Fluorescent profiling of natural product producers

The identification of natural product producer organisms remains a problem for both isolation and natural product classification. A concise screen is developed through fluorescent modification of a set of natural products that offer a common activity. Through real-time multicolor microscopy, the processing, storage, and effects of a natural product are rapidly screened at the level of the strain and individual organism.     

Natural Product Synthesis at the Interface of Chemistry and Biology

Nature has evolved to produce unique and diverse natural products that possess high target affinity and specificity. Natural products have been the richest sources for novel modulators of biomolecular function. Since the chemical synthesis of urea by Wöhler, organic chemists have been intrigued by natural products, leading to the evolution of the field of natural product synthesis over the past two centuries. Natural product synthesis has enabled natural products to play an essential role in drug discovery and chemical biology. With the introduction of novel, innovative concepts and strategies for synthetic efficiency, natural product synthesis in the 21st century is well poised to address the challenges and complexities faced by natural product chemistry and will remain essential to progress in biomedical sciences.     

An Improved Synthesis of the Natural Product Isorhapontigenin

lsorhapontigenin (I ) is a natural product with many biological activities. M. Linel a/ first isolated it from the traditional Chinese herb, G.parvdoliunl 1. The totalsynthesis of (I ) has been reported' using miting reaction and TMS as the protectinggroup. the reaction gives both E and Z-stilbene, In an attempt to obtain enough sample of(I ) for screening its bioactivities, we have developed an alternative synthetic route toprepare isorhapontigenin through a 7 steps reaction sequence 3. H…     

The value of natural products to future pharmaceutical discovery

Natural products have provided considerable value to the pharmaceutical industry over the past half century. In particular, the therapeutic areas of infectious diseases and oncology have benefited from numerous drug classes derived from natural product sources. Unfortunately, pharmaceutical companies have significantly decreased activities in natural product discovery during the past several years. Biotechnology companies working in the fields of combinatorial biosynthesis, genetic engineering and metagenomic approaches to identify novel natural product lead molecules have had limited success. Despite what appears to be a slow death of natural product discovery research, many new and interesting molecules with biological activity have been published in the past few years. If natural product materials continue to be tested for desirable therapeutic activities, we believe that significant progress in identifying new antibiotics, oncology therapeutics and other useful medicines will be made.     

Enantioselective synthesis of possible diastereomers of heptadeca-1-ene-4,6-diyne-3,8,9,10-tetrol; putative structure of a conjugated diyne natural product isolated from Hydrocotyle leucocephala

Enantioselective synthesis of possible diastereomers of heptadeca-1-ene-4,6-diyne-3,8,9,10-tetrol, a structure proposed for the natural product isolated from Hydrocotyle leucocephala is accomplished. The reported spectral data of the natural product did not match those of any of the isomers that were synthesized and established that the structure proposed for the natural product is not correct and requires revision.     

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．     

First total synthesis and structure confirmation of diacetylenic polyol (+)-oploxyne B

The first total synthesis of the natural product (+)-oploxyne B is achieved. The synthesis has led to the confirmation of absolute stereochemistry of the natural product. The natural product displayed cytotoxic activity with IC₅₀ values varying from 16 to 53 μM in four cancer cell lines tested.     

天然产物化学研究的挑战和机遇

本文论述了目前我国天然产物化学研究中所存在的问题以及面临的挑战和机遇,同时就如何促进我国天然产物的新结构、新功能及其合成化学等方面的原始性创新研究和相应的对策进行了评述。     

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.     

Natural Product Chemistry: From Plants to Human

Conventionally, natural product chemistry deals with the isolation, characterization, and synthesis of compounds from plants. It a broad sense, natural product chemistry may include all fields of biochemistry. Two projects are presented to illustrate the expanded definition of natural product chemistry. One deals with phosphatidylinositol (PI) and the key enzyme involved in its metabolism, PI-specific phospholipase C. The other project is on the structure-function relationship of human tumor suppressor p16.     

Natural Products Inhibitors of Monoamine Oxidases—Potential New Drug Leads for Neuroprotection,Neurological Disorders,and Neuroblastoma

Monoamine oxidase inhibitors (MAOIs) are an important class of drugs prescribed for treatment of depression and other neurological disorders. Evidence has suggested that patients with atypical depression preferentially respond to natural product MAOIs. This review presents a comprehensive survey of the natural products, predominantly from plant sources, as potential new MAOI drug leads. The psychoactive properties of several traditionally used plants and herbal formulations were attributed to their MAOI constituents. MAO inhibitory constituents may also be responsible for neuroprotective effects of natural products. Different classes of MAOIs were identified from the natural product sources with non-selective as well as selective inhibition of MAO-A and -B. Selective reversible natural product MAOIs may be safer alternatives to the conventional MAOI drugs. Characterization of MAO inhibitory constituents of natural products traditionally used as psychoactive preparations or for treatment of neurological disorders may help in understanding the mechanism of action, optimization of these preparations for desired bioactive properties, and improvement of the therapeutic potential. Potential therapeutic application of natural product MAOIs for treatment of neuroblastoma is also discussed.     

Natural products--a simple model to explain chemical diversity

A simple evolutionary model is presented which explains why organisms produce so many natural products, why so many have low biological activity, why enzymes involved in natural product synthesis have the properties they do and why natural product metabolism is shaped as it is.     

Natural products to drugs: natural product-derived compounds in clinical trials

Natural product and natural product-derived compounds that are being evaluated in clinical trials or are in registration (as at 31st December 2007) have been reviewed, as well as natural product-derived compounds for which clinical trials have been halted or discontinued since 2005. Also discussed are natural product-derived drugs launched since 2005, new natural product templates and late-stage development candidates.     

