- Synthesis of HIV-1 capsid protein assembly inhibitor (CAP-1) and its analogues based on a biomass approach
-
A biomass-derived platform chemical was utilized to access a demanded pharmaceutical substance with anti-HIV activity (HIV, human immunodeficiency virus) and a variety of structural analogues. Step economy in the synthesis of the drug core (single stage from cellulose) is studied including flexible variability of four structural units. The first synthesis and X-ray structure of the inhibitor of HIV-1 capsid protein assembly (CAP-1) is described.
- Romashov, Leonid V.,Ananikov, Valentine P.
-
-
Read Online
- Coenzyme A hemithioacetals as easily prepared inhibitors of CoA ester-utilizing enzymes
-
Hemithioacetals are formed by reactions of coenzyme A (CoA) with aldehydes in aqueous solution. Equilibria for hemithioacetal formation with four commercially available aldehydes and rate constants for hemithioacetal dissociation have been studied. The hemithioacetals are viewed as acyl-CoA analogs having a tetrahedral center in place of the planar trigonal thioester carbonyl carbon. These compounds may serve as mimics of the tetrahedral intermediate or transition state in the reactions of acyl-CoA dependent acyltransferase enzymes. The hemithioacetal generated by reaction of CoA with formaldehyde is a poor inhibitor of chloramphenicol acetyltransferase, with a K(i) more than 6-fold higher than the K(m) for the substrate acetyl-CoA. The hemithioacetals formed by reaction of CoA with acetaldehyde and trifluroacetaldehyde are substantially better inhibitors, with K(i) values approximately 2.4-fold and 10-fold lower than the K(m) values for acetyl-CoA, respectively. The hemithioacetal formed by reaction of CoA with succinic semialdehyde inhibits succinic thiokinase, with a K(i) 4-fold lower than the K(m) for the substrate succinyl-CoA. The CoA hemithioacetals provide a novel readily accessible new class of acyl-CoA analogs for use in mechanistic and structural studies of CoA ester-utilizing enzymes.
- Schwartz, Benjamin,Vogel, Kurt W.,Drueckhammer, Dale G.
-
-
Read Online
- Formicins, N-Acetylcysteamine-Bearing Indenone Thioesters from a Wood Ant-Associated Bacterium
-
Formicins A-C (1-3) were discovered from Streptomyces sp. associated with wood ants. The structures of 1 and 2 were elucidated as indenone thioesters bearing N-acetylcysteamine based on spectroscopic analysis. The configurations of 1-3 were determined by the analysis of ROESY correlations, the phenylglycine methyl ester method, and chemical derivatization from 3 to 2. Formicin A inhibited the growth of human triple-negative breast cancer cells by regulating the liver kinase B1-mediated AMPK signaling pathway.
- Byun, Woong Sub,Du, Young Eun,Hong, Suckchang,Hwang, Sunghoon,Jang, Yong-Joon,Lee, Sang Kook,Lee, Seok Beom,Oh, Dong-Chan,Shin, Bora,Shin, Jongheon,Shin, Yern-Hyerk
-
-
Read Online
- Step-Economic Synthesis of Biomimetic β-Ketopolyene Thioesters and Demonstration of Their Usefulness in Enzymatic Biosynthesis Studies
-
Studies on the biosynthetic processing of polyene thioester intermediates are complicated by limited access to appropriate substrate surrogates. We present a step-economic synthetic access to biomimetic β-ketopolyene thioesters that is based on an Ir-catalyzed reductive Horner-Wadsworth-Emmons olefination. New β-ketotriene and pentaenethioates of pantetheine and N-acetylcysteamine were exemplarily synthesized via short and concise routes. The usefulness of these compounds was demonstrated in an in vitro assay with the ketoreductase domain MycKRB from mycolactone biosynthesis.
