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.     

TMC-95A–D and analogues: Chemistry and biology

The proteasome regulates diverse intracellular processes, including cell-cycle progression, cell adhesion and migration, apoptosis and antigen presentation: selective inhibitors of the proteasome, therefore, have great therapeutic potential for the treatment of cancer. TMC-95A–D are unique natural products and represent a new class of noncovalent, reversible, and selective proteasome inhibitors with exceptionally strong bioactivity profiles and interesting structural properties. Significant recent advances in the syntheses of these natural products have led to intense interest in the development of related compounds as potential anticancer agents: the chemistry and biology of these natural products and analogues will be described in this review article.     

卟啉及其光电化学研究进展

卟啉及金属卟啉在自然界中广泛存在,其光学、电化学等特性可通过分子结构中多个反应位点进行调控. 随着全球能源环境问题日益凸显,卟啉在太阳能电池、光催化制氢领域的研究成为热点. 本文简介了作者课题组近年来通过国内外合作开展的D-π-A结构卟啉分子结构改性及其对光电化学性质和器件光伏特性影响的进展,并对未来卟啉光电化学研究的发展进行了简要的探讨.     

Photochemical reaction detection of phylloquinone and menaquinones. A comparison with chemical post-columns reduction for fluorescence detection

Summary A new photochemical reaction method for the on-line fluorimetric detection of natural vitamin K homologs was developed. In addition to its high sensitivity, the method features an interesting selectivity for the determination of these compounds in a complex matrix such as human serum. The formation of different photolysis products as a function of reaction conditions, and the optimalisation of a segmented flow reaction system will be discussed. The results indicate that the method is 4 times more sensitive than UV detection, and at least as selective as fluorescence detection after post-column chemical reduction.     

In situ hydrothermal synthesis of tetrazole coordination polymers with interesting physical properties

Tetrazole compounds have been studied for more than one hundred years and applied in various areas. Several years ago Sharpless and his co-workers reported an environmentally friendly process for the preparation of 5-substituted 1H-tetrazoles in water with zinc salt as catalysts. To reveal the exact role of the zinc salt in this reaction, a series of hydrothermal reactions aimed at trapping and characterizing the solid intermediates were investigated. This study allowed us to obtain a myriad interesting metal-organic coordination polymers that not only partially showed the role of the metal species in the synthesis of tetrazole compounds but also provided a class of complexes displaying interesting chemical and physical properties such as second harmonic generation (SHG), fluorescence, ferroelectric and dielectric behaviors. In this tutorial review, we will mainly focus on tetrazole coordination compounds synthesized by in situ hydrothermal methods. First, we will discuss the synthesis and crystal structures of these compounds. Their various properties will be mentioned and we will show the applications of tetrazole coordination compounds in organic synthesis. Finally, we will outline some expectations in this area of chemistry. The direct coordination chemistry of tetrazoles to metal ions and in situ synthesis of tetrazole through cycloaddition between organotin azide and organic cyano group will be not discussed in this review.     

A Concise Review of Current In Vitro Chemical and Cell-Based Antioxidant Assay Methods

Antioxidants remain interesting molecules of choice for suppression of the toxic effects of free radicals in foods and human systems. The current practice involves the use of mainly synthetic molecules as potent antioxidant agents. However, due to the potential negative impact on human health, there is an intensive effort within the research community to develop natural alternatives with similar antioxidant efficacy but without the negative side effects of synthetic molecules. Still, the successful development of new molecules depends on the use of reliable chemical or cell culture assays to screen antioxidant properties. Chemical antioxidant assays include the determination of scavenging ability against free radicals such as DPPH, superoxide anion radicals, hydroxyl radicals, hydrogen peroxide, and nitric oxide. Other antioxidant tests include the ability of compounds to bind and sequester prooxidant metal cations, reduce ferric iron, and attenuate the rate of lipid oxidation. Ex vivo tests utilize cell cultures to confirm entry of the molecules into cells and the ability to quench synthetic intracellular free radicals or to stimulate the increased biosynthesis of endogenous antioxidants. In order to assist researchers in their choice of antioxidant evaluation methods, this review presents background scientific information on some of the most commonly used antioxidant assays with a comparative discussion of the relevance of published literature data to food science and human nutrition applications.     

