Solution-phase total synthesis of the hydrophilic natural product argifin using 3,4,5-tris(octadecyloxy)benzyl tag

A solution-phase total synthesis of argifin using 3,4,5-tris(octadecyloxy)benzyl tag as a hydrophobic protective group of carboxylic acid was developed to produce 44% overall yield for 16 linear steps. Argifin, a novel class of natural product chitinase inhibitor, is a highly water-soluble cyclic pentapeptide, so hitherto, only solid-phase synthesis techniques have been used to conveniently prepare the compound and its derivatives. 3,4,5-Tris(octadecyloxy)benzyl alcohol (HO-TAGa) and its esters are highly crystalline materials and highly capable of dissolving in less-polar solvents such as dichloromethane, benzene, THF, etc., but insoluble in polar solvents such as methanol and DMSO. The combination of HO-TAGa and Fmoc-based peptide synthesis, together with simple purification by recrystallization from MeOH solution, furnished an efficient and practical route of argifin production in the liquid-phase.     

Specificity and affinity of natural product cyclopentapeptide inhibitors against A. fumigatus, human, and bacterial chitinases

Family 18 chitinases play key roles in organisms ranging from bacteria to man. There is a need for specific, potent inhibitors to probe the function of these chitinases in different organisms. Such molecules could also provide leads for the development of chemotherapeuticals with fungicidal, insecticidal, or anti-inflammatory potential. Recently, two natural product peptides, argifin and argadin, have been characterized, which structurally mimic chitinase-chitooligosaccharide interactions and inhibit a bacterial chitinase in the nM-mM range. Here, we show that these inhibitors also act on human and Aspergillus fumigatus chitinases. The structures of these enzymes in complex with argifin and argadin, together with mutagenesis, fluorescence, and enzymology, reveal that subtle changes in the binding site dramatically affect affinity and selectivity. The data show that it may be possible to develop specific chitinase inhibitors based on the argifin/argadin scaffolds.     

Analyzing airway inflammation with chemical biology: dissection of acidic mammalian chitinase function with a selective drug-like inhibitor

Acidic mammalian chitinase (AMCase) is produced in the lung during allergic inflammation and asthma, and inhibition of enzymatic activity has been considered as a therapeutic strategy. However, most chitinase inhibitors are nonselective, additionally inhibiting chitotriosidase activity. Here, we describe bisdionin F, a competitive AMCase inhibitor with 20-fold selectivity for AMCase over chitotriosidase, designed by?utilizing the AMCase crystal structure and dicaffeine scaffold. In a murine model of allergic inflammation, bisdionin F-treatment attenuated chitinase activity and alleviated the primary features of allergic inflammation including eosinophilia. However, selective AMCase inhibition by bisdionin F also caused dramatic and unexpected neutrophilia in the lungs. This class of inhibitor will be a powerful tool to dissect the functions of mammalian chitinases in disease and represents a synthetically accessible scaffold to optimize inhibitory properties in terms of airway inflammation.     

Structure-based dissection of the active site chemistry of leukotriene A4 hydrolase: implications for M1 aminopeptidases and inhibitor design

M1 aminopeptidases comprise a large family of biologically important zinc enzymes. We show that peptide turnover by the M1 prototype, leukotriene A4 hydrolase/aminopeptidase, involves a shift in substrate position associated with exchange of zinc coordinating groups, while maintaining the overall coordination geometry. The transition state is stabilized by residues conserved among M1 members and in the final reaction step, Glu-296 of the canonical zinc binding HEXXH motif shuffles a proton from the hydrolytic water to the leaving group. Tripeptide substrates bind along the conserved GXMEN motif, precisely occupying the distance between Glu-271 and Arg-563, whereas the Arg specificity is governed by a narrow S1 pocket capped with Asp-375. Our data provide detailed insights to the active site chemistry of M1 aminopeptidases and will aid in the development of novel enzyme inhibitors.     

适用于酸性介质的天然产物提取型缓蚀剂研究进展

缓蚀剂的加入可使金属材料在环境介质中的腐蚀速度降低,同时还能保持金属原来的物理、力学性能不变,已成为防腐蚀技术中应用最广泛的方法之一.从天然植物中提取植物型缓蚀剂成本低、来源广、环境污染小,是一种绿色环保型缓蚀剂,在缓蚀剂研究领域中具有重要地位.本文阐述了近年来天然植物提取物在酸性介质下对低碳钢、金属铝、金属锌腐蚀的抑制作用和相关的研究进展,展望了天然绿色缓蚀剂的发展与应用前景.     

Natural product-guided discovery of a fungal chitinase inhibitor

Natural products are often large, synthetically intractable molecules, yet frequently offer surprising inroads into previously unexplored chemical space for enzyme inhibitors. Argifin is a cyclic pentapeptide that was originally isolated as a fungal natural product. It competitively inhibits family 18 chitinases by mimicking the chitooligosaccharide substrate of these enzymes. Interestingly, argifin is a nanomolar inhibitor of the bacterial-type subfamily of fungal chitinases that possess an extensive chitin-binding groove, but does not inhibit the much smaller, plant-type enzymes from the same family that are involved in fungal cell division and are thought to be potential drug targets. Here we show that a small, highly efficient, argifin-derived, nine-atom fragment is a micromolar inhibitor of the plant-type chitinase ChiA1 from the opportunistic pathogen Aspergillus fumigatus. Evaluation of the binding mode with the first crystal structure of an A. fumigatus plant-type chitinase reveals that the compound binds the catalytic machinery in the same manner as observed for argifin with the bacterial-type chitinases. The structure of the complex was used to guide synthesis of derivatives to explore a pocket near the catalytic machinery. This work provides synthetically tractable plant-type family 18 chitinase inhibitors from the repurposing of a natural product.     