- Hahn, Frank,Ro?, Theresa,Schr?der, Marius,Wunderlich, Johannes
-
-
Read Online
- Biosynthetic Studies of Brevetoxins, Potent Neurotoxins Produced by the Dinoflagellate Gymnodinium breve
-
Blooms of the dinoflegellate Gymnodinium breve (Ptychodiscus brevis) commonly known as "red tide" have led to massive fish kills, mollusk contamination, and human food intoxications along the Florida coast and the Gulf of Mexico.The toxins from G. breve responsible for these phenomena are the brevetoxins (BTX's), a group of potent neurotoxins with polycyclic trans-fused ether rings which presumably depolarize the sodium channels of the excitable membranes.BTX-B, C50H70O14, the first of these neurotoxins whose structure was elucidated, has an unprecedented structure consisting of 6/6/6/7/7/6/6/8/6/6/6 ether rings trans-fused in a ladder-like manner.Another member of these toxins, BTX-A, C49H70O13, has another remarkable structure consisting of trans-fused 5/8/6/7/9/6/6/6 ether rings.Although the carbon skeletons of BTX-B and BTX-A are different, both consist of a single carbon chain that is polyoxygenated with methyl substituent groups.This is consistent with polyketide biosynthesis, i.e., condensation of acetate units with the methyl groups originating from either S-adenosylmethionine or propionate.Labeling experiments using sodium - and acetate and methionine demonstrate that the labeling patterns of BTX-B and BTX-A are similar and that the biosynthesis of brevetoxins is not of simple polyketide origin.These labeling studies suggest that the citric acid cycle is involved in the biosynthetis of BTX-B and BTX-A, the degree of its involvement being unusually high.Furthermore, CO2 participates in a unique manner in the biosynthesis of C-1 of BTX-B and BTX-A.
- Lee, Min S.,Qin, Guo-wei,Nakanishi, Koji,Zagorski, Michael G.
-
-
Read Online
- Identification of crucial bottlenecks in engineered polyketide biosynthesis
-
The concept of combinatorial biosynthesis promises access to compound libraries based on privileged natural scaffolds. Ever since the elucidation of the biosynthetic pathway towards the antibiotic erythromycin A in 1990, the predictable manipulation of type I polyketide synthase megaenzymes was investigated. However, this goal was rarely reached beyond simplified model systems. In this study, we identify the intermediates in the biosynthesis of the polyether monensin and numerous mutated variants using a targeted metabolomics approach. We investigate the biosynthetic flow of intermediates and use the experimental setup to reveal the presence of selectivity filters in polyketide synthases. These obstruct the processing of non-native intermediates in the enzymatic assembly line. Thereby we question the concept of a truly modular organization of polyketide synthases and highlight obstacles in substrate channeling along the cascade. In the search for the molecular origin of a selectivity filter, we investigate the role of different thioesterases in the monensin gene cluster and the connection between ketosynthase sequence motifs and incoming substrate structures. Furthermore, we demonstrate that the selectivity filters do not apply to new-to-nature side-chains in nascent polyketides, showing that the acceptance of these is not generally limited by downstream modules.
- Grote, Marius,Kushnir, Susanna,Pryk, Niclas,M?ller, David,Erver, Julian,Ismail-Ali, Ahmed,Schulz, Frank
-
-
Read Online
- Functional characterization of an NADPH dependent 2-alkyl-3-ketoalkanoic acid reductase involved in olefin biosynthesis in stenotrophomonas maltophilia
-
OleD is shown to play a key reductive role in the generation of alkenes (olefins) from acyl thioesters in Stenotrophomonas maltophilia. The gene coding for OleD clusters with three other genes, oleABC, and all appear to be transcribed in the same direction as an operon in various olefin producing bacteria. In this study, a series of substrates varying in chain length and stereochemistry were synthesized and used to elucidate the functional role and substrate specificity of OleD. We demonstrated that OleD, which is an NADP(H) dependent reductase, is a homodimer which catalyzes the reversible stereospecific reduction of 2-alkyl-3-ketoalkanoic acids. Maximal catalytic efficiency was observed with syn-2-decyl-3-hydroxytetradecanoic acid, with a kcat/Km 5- and 8-fold higher than for syn-2-octyl-3- hydroxydodecanoic acid and syn-2-hexyl-3-hydroxydecanoic acid, respectively. OleD activity was not observed with syn-2-butyl-3-hydroxyoctanoic acid and compounds lacking a 2-alkyl group such as 3-ketodecanoic and 3-hydroxydecanoic acids, suggesting the necessity of the 2-alkyl chain for enzyme recognition and catalysis. Using diastereomeric pairs of substrates and 4 enantiopure isomers of 2-hexyl-3-hydroxydecanoic acid of known stereochemistry, OleD was shown to have a marked stereochemical preference for the (2R,3S)-isomer. Finally, experiments involving OleA and OleD demonstrate the first 3 steps and stereochemical course in olefin formation from acyl thioesters; condensation to form a 2-alkyl-3-ketoacyl thioester, subsequent thioester hydrolysis, and ketone reduction.
