Fluorescent taxoids

Background: Taxol^* is a natural product produced by the Pacific Yew, Taxus brevifolia, that has emerged as a prominent chemotherapeutic agent for the treatment of solid tumors. Taxol's biochemical mode of action has been well studied: it binds to microtubules, stabilizing them and preventing their depolymerization to tubulin subunits. At lower dosage levels, taxol also interferes with the normal dynamics of the tubulin—microtubule equilibrium. This biochemical effect causes taxol's ultimate physiological effect, cell cycle arrest; taxol is thought to block anaphase A of mitosis. Taxol also causes a number of intriguing secondary effects on interphase cells that are poorly understood. We believed that a bio-active fluorescent taxol derivative could be a useful tool in the study of these cellular mechanisms, especially in interphase cells.Results: We have synthesized and characterized a series of stable, fluorescently labeled derivatives of taxol that bind to microtubules and have cytotoxicities similar to that of taxol. Fluorescence microscopy experiments in interphase human foreskin fibroblast (HFF) cells indicate that one of these, a sulforhodamine taxoid, is particularly well suited for optical microscopy. The use of this taxoid in HFF cells revealed a previously undetected localization of taxoids to the nucleolus during interphase.Conclusion: The production of a new fluorescent derivative of taxol provides a useful tool, enabling cellular biologists to study taxol's mechanism of action. It is hoped that this material will prove particularly useful for the study of taxol's effects upon interphase cells.     

ortho-Quinols in (Bio)Synthesis of Natural Products

6-Alkyl-6-hydroxycyclohexa-2,4-dienone derivatives, commonly referred to as ortho-quinols, and their simple ester and ether variants constitute a class of organic compounds that aroused much interest amongst chemists over the past 70 years for several reasons related to organic synthesis, natural product chemistry and biochemistry. It was very early on that organic chemists understood the potential of the unique yet versatile chemical reactivity of such compounds to synthesize more complex structures, and it soon emerged that ortho-quinols could constitute key intermediates in the biosynthesis of certain natural products of various origins. This minireview discusses the chemistry of ortho-quinols from the point of view of their role in the synthesis and biosynthesis of natural products. Examples of completed syntheses of natural products mostly taken in the literature of the last 20 years or so, together with some chosen pieces from older but pioneering and most remarkable works, are highlighted to illustrate this discussion.     

Preparation and Properties,Reactions, and Applications of Radialenes

Radialenes are alicyclic compounds in which every ring atom is sp²-hybridized and carries an exocyclic C? C double bond. Because of their unusual topology and electronic structures these hydrocarbons have aroused the interest of both preparative chemists and theoreticians. Although considerable progress has been achieved recently, directed and efficient syntheses of these molecules remain a challenge. The study of their chemical behavior offers vast opportunities. Very recently materials scientists have become interested in these unusual compounds in their search for organic conductors and ferromagnets.     

Rewiring cellular metabolism for heterologous biosynthesis of Taxol

Abstract

Taxol is one of the anticancer drugs synthesized naturally in the evergreen Taxus brevifolia forest tree belonging to the yew family (Taxaceae) growing on the Pacific. There are reportedly evidence for treating ovarian, breast and lung cancers through this drug given its unique structural and functional features. Extraction of this drug from yew trees bark is one of the most common ways of producing this drug, but 3000 trees are needed to obtain a kilogram of Taxol. Hence, further attention has recently been attracted to the metabolic engineering strategies, including, engineering cellular metabolism of microorganisms and their optimization. Accordingly, the present paper article was aimed to review recent advances in elevating the production and commercialization of Taxol through metabolic engineering techniques.     

抗癌药物紫杉醇的制备、抗癌机理和应用前景

紫杉醇具有显著的抗癌活性和独特的作用机理,现主要用于治疗晚期乳腺癌和卵巢癌等。紫杉醇分子结构复杂,具有特殊的三环[6+8+6]碳架和桥头双键以及众多的含氧取代基,其全合成引起国内外许多有机化学家的兴趣。本文简述紫杉醇的制备、抗癌机理和不良反应。     

Taxol® (Paclitaxel)

Taxol® (paclitaxel) has been hailed by many as the most promising new cancer treatment in two decades. The FDA requires that paclitaxel intended for human consumption be obtained only from the bark ofTaxus brevifolia, the Pacific yew. As this may become increasingly uneconomical, new strategies must be explored to ensure the continued availability of taxol and related molecules. This article examines the planning that must be engaged in and the contingencies that must be prepared for in this changing arena.     

