more and more elaborate chemical probes with increased specificity towards given enzyme/protein families and amenability to various reaction conditions were used. Among the chemical probes, peptidyl-epoxysuccinates represent one of the first types of compounds used to investigate the activity of the cysteine protease papain-like family of enzymes. Structurally derived from the natural substrate, a wide body of inhibitors and activity- or affinity-based probes bearing the electrophilic oxirane unit for covalent labeling of active enzymes now exists. Herein, we review the literature regarding the synthetic approaches to epoxysuccinate-based chemical probes together with their reported applications, from biological chemistry and inhibition studies to supramolecular chemistry and the formation of protein arrays.     

Recent Progress in the Synthesis of Homogeneous Erythropoietin (EPO) Glycoforms

Erythropoietin (EPO) has been regarded as a therapeutic glycoprotein for the clinical treatment of anaemia since its approval by the Food and Drug Administration (FDA) in 1989. Commercial production of the 165-residue glycoprotein is by recombinant protein expression using mammalian cell lines that renders a complex mixture of glycoforms that have an identical amino acid sequence but variations in the structures of the pendant glycans. This heterogeneous nature of human recombinant EPO restricts structural and bioactivity studies in medicinal chemistry. Consequently, chemical synthesis provides an elegant approach for the preparation of complex homogeneous glycoproteins from a readily accessible pool of amino acids and sugars. In addition, the combination of chemical and biosynthesis enables robust and large-scale production of homogeneous EPO. The scope of this minireview is to summarise the recent advances in the chemical and semisyntheses of homogeneous EPO glycoforms, highlighting the versatile approaches to the preparation and structural manipulations of the carbohydrate chains incorporated into synthetic EPO glycoproteins.     

Synthetic Studies toward Communesins

Communesins A–H are a growing family of natural products isolated from a marine fungal strain of Penicillium species. Preliminary biological evaluation has revealed that these compounds possess insecticidal activity and cytotoxicity against several tumor cell lines. Their interesting biological activities and unique structures have attracted considerable attention of synthetic chemists worldwide. To date, several elegant protocols for assembling the core structure of these indole alkaloids have been described, including intermolecular Diels–Alder reaction of methylated aurantioclavine with quinine methide imine and intramolecular hetero Diels–Alder reaction of the azaortho-xylylene intermediates. Recently, three completed total syntheses for communesin F have been disclosed, in which the crucial vicinal quaternary stereogenic centers were constructed by employing an intramolecular cyclopropanation; an intramolecular Heck reaction of a tetrasubstituted alkene, or an oxidative coupling of a 3-substituted indole, as the key step. Accompanying the total synthesis, the absolute configuration of natural communesin F was established as 6R,7R,8R,9S,11R. However, total syntheses of other members of communesin family that contain an epoxide moiety have not been achieved, which will stimulate more synthetic studies.     

Chemical Biology: Here to Stay?

The term chemical biology emerged about 25 years ago and encompasses a set of research inquiries at the intersections of chemistry and biology. Before chemical biology there was biological chemistry for 100 years or more, but the traverse from one to the other has not just been a switching of noun and adjective. Over the past quarter century chemists, many from organic synthetic lineages, have become convinced that the open systems of biology have become appropriate venues to bring chemical thinking for library design, screening, and molecular scaffold optimization. Whereas biological chemistry may be described as the universe of chemistry that happens in nature, chemical biologists often bring new, unnatural molecular scaffolds to decipher the logics of biology. That seems a limiting definition and I prefer the mantra: think chemically, act biologically.     

NaClO-Mediated Cross Installation of Indoles and Azoles Benefits Anticancer Hit Discovery

Innovations in synthetic chemistry have a profound impact on the drug discovery process, and will always be a necessary driver of drug development. As a result, it is of significance to develop novel simple and effective synthetic installation of medicinal modules to promote drug discovery. Herein, we have developed a NaClO-mediated cross installation of indoles and azoles, both of which are frequently encountered in drugs and natural products. This effective toolbox provides a convenient synthetic route to access a library of N-linked 2-(azol-1-yl) indole derivatives, and can be used for late-stage modification of drugs, natural products and peptides. Moreover, biological screening of the library has revealed that several adducts showed promising anticancer activities against A549 and NCI-H1975 cells, which give us a hit for anticancer drug discovery.     

Recent trends in the chemistry of 2-aminobenzothiazoles

The chemistry of 2-aminobenzothiazoles has gained increased interest in both synthetic organic chemistry and biological fields, since a large number of developments in the use of such compounds, covering the literature up to 2007, seem to be of considerable value. The present review presents their synthetic methods and chemical reactions. The reactions are subdivided in groups that cover reactions at the amino substituent without touching the benzene ring and reactions which involve both nitrogen in the formal amidine system to give fused heterocyclic systems. Most imaginable reaction types have been successfully applied and used, as many of the synthesized compounds exhibit interesting biological activity in various fields.     