- Bonnett, Shilah A.,Papireddy, Kancharla,Higgins, Samuel,Del Cardayre, Stephen,Reynolds, Kevin A.
-
-
Read Online
- Preprogramming Complex Hydrogel Responses using Enzymatic Reaction Networks
-
The creation of adaptive matter is heavily inspired by biological systems. However, it remains challenging to design complex material responses that are governed by reaction networks, which lie at the heart of cellular complexity. The main reason for this slow progress is the lack of a general strategy to integrate reaction networks with materials. Herein we use a systematic approach to preprogram the response of a hydrogel to a trigger, in this case the enzyme trypsin, which activates a reaction network embedded within the hydrogel. A full characterization of all the kinetic rate constants in the system enabled the construction of a computational model, which predicted different hydrogel responses depending on the input concentration of the trigger. The results of the simulation are in good agreement with experimental findings. Our methodology can be used to design new, adaptive materials of which the properties are governed by reaction networks of arbitrary complexity.
- Postma, Sjoerd G. J.,Vialshin, Ilia N.,Gerritsen, Casper Y.,Bao, Min,Huck, Wilhelm T. S.
-
-
Read Online
- The biosynthesis of pramanicin in Stagonospom sp. ATCC 74235: A modified acyltetramic acid
-
Biosynthetic incorporations of acetate, malonate and serine precursors which had been isotopically labelled with 2H, 13C, 15N and 18O into pramanicin 1 in Stagonospora sp. ATCC 74235 were demonstrated. Intact incorporation of a starter acetate and six extender malonates generates the acyclic, hydrophobic tail. A further intact acetate, in preference to malonate, and a serine entity which is incorporated only as the L-enantiomer and with the O=C-CH(N)-CH2 entity intact, provide the pyrrolidone ring and hydroxymethyl group of 1. The results are fully consistent with a biosynthetic pathway involving an acyltetramic acid (2). The olefinic precursor 3 of the epoxide in 1 is described, and is also shown to co-occur in the cultures. The ratio of 1:3 can be controlled by addition of precursors. The Royal Society of Chemistry 2000.
- Harrison, Paul H.M.,Duspara, Petar A.,Jenkins, Stephen I.,Kassam, Salima A.,Liscombe, David K.,Hughes, Donald W.
-
-
Read Online
- Enzymatic extender unit generation for in vitro polyketide synthase reactions: Structural and functional showcasing of Streptomyces coelicolor MatB
-
In vitro experiments with modular polyketide synthases (PKSs) are often limited by the availability of polyketide extender units. To determine the polyketide extender units that can be biocatalytically accessed via promiscuous malonyl-CoA ligases, structural and functional studies were conducted on Streptomyces coelicolor MatB. We demonstrate that this adenylate-forming enzyme is capable of producing most CoA-linked polyketide extender units as well as pantetheine- and N-acetylcysteamine-linked analogs useful for in vitro PKS studies. Two ternary product complex structures, one containing malonyl-CoA and AMP and the other containing (2R)-methylmalonyl-CoA and AMP, were solved to 1.45 A and 1.43 A resolution, respectively. MatB crystallized in the thioester-forming conformation, making extensive interactions with the bound extender unit products. This first structural characterization of an adenylate-forming enzyme that activates diacids reveals the molecular details for how malonate and its derivatives are accepted. The orientation of the α-methyl group of bound (2R)-methylmalonyl-CoA, indicates that it is necessary to epimerize α-substituted extender units formed by MatB before they can be accepted by PKS acyltransferase domains. We demonstrate the in vitro incorporation of methylmalonyl groups ligated by MatB to CoA, pantetheine, or N-acetylcysteamine into a triketide pyrone by the terminal module of the 6-deoxyerythronolide B synthase. Additionally, a means for quantitatively monitoring certain in vitro PKS reactions using MatB is presented.