Total syntheses of colchicine in comparison: a journey through 50 years of synthetic organic chemistry

Colchicine, the major alkaloid of the meadow saffron, is one of the most prominent natural products and, like other tubulin-binding natural products (e.g. taxol and the epothilones), exhibits great pharmaceutical potential. The first syntheses in the late 1950s were milestones in natural product synthesis. But even today this structurally supposedly simple molecule poses a challenge to synthetic chemists. Only in the last years have syntheses been developed that are efficient enough to provide novel structurally modified colchicine analogues. The comparative examination of all known colchicine total syntheses undertaken in this Review not only reveals the tremendous progress in synthetic organic methodology over the past decades, but also shows how the unique synthetic problems posed by this molecule can be solved in an exceptionally creative manner. Only a few target molecules have been synthesized in such multifaceted ways.     

Materials and biological applications of 1,2,3-selenadiazoles: a review

In recent years, chemistry of metal-nitrogen–bonded compounds have attracted tremendous attention mainly because of unusual properties resulting from such a bond involving carbon and other heteroatoms. M?N–bonded compounds, when containing group VI elements, especially selenium, has attracted great attention in materials chemistry. In addition, the increased interest in synthesis of N-containing bioactive compounds with other heteroatoms such as selenium, sulfur, etc is mainly because of their tremendous potential as antioxidants, additives, dyes for polymers, and as insecticides, in solvent extraction, and in nanotechnology. Thus, the synthesis and applications of 1,2,3-selenadiazoles have attracted recent interest of materials scientists, including nanotechnologists, pharmaceutical chemists, and organic chemists. The chemistry of 1,2,3-selenadiazoles is highly rich and has been practiced ever since its first report in 1972. Such N-containing Se-heterocycles form several types of selenadiazoles that are a rich source of selenium for semiconductor nanoparticles of metal selenides. The materials chemistry of such molecules has been documented for over three decades, and their great scope in semiconductors has emerged. This review article is an attempt to bring a variety of materials and biological application of 1,2,3-selenadiazoles for better understanding of the researchers.     

Phosphaalkynes—Syntheses,Reactions, Coordination Behavior [New Synthetic Methods (73)]

Organophosphorus compounds have been applied in two ways in chemical synthesis. They can either be used as a reagent in a step of the synthesis (for example, in the Wittig reaction) or they can be incorporated directly into the target molecule. This second application, in particular, has expanded greatly in the last few years with the preparation of low-coordination phosphorus compounds. These include the phosphaalkynes, which are of great interest to organic and inorganic chemists. Phosphaalkynes have been employed in the synthesis of heterocyclic compounds, phosphaarenes and their valence isomers, and polycyclic compounds. Further applications have been the use of phosphaalkynes as new ligand systems in complex chemistry and their cyclooligomerization with organometallic reagents. While the chemical properties of phosphaalkynes have little in common with those of nitriles, they are in many ways very similar to those of the isoelectronic acetylenes.     

Advances and challenges in the identification of volatiles that mediate interactions among plants and arthropods

The relatively new research field of Chemical Ecology has, over the last two decades, revealed an important role of plant-produced volatile organic compounds (VOCs) in mediating interactions between plants and other organisms. Of particular interest are the volatile blends that plants actively emit in response to herbivore damage. Various efforts are underway to pinpoint the bioactive compounds in these complex blends, but this has proven to be exceedingly difficult. Here we give a short overview on the role of herbivore-induced plant volatiles in interactions between plants and other organisms and we review methods that are currently employed to collect and identify key volatile compounds mediating these interactions. Our perspective on future directions of this fascinating research field places special emphasis on the need for an interdisciplinary approach. Joint efforts by chemists and biologists should not only facilitate the elucidation of crucial compounds, but can also be expected to lead to an exploitation of this knowledge, whereby ecological interactions may be chemically manipulated in order to protect crops and the environment.     