常山化学成分及生物活性研究进展

常山（Dichroa febrifuga Lour.）主要含有生物碱、香豆素、甾体、多酚等化学成分。药理研究表明,常山不但具有良好的抗疟疾活性,还具有抗肿瘤、消炎、促进伤口愈合等生物活性。本文综述了近年来国内外对常山化学成分和生物活性的研究概况。     

噁二唑啉类化合物合成方法综述

噁二唑啉类化合物由于其良好的生物活性广泛应用于医药,农药领域。将噁二唑啉杂环引入其他化合物中,往往能生成一系列具有广谱生物活性的新化物。因此,在新药设计中,噁二唑啉杂环常被用于化合物的结构修饰。近年来,有关这类化合物的合成方法不断得到更新。作者对近年来噁二唑啉类化合物合成方法及反应机理进行了全面综述。     

The unique role of fluorine in the design of active ingredients for modern crop protection

The task of inventing and developing active ingredients with useful biological activities requires a search for novel chemical substructures. This process may trigger the discovery of whole classes of chemicals of potential commercial interest. Similar biological effects can often be achieved by completely different compounds. However, compounds within a given structural family may exhibit quite different biological activities depending on their interactions with different intracellular proteins like enzymes or receptors. By varying the functional groups and structural elements of a lead compound, its interaction with the active site of the target protein, as well as its physicochemical, pharmacokinetic, and dynamic properties can be improved. In this context, the introduction of fluorine into active ingredients has become an important concept in the quest for a modern crop protection product with optimal efficacy, environmental safety, user friendliness, and economic viability. Fluorinated organic compounds represent an important and growing family of commercial agrochemicals. A number of recently developed agrochemical candidates represent novel classes of chemical compounds with new modes of action; several of these compounds contain new fluorinated substituents. However, the complex structure-activity relationships associated with biologically active molecules mean that the introduction of fluorine can lead to either an increase or a decrease in the efficacy of a compound depending on its changed mode of action, physicochemical properties, target interaction, or metabolic susceptibility and transformation. Therefore, it is still difficult to predict the sites in a molecule at which fluorine substitution will result in optimal desired effects.     

单萜吲哚生物碱士的宁的合成研究进展

士的宁属于单萜吲哚生物碱,是中药马钱子的主要有效成分,具有复杂的化学结构,包含7个环系和6个手性中心。Woodward经典合成代表了有机合成领域的里程碑。经过半个多世纪的努力已有十几个科研小组以不同策略对士的宁分子进行全合成,丰富和发展了有机合成工艺。士的宁是试验新反应和新合成策略的重要目标。按照成环方式对单萜吲哚生物碱士的宁的多种合成途径进行了总结,以促进相关研究。     

A Review of Pigments Derived from Marine Natural Products

Since the early 20th century, a number of active natural pigments have been identified from marine sources, especially algae and marine microorganisms. This review presents 81 marine pigments, covering over 90 % known natural marine pigments. The objective of this article is to provide an overview on the types of pigments, their structural characterization, origins and biological functions that make them unique. We divide the major categories of pigments by chemical structure, either as carotenoids, indole derivatives (quinones and violacein), alkaloids (prodiginines and tambjamines), polyenes, macrolides, peptides, or terpenoids. Many of these pigments have a variety of biological activities, including antitumor, antibacterial, antioxidant and anti‐inflammatory. In addition, we discuss the development of biotechnology, and the contribution and utilization of marine natural pigments and the potential applications in the field of pharmaceutical research.     

Malassezin, a novel agonist of the aryl hydrocarbon receptor from the yeast Malassezia furfur, induces apoptosis in primary human melanocytes

Pityriasis versicolor is the most common skin mycosis in humans worldwide. Yeasts of the genus Malassezia, particularly M. furfur, a saprophyte occurring widely on human skin, are generally regarded as the causative agents. Pityriasis versicolor is often accompanied by a long-lasting depigmentation that persists even after successful antimycotic therapy. M. furfur is able to convert tryptophan into a variety of indole alkaloids, some of them showing biological properties that correlate well with certain clinical features of pityriasis versicolor. This suggests a possible role for these compounds in the depigmentation process. We now report that human melanocytes undergo apoptosis when exposed to the crude mixture of tryptophan metabolites from M. furfur. The active compound was identified as malassezin, previously isolated by us from the same source and characterized as an agonist of the aryl hydrocarbon (Ah) receptor. The compound could, therefore, contribute to the marked depigmentation observed during the course of pityriasis versicolor.