- Hughes, Amanda J.,Keatinge-Clay, Adrian
-
-
Read Online
- Structural and functional analysis of the loading acyltransferase from avermectin modular polyketide synthase
-
The loading acyltransferase (AT) domains of modular polyketide synthases (PKSs) control the choice of starter units incorporated into polyketides and are therefore attractive targets for the engineering of modular PKSs. Here, we report the structural and biochemical characterizations of the loading AT from avermectin modular PKS, which accepts more than 40 carboxylic acids as alternative starter units for the biosynthesis of a series of congeners. This first structural analysis of loading ATs from modular PKSs revealed the molecular basis for the relaxed substrate specificity. Residues important for substrate binding and discrimination were predicted by modeling a substrate into the active site. A mutant with altered specificity toward a panel of synthetic substrate mimics was generated by site-directed mutagenesis of the active site residues. The hydrolysis of the N-acetylcysteamine thioesters of racemic 2-methylbutyric acid confirmed the stereospecificity of the avermectin loading AT for an S configuration at the C-2 position of the substrate. Together, these results set the stage for region-specific modification of polyketides through active site engineering of loading AT domains of modular PKSs.
- Wang, Fen,Wang, Yanjie,Ji, Junjie,Zhou, Zhan,Yu, Jingkai,Zhu, Hua,Su, Zhiguo,Zhang, Lixin,Zheng, Jianting
-
-
Read Online
- Quantification of N-acetylcysteamine activated methylmalonate incorporation into polyketide biosynthesis
-
Polyketides are biosynthesized through consecutive decarboxylative Claisen condensations between a carboxylic acid and differently substituted malonic acid thioesters, both tethered to the giant polyketide synthase enzymes. Individual malonic acid derivatives are typically required to be activated as coenzyme A-thioesters prior to their enzyme-catalyzed transfer onto the polyketide synthase. Control over the selection of malonic acid building blocks promises great potential for the experimental alteration of polyketide structure and bioactivity. One requirement for this endeavor is the supplementation of the bacterial polyketide fermentation system with tailored synthetic thioester-activated malonates. The membrane permeable N-acetylcysteamine has been proposed as a coenzyme A-mimic for this purpose. Here, the incorporation efficiency into different polyketides of N-acetylcysteamine activated methylmalonate is studied and quantified, showing a surprisingly high and transferable activity of these polyketide synthase substrate analogues in vivo.
- Klopries, Stephan,Sundermann, Uschi,Schulz, Frank
-
-
Read Online
- Iodate oxidation of n-acetyl l-cysteine: Application in drug determination and characterization of its oxidation and degradation product by mass spectrometry
-
A kinetic spectrophotometric method based on the initial rate measurement has been developed for the determination of N-acetyl L-cysteine. The developed method is based on the oxidation of N-acetyl L-cysteine with iodate. The reaction product was studied and characterized using the mass spectrometry and the structure of the product was proposed. From the mass spectrometric studies it was concluded that the oxidation of the drug resulted in the formation of a disulfide. The developed method was validated as per the guidelines of international conference on harmonization. The developed initial rate method was found to be linear in the concentration range of 1.25-30 μg ml-1. The detection and quantitation limits were found to be 0.018 and 0.056 μg ml-1. In the current study, the degradation product of N-acetyl L cysteine was also prepared and identified using mass spectrometry.
- Siddiqui, Masoom Raza,Wabaidur, Saikh Mohammad,Alothman, Zied A.,Rahman, Habibur,Alam, Md.Sarfaraz,Ali, Md.Sajid
-
-
Read Online
- Monitoring biocatalytic transformations mediated by polyketide synthase enzymes in cell lysate via fluorine NMR
-
The biocatalytic employment of modular polyketide synthase enzymes in cell lysate has become a viable route to preparative quantities of synthetically valuable polyketide fragments. We report the quantitative, uninvasive, and continuous monitoring of such biocatalytic reactions by observing trifluoromethyl-bearing substrates via 19F NMR spectroscopic analysis. To demonstrate the utility of this technique, we followed reactions catalyzed by a thioesterase and several ketoreductases.