Recent progress on the synthesis of cyclic polymers via ring-expansion strategies

Cyclic polymers are the simplest topological isomers of linear macromolecules, but exhibit properties that differ from linear chains in ways that remain imperfectly understood. The difficulty of synthesizing appropriately pure and high molecular weight cyclic samples has hindered experimental studies. Ring-closure methods, while versatile, are inherently limited in the range of molecular weights that can be achieved. Ring-expansion methods are a much more promising strategy toward obtaining high molecular weight cyclic polymers. The current review focuses on recent developments in ring-expansion polymerization strategies toward the synthesis of high molecular weight cyclic polymers. Significant progress in the last decade has made the synthesis of cyclic polymers possible by a variety of methods, such as ruthenium- and tungsten-catalyzed ring-expansion metathesis polymerization, organocatalytic and Lewis acid-catalyzed zwitterionic polymerization, RAFT and nitroxide-mediated radical polymerization, among many others. While the study of cyclic polymers has long been hampered by synthetic challenges, the recent resurgence of interest in this field presents an exciting opportunity for chemists. © 2017 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2017 , 55, 2892–2902     

Ionic liquids in the synthesis and modification of polymers

Ionic liquids are organic salts that are liquid at ambient temperatures, preferably at room temperature. They are nonvolatile, thermally and chemically stable, highly polar liquids that dissolve many organic, inorganic, and metallo‐organic compounds. Many combinations of organic cations with different counterions are already known, and the properties of ionic liquids may be adjusted by the proper selection of the cation and counterion. In the last decade, there has been increasing interest in using ionic liquids as solvents for chemical reactions. The interest is stimulated not only by their nonvolatility (green solvents) but also by their special properties, which often affect the course of a reaction. In recent years, ionic liquids have also attracted the attention of polymer chemists. Although the research on using ionic liquids in polymer systems is still in its infancy, several interesting possibilities have already emerged. Ionic liquids are used as solvents for polymerization processes, and in several systems they indeed show some advantages. In radical polymerization, the k_p/k_t ratio (where k_p is the rate constant of propagation and k_t is the rate constant of termination) is higher than in organic media, and thus better control of the process can be achieved. Ionic liquids, as electrolytes, have also attracted the attention of researchers in the fields of electrochemical polymerization and the synthesis of conducting polymers. Finally, the blending of ionic liquids with polymers may lead to the development of new materials (ionic liquids may act as plasticizers, electrolytes dispersed in polymer matrices, or even porogens). In this article, the new developments in these fields are briefly discussed. © 2005 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 43: 4675–4683, 2005     

Resonance‐Assisted Hydrogen Bonding as a Driving Force in Synthesis and a Synthon in the Design of Materials

Resonance‐assisted hydrogen bonding (RAHB), a concept introduced by Gilli and co‐workers in 1989, concerns a kind of intramolecular H‐bonding strengthened by a conjugated π‐system, usually in 6‐, 8‐, or 10‐membered rings. This Review highlights the involvement of RAHB as a driving force in the synthesis of organic, coordination, and organometallic compounds, as a handy tool in the activation of covalent bonds, and in starting moieties for synthetic transformations. The unique roles of RAHB in molecular recognition and switches, E/Z isomeric resolution, racemization and epimerization of amino acids and chiral amino alcohols, solvatochromism, liquid‐crystalline compounds, and in synthons for crystal engineering and polymer materials are also discussed. The Review can provide practical guidance for synthetic chemists that are interested in exploring and further developing RAHB‐assisted synthesis and design of materials.     

Exploiting nature's rich source of proteasome inhibitors as starting points in drug development

Cancer is the No. 2 cause of death in the Western world and one of the most expensive diseases to treat. Thus, it is not surprising, that every major pharmaceutical and biotechnology company has a blockbuster oncology product. In 2003, Millennium Pharmaceuticals entered the race with Velcade?, a first-in-class proteasome inhibitor that has been approved by the FDA for treatment of multiple myeloma and its sales have passed the billion dollar mark. Velcade?'s extremely toxic boronic acid pharmacophore, however, contributes to a number of severe side effects. Nevertheless, the launching of this product has validated the proteasome as a target in fighting cancer and further proteasome inhibitors have entered the market as anti-cancer drugs. Additionally, proteasome inhibitors have found application as crop protection agents, anti-parasitics, immunosuppressives, as well as in new therapies for muscular dystrophies and inflammation. Many of these compounds are based on microbial metabolites. In this review, we emphasize the important role of the structural elucidation of the various unique binding mechanisms of these compounds that have been optimized throughout evolution to target the proteasome. Based on this knowledge, medicinal chemists have further optimized these natural products, resulting in potential drugs with reduced off-target activities.     