Modern Approaches in the Discovery and Development of Plant-Based Natural Products and Their Analogues as Potential Therapeutic Agents

Natural products represents an important source of new lead compounds in drug discovery research. Several drugs currently used as therapeutic agents have been developed from natural sources; plant sources are specifically important. In the past few decades, pharmaceutical companies demonstrated insignificant attention towards natural product drug discovery, mainly due to its intrinsic complexity. Recently, technological advancements greatly helped to address the challenges and resulted in the revived scientific interest in drug discovery from natural sources. This review provides a comprehensive overview of various approaches used in the selection, authentication, extraction/isolation, biological screening, and analogue development through the application of modern drug-development principles of plant-based natural products. Main focus is given to the bioactivity-guided fractionation approach along with associated challenges and major advancements. A brief outline of historical development in natural product drug discovery and a snapshot of the prominent natural drugs developed in the last few decades are also presented. The researcher’s opinions indicated that an integrated interdisciplinary approach utilizing technological advances is necessary for the successful development of natural products. These involve the application of efficient selection method, well-designed extraction/isolation procedure, advanced structure elucidation techniques, and bioassays with a high-throughput capacity to establish druggability and patentability of phyto-compounds. A number of modern approaches including molecular modeling, virtual screening, natural product library, and database mining are being used for improving natural product drug discovery research. Renewed scientific interest and recent research trends in natural product drug discovery clearly indicated that natural products will play important role in the future development of new therapeutic drugs and it is also anticipated that efficient application of new approaches will further improve the drug discovery campaign.     

Natural products to drugs: natural product derived compounds in clinical trials

Natural product and natural product-derived compounds that are being evaluated in clinical trials or in registration (current 31 December 2004) have been reviewed. Natural product derived drugs launched in the United States of America, Europe and Japan since 1998 and new natural product templates discovered since 1990 are discussed.     

Synthesis and evaluation of derrubone and select analogues

Recently, we reported that the natural product derrubone exhibits Hsp90 inhibitory activity. Due to its unique architectural scaffold and proposed rapid assembly, the synthesis of this natural product was pursued with the aim of identifying structure--activity relationships. Synthesis of the natural product was accomplished in eight highly convergent steps, which led to a facile method for the construction of related compounds. Biological evaluation of derrubone and its analogues identified several compounds that exhibit low micromolar inhibitory activity against breast and colon cancer cell lines.     

Total synthesis, structure revision, and absolute configuration of (-)-brevenal

Total synthesis of structure 1 originally proposed for brevenal, a nontoxic polycyclic ether natural product isolated from the Florida red tide dinoflagellate, Karenia brevis, was accomplished. The key features of the synthesis involved (i) convergent assembly of the pentacyclic polyether skeleton based on our developed Suzuki-Miyaura coupling chemistry and (ii) stereoselective construction of the multi-substituted (E,E)-dienal side chain by using copper(I) thiophen-2-carboxylate (CuTC)-promoted modified Stille coupling. The disparity of NMR spectra between the synthetic material and the natural product required a revision of the proposed structure. Detailed spectroscopic comparison of synthetic 1 with natural brevenal, coupled with the postulated biosynthetic pathway for marine polyether natural products, suggested that the natural product was most likely represented by 2, the C26 epimer of the proposed structure 1. The revised structure was finally validated by completing the first total synthesis of (-)-2, which also unambiguously established the absolute configuration of the natural product.     

Total synthesis based modification of benzoquinone ansamycin antibiotics: C8 diversification of C5-C15 fragments

Benzoquinone ansamycins are known to be potent Heat shock protein (Hsp90) inhibitors, and total-synthesis-based structure modification of this natural product family may lead to the discovery of novel cancer chemotherapeutics. Described in this paper is a unified synthetic route that gives access to both natural and C-8-modified C5-C15 fragments of this natural product family.     

Enantioselective total synthesis and confirmation of the absolute and relative stereochemistry of streptorubin B

The enantioselective total synthesis of the pyrrolophane natural product streptorubin B is described. Key steps in the concise route include the application of a one-pot enantioselective aldol cyclization/Wittig reaction and an anionic oxy-Cope rearrangement to forge the crucial 10-membered ring. Comparisons between CD spectra of synthetic and natural samples of streptorubin B coupled with X-ray crystallography allowed for the determination of the absolute stereochemistry of this natural product for the first time. These studies also provided unambiguous proof of the relative configuration between the butyl side chain and the bispyrrole subunit. Additional studies revealed a novel atropstereoselective Paal-Knorr pyrrole condensation and provided fundamental experimental insight into the barrier for atropisomerization of the natural product.     

Conformationally restricted (+)-cacospongionolide B analogues. Influence on secretory phospholipase A2 inhibition

A new approach to (+)-cacospongionolide was developed to access conformationally restricted variants of the natural product. The flexible aliphatic region between the decalin and side chain portion of the natural product was replaced with alkenyl and alkynyl linkers to probe the influence of structural rigidity in the inhibition of secretary phospholipase A2 (sPLA2). It was found that when the aliphatic section is replaced with a Z-olefin or an alkyne, sPLA2 inhibitory activity suffered relative to the natural product; however, an E-olefin-containing analogue led to an enhanced activity. These results suggest that preferred sPLA2 binding conformation of the natural product is similar to the geometry of the E-olefin-containing analogue.