- Piasecki, Shawnk.,Keatinge-Clay, Adrian T.
-
-
Read Online
- CONDENSED HETEROCYCLES AS BCL-2 INHIBITORS
-
The disclosure includes compounds of Formula (A) wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, and R11, h, j, m, n, k, v, s, g, V, W, L, Z1 Q1, Q2, Q3, Q4, Q5, Q6, and Q7, are defined herein. Also disclosed is a method for treating a neoplastic disease, an autoimmune disease, or a neorodegenerative disease with these compounds.
- -
-
Page/Page column 297
(2021/04/10)
-
- HOT MELT EXTRUDED SOLID DISPERSIONS CONTAINING A BCL2 INHIBITOR
-
A pro-apoptotic solid dispersion comprises, a Bcl -2 family protein inhibitory compound of Formula A as defined herein, dispersed in a solid matrix that comprises (a) a pharmaceutically acceptable water-soluble polymeric carrier, and (b) a pharmaceutically acceptable surfactant. A process for preparing such a solid dispersion comprises subjecting to elevated temperature the compound of Formula A, the water-soluble polymeric carrier, and the surfactant to provide an extrudable semi-solid mixture; extruding the semi-solid mixture; and cooling the resulting extrudate to provide a solid matrix comprising the polymeric carrier, and the surfactant and having the compound dispersed in essentially non-crystalline form therein. The solid dispersion is suitable for oral administration to a subject in need thereof for treatment of a disease characterized by overexpression of one or more anti-apoptotic Bcl -2 family proteins, for example cancer or an immune or autoimmune disease.
- -
-
Page/Page column 73
(2021/09/04)
-
- BCL-2 INHIBITORS
-
The disclosure includes compounds of Formula (A), (A) wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, and R11, h, j, m, n, k, v, s, g, V, W, L, Z1, Q1, Q2, Q3, Q4, Q5, Q6, and Q7, are defined herein. Also disclosed is a method for treating a neoplastic disease, an autoimmune disease, or a neorodegenerative disease with these compounds.
- -
-
Page/Page column 235
(2020/03/15)
-
- Catalytic Hydrogenation of Thioesters, Thiocarbamates, and Thioamides
-
Direct hydrogenation of thioesters with H2 provides a facile and waste-free method to access alcohols and thiols. However, no report of this reaction is documented, possibly because of the incompatibility of the generated thiol with typical hydrogenation catalysts. Here, we report an efficient and selective hydrogenation of thioesters. The reaction is catalyzed by an acridine-based ruthenium complex without additives. Various thioesters were fully hydrogenated to the corresponding alcohols and thiols with excellent tolerance for amide, ester, and carboxylic acid groups. Thiocarbamates and thioamides also undergo hydrogenation under similar conditions, substantially extending the application of hydrogenation of organosulfur compounds.
- Luo, Jie,Rauch, Michael,Avram, Liat,Ben-David, Yehoshoa,Milstein, David
-
supporting information
p. 21628 - 21633
(2021/01/11)
-
- Chemical synthesis of tripeptide thioesters for the biotechnological incorporation into the myxobacterial secondary metabolite argyrin via mutasynthesis
-
The argyrins are secondary metabolites from myxobacteria with antibiotic activity against Pseudomonas aeruginosa. Studying their structure–activity relationship is hampered by the complexity of the chemical total synthesis. Mutasynthesis is a promising approach where simpler and fully synthetic intermediates of the natural product’s biosynthesis can be biotechnologically incorporated. Here, we report the synthesis of a series of tripeptide thioesters as mutasynthons containing the native sequence with a dehydroalanine (Dha) Michael acceptor attached to a sarcosine (Sar) and derivatives. Chemical synthesis of the native sequence D-Ala-Dha-Sar thioester required revision of the sequential peptide synthesis into a convergent strategy where the thioester with sarcosine was formed before coupling to the Dha-containing dipeptide.