Theoretical studies on the structure and spectroscopic properties of pseudohalides

Pseudohalogen-containing compounds have attracted significant interest among nonmetal chemists and theorists, not only owing to their potential use in various fields but also due to difficulties in their experimental preparation and characterization. Since its introduction in 1925, the pseudohalide principle has been used extensively and, therefore, a remarkable progress has been made in the experimental and theoretical research on the compounds of this kind. In this work, we review studies on structural investigations and theoretical characterizations of several pseudohalide-containing compounds in order to contribute to better understanding of the chemistry of many such species.     

微波辐射下氧化N-烷基酰胺合成二酰亚胺

二酰亚胺是一个很有用的官能团, 它广泛存在于天然产物和有药物活性的分子中. 通过微波辐射条件合成它吸引了很多化学家的注意. 极性反应物可以吸收微波辐射, 化学家将微波应用于一些化学反应中. N-烷基酰胺(NH邻位有一个亚甲基CH₂)和N上没有取代的内酰胺可以被过氧化物和过渡金属盐氧化成二酰亚胺. 报道了在乙酸乙酯中过氧叔丁醇和乙酰丙酮锰(III)在微波条件(90 W, 5 min)下, 酰胺迅速、高选择性地、高产率地转变为二酰亚胺的方法.     

Metal alkynyl sigma complexes: synthesis and materials

Metal alkynyl complexes hold a fascination for synthetic chemists, structural chemists, and materials scientists alike. Harnessing the unique overlap of metal and carbon orbitals is a challenge that can be overcome in many ways and hence, there are many synthetic routes toward M-C=C-bond-forming reactions that utilize a wide variety of transition-metal and alkynyl reagents. Some methods can be widely applied, while others are specific to a particular metal or compound. The linear geometry of the alkynyl unit and its pi-unsaturated character have led to metal alkynyls becoming attractive building blocks for molecular wires and polymeric organometallic materials, which can possess interesting properties, such as optical nonlinearity, luminescence, liquid crystallinity, and electrical conductivity. A unique, multifaceted approach, often combining talents from all three of the above chemical disciplines, has served as a driving force behind the intense research into the development of metal alkynyl sigma complexes, the progress of which, particularly in the last ten years, is summarized in this review.     

(+)-Discodermolide binds to microtubules in stoichiometric ratio to tubulin dimers,blocks taxol binding and results in mitotic arrest

Background: The marine natural product (+)-discodermolide has potent immunosuppressive activity. It inhibits proliferation of a wide range of human and murine cells, induces cell cycle arrest in the G2 or M phase and was recently shown to stabilize microtubules. Total synthesis of discodermolide has made it possible to generate variants of the compound to study its intracellular function in detail.Results: We have determined that (+)-discodermolide arrests MG63 cells at M phase, and has a stabilizing effect on microtubules. In vitro studies show that discodermolide induces polymerization of purified tubulin in the absence of microtubule-associated proteins, and that it binds to tubulin dimers in microtubules at 1:1 stoichiometry. Discodermolide binds taxol-polymerized microtubules at near stoichiometric level, whereas taxol binds discodermolide-induced microtubules poorly. Competition data show that the binding of microtubules by discodermolide and taxol are mutually exclusive; discodermolide binds with higher affinity than taxol. The results of binding assays carried out in vivo or in cell lysates also suggest that the microtubule network is discodermolide's cellular target.Condusions: (+)-Discodermolide causes cell cycle arrest at the metaphase-anaphase transition in mitosis, presumably due to its stabilizing effect on microtubules. In vitro, discodermolide polymerizes purified tubulin potently in the absence of MAPs. It binds microtubules at one molecule per tubulin dimer with a higher affinity than taxol, and the binding of microtubules by discodermolide and taxol are mutually exclusive. In total cell lysates discodermolide displays binding activity that is consistent with its effects on microtubules.     

Total Synthesis of Aspidosperma and Strychnos Alkaloids through Indole Dearomatization

Monoterpenoid indole alkaloids are the major class of tryptamine-derived alkaloids found in nature. Together with their structural complexity, this has attracted great interest from synthetic organic chemists. In this Review, the syntheses of Aspidosperma and Strychnos alkaloids through dearomatization of indoles are discussed.