Chemical Syntheses and Chemical Biology of Carboxyl Polyether Ionophores: Recent Highlights

A central goal of chemical biology is to develop molecular probes that enable fundamental studies of cellular systems. In the hierarchy of bioactive molecules, the so‐called ionophore class occupies an unflattering position in the lower branches, with typical labels being “non‐specific” and “toxic”. In fact, the mere possibility that a candidate molecule possesses “ionophore activity” typically prompts its removal from further studies; ionophores—from a chemical genetics perspective—are molecular outlaws. In stark contrast to this overall poor reputation of ionophores, synthetic chemistry owes some of its most amazing achievements to studies of ionophore natural products, in particular the carboxyl polyethers renowned for their intricate molecular structures. These compounds have for decades been academic battlegrounds where new synthetic methodology is tested and retrosynthetic tactics perfected. Herein, we review the most exciting recent advances in carboxyl polyether ionophore (CPI) synthesis and in addition discuss the burgeoning field of CPI chemical biology.     

Aurones: interesting natural and synthetic compounds with emerging biological potential

Aurones [2-benzylidenebenzofuran-3(2H)-ones] are either natural or synthetic compounds, belonging to the flavonoid family. They are isomeric to flavones and provide a bright yellow color to the plants in which they occur. Today, a literature survey indicates that the related flavonoids have been studied not only for their physiological properties and effects on Nature, but also for their therapeutic potential. Aurones are recently attracting the interest of an increasing number of research groups, and, since the last review, some interesting advances have been made in understanding the aurones. In this review, we report the recent advances made on the synthetic routes towards aurones. We also highlight their activity in different biological areas, as well as applied genetic plant modifications to produce these colored compounds. Their synthesis, structure-activity relationships and the importance of the substitution pattern will also be mentioned. Finally, some aspects regarding the possible development of aurones will be discussed briefly.     

Recent advances on carborane-based ligands in low-valent group 13 and group 14 elements chemistry

Carboranes are a class of polyhedral boron-carbon molecular clusters, they can serve as versatile ligands in stabilizing low-valent main group element compounds, due to their exceptionally thermal and chemical stabilities, easy modifications at the cage carbon vertices, as well as large spherical steric effects. These carborane-based ligands provide interesting opportunities for the synthesis of low-valent main group element compounds with novel structure and reactivity, which indeed enrich the chemistry of low-valent element main group compounds. This review summarizes the recent advances in the chemistry of low-valent group 13 and group 14 element compounds supported by carborane-based ligands. Achievements and perspectives in this new and flourishing field are discussed in this review.     

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.     

Coupling HPLC to on-line, post-column (bio)chemical assays for high-resolution screening of bioactive compounds from complex mixtures

It is challenging to screen and identify bioactive compounds from complex mixtures. We review a recently developed technique that couples high-performance liquid chromatography (HPLC) to on-line, post-column (bio)chemical assays and parallel chemical analysis to screen and identify bioactive compounds from complex mixtures without the need for cumbersome purification and subsequent screening. In this system, HPLC separates complex mixtures and a post-column (bio)chemical assay determines the activity of the individual compounds present in the mixtures. Parallel chemical-detection methods (e.g., diode-array detection, mass spectrometry and nuclear magnetic resonance) identify and quantify the active compounds simultaneously. We focus on relatively widely used on-line, post-column assays for antioxidant screening and less widely used hyphenated systems involving assays based on enzymes and receptors. These strategies have proved to be very useful for rapid profiling and identification of individual active components in mixtures to provide a powerful method for natural product-based drug discovery.     

蝴蝶霉素及其类似物的化学合成进展

蝴蝶霉素是一种新型的天然抗生素,由于具有特殊的抗肿瘤活性而引起了人们的关注。然而,由于一些不利因素导致蝴蝶霉素无法直接运用于临床。为了寻找活性更好的药物先导化合物,人们对蝴蝶霉素的结构进行修饰和改造,通过生物方法和化学方法,合成了大量的类似物。本文将从化学合成角度出发,立足蝴蝶霉素及其类似物结构构造的关键步骤,对近年来的合成研究进行综述。     

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.     

Anticancer drugs from nature--natural products as a unique source of new microtubule-stabilizing agents

This review article provides an overview on the current state of research in the area of microtubule-stabilizing agents from natural sources, with a primary focus on the biochemistry, biology, and pharmacology associated with these compounds. A variety of natural products have been discovered over the last decade to inhibit human cancer cell proliferation through a taxol-like mechanism. These compounds represent a whole new range of structurally diverse lead structures for anticancer drug discovery.     