- Siebert, David C.B.,Sommer, Roman,Pogorevc, Domen,Hoffmann, Michael,Wenzel, Silke C.,Müller, Rolf,Titz, Alexander
-
supporting information
p. 2922 - 2929
(2019/12/23)
-
- Structural Basis of a Broadly Selective Acyltransferase from the Polyketide Synthase of Splenocin
-
Polyketides are a large family of pharmaceutically important natural products, and the structural modification of their scaffolds is significant for drug development. Herein, we report high-resolution X-ray crystal structures of the broadly selective acyltransferase (AT) from the splenocin polyketide synthase (SpnD-AT) in the apo form and in complex with benzylmalonyl and pentynylmalonyl extender unit mimics. These structures revealed the molecular basis for the stereoselectivity and substrate specificity of SpnD-AT, and enabled the engineering of the industrially important Ery-AT6 to broaden its substrate scope to include three new types of extender units.
- Li, Yuan,Zhang, Wan,Zhang, Hui,Tian, Wenya,Wu, Lian,Wang, Shuwen,Zheng, Mengmeng,Zhang, Jinru,Sun, Chenghai,Deng, Zixin,Sun, Yuhui,Qu, Xudong,Zhou, Jiahai
-
supporting information
p. 5823 - 5827
(2018/05/14)
-
- The Catalytic Mechanism of the Class C Radical S-Adenosylmethionine Methyltransferase NosN
-
S-Adenosylmethionine (SAM) is one of the most common co-substrates in enzyme-catalyzed methylation reactions. Most SAM-dependent reactions proceed through an SN2 mechanism, whereas a subset of them involves radical intermediates for methylating non-nucleophilic substrates. Herein, we report the characterization and mechanistic investigation of NosN, a class C radical SAM methyltransferase involved in the biosynthesis of the thiopeptide antibiotic nosiheptide. We show that, in contrast to all known SAM-dependent methyltransferases, NosN does not produce S-adenosylhomocysteine (SAH) as a co-product. Instead, NosN converts SAM into 5′-methylthioadenosine as a direct methyl donor, employing a radical-based mechanism for methylation and releasing 5′-thioadenosine as a co-product. A series of biochemical and computational studies allowed us to propose a comprehensive mechanism for NosN catalysis, which represents a new paradigm for enzyme-catalyzed methylation reactions.
- Ding, Wei,Li, Yongzhen,Zhao, Junfeng,Ji, Xinjian,Mo, Tianlu,Qianzhu, Haocheng,Tu, Tao,Deng, Zixin,Yu, Yi,Chen, Fener,Zhang, Qi
-
supporting information
p. 3857 - 3861
(2017/03/27)
-
- Critical Influence of 5-Hydroxymethylfurfural Aging and Decomposition on the Utility of Biomass Conversion in Organic Synthesis
-
Spectral studies revealed the presence of a specific arrangement of 5-hydroxymethylfurfural (5-HMF) molecules in solution as a result of a hydrogen–bonding network, and this arrangement readily facilitates the aging of 5-HMF. Deterioration of the quality of this platform chemical limits its practical applications, especially in synthesis/pharma areas. The model drug Ranitidine (Zantac) was synthesized with only 15 % yield starting from 5-HMF which was isolated and stored as an oil after a biomass conversion process. In contrast, a much higher yield of 65 % was obtained by using 5-HMF isolated in crystalline state from an optimized biomass conversion process. The molecular mechanisms responsible for 5-HMF decomposition in solution were established by NMR and ESI-MS studies. A highly selective synthesis of a 5-HMF derivative from glucose was achieved using a protecting group at O(6) position.
- Galkin, Konstantin I.,Krivodaeva, Elena A.,Romashov, Leonid V.,Zalesskiy, Sergey S.,Kachala, Vadim V.,Burykina, Julia V.,Ananikov, Valentine P.
-
supporting information
p. 8338 - 8342
(2016/07/19)
-
- NOVEL CELL-PERMEABLE SUCCINATE COMPOUNDS
-
The present invention provides novel cell-permeable succinates and cell permeable precursors of succinate aimed at increasing ATP-production in mitochondria. The main part of ATP produced and utilized in the eukaryotic cell originates from mitochondrial oxidative phosphorylation, a process to which high-energy electrons are provided by the Kreb's cycle. Not all Kreb's cycle intermediates are readily permeable to the cellular membrane, one of them being succinate. The provision of the novel cell permeable succinates is envisaged to allow passage over the cellular membrane and thus the cell permeable succinates can be used to enhance mitochondrial ATP-output.