Synthetic studies toward cytostatin, a natural product inhibitor of protein phosphatase 2A

Synthetic approaches toward the natural product cytostatin, an inhibitor of protein phosphatase 2A possessing cytotoxic and antimetastatic activities, have been investigated. A formal synthesis of cytostatin has been achieved according to a strategy relying on the formation of the C8-C9 bond by a nucleophilic addition of a functionalized organolithium (C1-C8 subunit) to an aldehyde (C9-C13 subunit).     

Synthetic and computational studies on liphagal: a natural product inhibitor of PI-3K

The natural product liphagal has been shown to function as a reasonably potent and selective inhibitor of the key signaling enzyme PI-3Kα. We have been interested in developing an analog class of PI-3K inhibitors based upon this unusual terpenoid natural product. Toward that end, we have evaluated the binding of the natural product to its target protein computationally and formulated a class of simplified analogs based on the structural analysis. Utilizing the cycloadduct derived from tetrabromocyclopropene and furan, we were able to generate a key, versatile scaffold upon which to pursue this analog design.     

Profiling natural product biosynthesis

Natural products are a rich source of therapeutics; however, artificially reengineering the biosynthetic pathways that generate these compounds could potentially generate "designer" drugs. Last month in Chemistry & Biology, Burkart and coworkers reported their technique to track and better understand the components of these pathways.     

Synthesis of the marine natural product barbamide

The first total synthesis of the trichlorinated natural product barbamide is described. The convergent approach involves coupling (S)-3-trichloromethylbutanoyl chloride with Meldrum's acid (2,2-dimethyl-1,3-dioxane-4,6-dione) to give 15 followed by addition of the novel secondary amine N-methyl-(S)-dolaphenine 2 (prepared in 6 steps and 24% overall yield from N-Cbz-L-phenylalanine) to give the beta-keto amide 16 which was converted directly to the required (E)-enol ether.     

Enantioselective total synthesis of a novel polyketide natural product (+)-integrasone, an HIV-1 integrase inhibitor

Enantioselective total synthesis of the recently isolated, novel polyketide natural product (+)-integrasone has been accomplished from the readily available Diels-Alder adduct of cyclopentadiene and p-benzoquinone. An enzymatically desymmetrized epoxyquinone building block has been elaborated through a series of regio- , chemo- and stereocontrolled steps to the final bicyclic framework of the natural product.     

A marine natural product database

A database of marine natural products has been developed. The database contains approximately 6000 chemical compounds derived from over 10,000 marine-derived materials. For each compound, the structure, physical and chemical properties, marine source, and biological activities are given. A computer program for searching this database has also been developed and is described.     

A cross-over inhibitor of the botulinum neurotoxin light chain B: a natural product implicating an exosite mechanism of action

Clostridium botulinum produces the most lethal toxins known to man, as such they are high risk terrorist threats, and alarmingly there is no approved therapeutic. We report the first cross-over small molecule inhibitor of these neurotoxins and propose a mechanism by which it may impart its inhibitory activity.     

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.     

Looking glass inhibitors: L-DMDP, a more potent and specific inhibitor of alpha-glucosidases than the enantiomeric natural product DMDP

L-DMDP, prepared from D-gulonolactone, is a highly specific inhibitor of a number of plant and mammalian alpha-glucosidases [between 2 and 4 orders of magnitude more potent than the enantiomeric natural product DMDP] but is not an inhibitor of bacterial and yeast alpha-glucosidases. Additionally N-butyl-DMDP is a potent inhibitor of ceramide-specific glucosyltransferase but N-butyl-L-DMDP shows no inhibition.     

Total synthesis and structural confirmation of the marine natural product Dysinosin A: a novel inhibitor of thrombin and Factor VIIa

The structure and absolute configuration of the marine antithrombotic product dysinosin A was confirmed by total synthesis. The strategy involved disconnections to three subunits, of which two were synthesized from the readily available l-glutamic acid, d-leucine, and d-mannitol. The Grubbs olefin metathesis carbocyclization reaction was utilized to prepare two intermediates.     

Biosynthetic origins of the natural product,thiolactomycin: a unique and selective inhibitor of type II dissociated fatty acid synthases

Thiolactomycin (TLM), a natural product produced by both Nocardia and Streptomyces spp., is a potent and highly selective inhibitor of the type II dissociated fatty acid synthases of plants and bacteria. The unique mode of action of TLM and its low toxicity make it an attractive compound for development of new antimicrobial agents. In this study, incorporation studies with 13C-labeled precursors demonstrate that TLM is derived from one acetate-derived starter unit and three methylmalonate-derived extender units. The unusual thiolactone represented by TLM represents a novel class of polyketide-derived antibiotics in which an unusual cyclization process, which terminates the biosynthetic pathway, involves incorporation of a sulfur atom from l-cysteine. Manipulation of this pathway through techniques such a combinatorial biosynthesis and mutasynthesis may provide a new route for economically viable production of useful TLM analogues.