In memory of Prof. Venkataraman: Recent advances in the synthetic methodologies of flavones

Flavones are present in a variety of medicines and natural products and are important structural motif due to their unique mode of physiological action. Hence the structural importance of flavone moiety has elicited a great deal of interest in the field of organic synthesis and chemical biology to develop some new and improved synthesis of this molecular skeleton. Herein, we have described an up to date overview on the recent advances in the diverse synthetic methodologies of flavones. The review covers the basic conceptual and practical catalytic synthesis like carbonylative annulation, cyclodehydration, Suzuki Miyaura coupling, Heck coupling, green methodologies, metal catalyzed reactions, organocatalytic transformations, microwave irradiation, etc. which are significant for constructing flavone skeleton. This review will satisfy the expectations of readers who are interested in the development of the field and looking for an update. It will stimulate researchers to develop new and creative synthetic access to this heterocyclic system, which will be instrumental in the advancement of flavone chemistry.     

基于天然产物的白血病细胞分化机制的化学生物学研究

天然产物由于具有结构多样性和新颖性,具有独特的生理活性和新的作用机制,因此是开展化学生物学研究的重要工具,同时也是创新药物和先导化合物的重要来源.最近,我们研究发现天然活性化合物腺花素能够在体内和体外诱导维甲酸敏感和耐药的急性粒细胞性白血病细胞发生分化,有效延长白血病小鼠生存时间.在此基础上,以腺花素为分子探针,＂垂钓＂其潜在的靶分子,结果发现腺花素特异性靶向过氧化还原酶（Peroxiredoxin）Ⅰ//Ⅱ蛋白,导致H2O2的积聚,H2O2作为第二信使可诱导白血病细胞分化的信号通路.本文对这些工作做了论述和展望.     

A one-bead, one-stock solution approach to chemical genetics: part 2

BACKGROUND: Chemical genetics provides a systematic means to study biology using small molecules to effect spatial and temporal control over protein function. As complementary approaches, phenotypic and proteomic screens of structurally diverse and complex small molecules may yield not only interesting individual probes of biological function, but also global information about small molecule collections and the interactions of their members with biological systems. RESULTS: We report a general high-throughput method for converting high-capacity beads into arrayed stock solutions amenable to both phenotypic and proteomic assays. Polystyrene beads from diversity-oriented syntheses were arrayed individually into wells. Bound compounds were cleaved, eluted, and resuspended to generate 'mother plates' of stock solutions. The second phase of development of our technology platform includes optimized cleavage and elution conditions, a novel bead arraying method, and robotic distribution of stock solutions of small molecules into 'daughter plates' for direct use in chemical genetic assays. This library formatting strategy enables what we refer to as annotation screening, in which every member of a library is annotated with biological assay data. This phase was validated by arraying and screening 708 members of an encoded 4320-member library of structurally diverse and complex dihydropyrancarboxamides. CONCLUSIONS: Our 'one-bead, multiple-stock solution' library formatting strategy is a central element of a technology platform aimed at advancing chemical genetics. Annotation screening provides a means for biology to inform chemistry, complementary to the way that chemistry can inform biology in conventional ('investigator-initiated') small molecule screens.     

Recent applications of ring-closing metathesis in the synthesis of lactams and macrolactams

Lactams are an important class of compounds owing to their presence in numerous biologically active molecules of natural and unnatural nature. They are also highly versatile intermediates that can be elaborated into interesting compounds for potential use in organic and medicinal chemistry endeavors. In this feature article, the reader will be given a background to olefin metathesis followed by concise discussions (with selected examples) to report recent applications of ring-closing metathesis to form lactams and macrolactams from acyclic diene precursors, an area which continues to deposit attractive applications in the chemical literature en route or in the final step to the target molecules.     

Supramolecular complexes based on cyclodextrins

A summary of the application of cyclodextrins (CDs) in the field of supramolecular chemistry has been given. Unique structural features of CDs, namely the separation of hydrophilic and hydrophobic groups, cause unusual physical and chemical properties of these molecules. The most important property of natural or chemically modified CDs is the ability to reversibly and selectively bind organic, inorganic, and biological molecules, forming inclusion complexes (ICs) of the “guest-host” type or nanostructured supramolecular assemblies. The most interesting examples of the application of ICs with CDs in pharmaceutical, food, and chemical industry, spectrometric analysis, separation technologies, of the use of CDs as models for molecular recognition in biology, as well as the cyclical component in the construction of supramolecular architectures (rotaxanes, pseudorotaxanes) are given in the review. The mechanism and methods of the formation of ICs, their properties and the methods of analysis have been described. Particular attention has been paid to molecular necklaces. One of the new promising directions of the application of CDs, namely, the preparation of nanosized materials, has been considered.     

SULFOXIMINES

Abstract

This review of sulfoximines is not intended to be an in-depth, detailed review but rather an overview of a relatively new class of reactive, interesting compounds. Topics selected for discussion reflect both the authors interests as well as the importance of the subjects.