- -
-
Page/Page column 66; 67
(2015/11/03)
-
- Biocatalytic synthesis of pikromycin, methymycin, neomethymycin, novamethymycin, and ketomethymycin
-
A biocatalytic platform that employs the final two monomodular type I polyketide synthases of the pikromycin pathway in vitro followed by direct appendage of d-desosamine and final C-H oxidation(s) in vivo was developed and applied toward the synthesis of a suite of 12- and 14-membered ring macrolide natural products. This methodology delivered both compound classes in 13 steps (longest linear sequence) from commercially available (R)-Roche ester in >10% overall yields.
- Hansen, Douglas A.,Rath, Christopher M.,Eisman, Eli B.,Narayan, Alison R. H.,Kittendorf, Jeffrey D.,Mortison, Jonathan D.,Yoon, Yeo Joon,Sherman, David H.
-
supporting information
p. 11232 - 11238
(2013/08/23)
-
- Sulfur-and n-acyl carbonyl oxygen-assisted heterolysis of the C(=O)-S bond in excited-state (Z)-nacyl-α-dehydro(1-naphthyl)alanine thioesters
-
Irradiation of the title thioesters (Z)-1 in nitrogen-saturated 1,2- dichloroethane at wavelengths greater than 280 nm was found to afford (Z)-4-(1- naphthylmethylene)-5(4H)-oxazolone derivatives (Z)-2, (E)-2, alkyl-substituted thiols 3, and (E)-1 without
- Hosoi, Yosuke,Igarashi, Tetsutaro,Sakurai, Tadamitsu
-
p. 117 - 126
(2013/08/23)
-
- Employing modular polyketide synthase ketoreductases as biocatalysts in the preparative chemoenzymatic syntheses of diketide chiral building blocks
-
Chiral building blocks are valuable intermediates in the syntheses of natural products and pharmaceuticals. A scalable chemoenzymatic route to chiral diketides has been developed that includes the general synthesis of α-substituted, β-ketoacyl N-acetylcysteamine thioesters followed by a biocatalytic cycle in which a glucose-fueled NADPH-regeneration system drives reductions catalyzed by isolated modular polyketide synthase (PKS) ketoreductases (KRs). To identify KRs that operate as active, stereospecific biocatalysts, 11 isolated KRs were incubated with 5 diketides and their products were analyzed by chiral chromatography. KRs that naturally reduce small polyketide intermediates were the most active and stereospecific toward the panel of diketides. Several biocatalytic reactions were scaled up to yield more than 100 mg of product. These syntheses demonstrate the ability of PKS enzymes to economically and greenly generate diverse chiral building blocks on a preparative scale.
- Piasecki, Shawn K.,Taylor, Clint A.,Detelich, Joshua F.,Liu, June,Zheng, Jianting,Komsoukaniants, Arkady,Siegel, Dionicio R.,Keatinge-Clay, Adrian T.
-
experimental part
p. 1331 - 1340
(2012/02/01)
-
- Improved syntheses of 5′- S -(2-Aminoethyl)-6- N -(4-nitrobenzyl)- 5′-thioadenosine (SAENTA), analogues, and fluorescent probe conjugates: Analysis of cell-surface human equilibrative nucleoside transporter 1 (hENT1) levels for prediction of the antitumor
-
5′-S-(2-Aminoethyl)-6-N-(4-nitrobenzyl)-5′-thioadenosine (SAENTA), 5′-S-(2-acetamidoethyl)-6-N-[(4-substituted)benzyl]-5′- thioadenosine analogues, 5′-S-[2-(6-aminohexanamido)]ethyl-6-N-(4- nitrobenzyl)-5′-thioadenosine (SAHENTA), and related compounds we
- Robins, Morris J.,Peng, Yunshan,Damaraju, Vijaya L.,Mowles, Delores,Barron, Geraldine,Tackaberry, Tracey,Young, James D.,Cass, Carol E.
-
supporting information; experimental part
p. 6040 - 6053
(2010/11/02)
-
- Efficient synthesis of taurine and structurally diverse substituted taurines from aziridines
-
(Chemical Equation Presented) Taurine and substituted taurines were synthesized efficiently from aziridines via ring-opening reaction with thioacetic acid, oxidation with performic acid, and hydrolysis in hydrochloric acid. The current method shows more benefit in purification and efficiency in the preparation of taurine and structurally diverse 2-substituted, 2,2-disubstituted, and 1,2-, 2,2-, and 2,N-alkylene taurines.
- Hu, Libo,Zhu, Hui,Du, Da-Ming,Xu, Jiaxi
-
p. 4543 - 4546
(2008/02/05)
-
- Bio-intermediates for use in the chemical synthesis of polyketides
-
The present invention relates to compounds made by a subset of modules from one or more polyketide synthase (“PKS”) genes that are used as starting material in the chemical synthesis of novel molecules, particularly naturally occurring polyketides or deri
- -
-
-
- Ketolide antibacterials
-
The present invention includes compounds of the formula wherein: X is hydrogen or halide; R2is hydrogen, acyl, or a hydroxy protecting group; R6is hydrogen, hydroxyl, or —ORawherein Rais a substituted or unsubstituted moiety selected from the group consisting of C1-C10alkyl, C2-C10alkenyl, C2-C10alkynyl, aryl, heterocyclo, aryl(C1-C10)alkyl, aryl(C2-C10)alkenyl, aryl(C2-C10)alkynyl, heterocyclo(C1-C10)alkyl, heterocyclo(C2-C10)alkenyl, and heterocyclo(C2-C10)alkynyl; R13is hydrogen or a substituted or unsubstituted moiety wherein the moiety is selected from the group consisting of methyl; C3-C10alkyl, C2-C10alkenyl, C2-C10alkynyl, aryl, heterocyclo, aryl(C1-C10)alkyl, aryl(C2-C10)alkenyl, aryl(C2-C10)alkynyl, heterocyclo(C1-C10)alkyl, heterocyclo(C2-C10)alkenyl, and heterocyclo(C2-C10)alkynyl; and, R is hydrogen or a substituted or unsubstituted moiety wherein the moiety is selected from the group consisting of C1-C10alkyl, C2-C10alkenyl, C2-C10alkynyl, aryl, heterocyclo, aryl(C1-C10)alkyl, aryl(C2-C10)alkenyl, aryl(C2-C10)alkynyl, heterocyclo(C1-C10)alkyl, heterocyclo(C2-C10)alkenyl, and heterocyclo(C2-C10)alkynyl; and the pharmaceutically acceptable salts, esters and pro-drug forms thereof. These compounds possess anti-infective activity and are useful for the treatment of bacterial and protozoal infections.
- -
-
-
- Macrolide antiinfective agents
-
The invention is directed towards antibacterial compounds. The invention concerns macrolide antibiotics useful as antiinfective agents.
- -
-
-
- Racemic thioesters for production of polyketides
-
Facile methods for preparing diketide and triketide thioesters are disclosed. The resulting thioesters may be used as intermediates in the synthesis of desired polyketides, and may contain functional groups which ultimately reside in side chains on the resulting polyketide and thus can be used further to manipulate the polyketide so as form derivatives. The polyketides produced may also be tailored by glycosylation, hydroxylation and the like. New polyketides and their derivatives and tailored forms are thereby produced.
- -
-
-
- Reaction of ascorbic acid with S-nitrosothiols: Clear evidence for two distinct reaction pathways
-
Ascorbate reacts with S-nitrosothiols generally, in the pH range 3-13 by way of two distinct pathways, (a) at low [ascorbate], typically below ~1 × 10-4 mol dm-3 which leads to the formation of NO and the disulfide, and (b) at higher [ascorbate] when the products are the thiol and NO. Reaction (a) is Cu2+-dependent, and is completely cut out in the presence of EDTA, whereas reaction (b) is totally independent of [Cu2+] and takes place readily whether EDTA is present or not. For S-nitrosoglutathione (GSNO) the two reactions can be made quite separate, although for some reactants the two reactions overlap. In reaction (a), ascorbate acts as a reducing agent, generating Cu+ from Cu2+, which in turn reacts with RSNO forming initially NO, Cu2+ and RS-. The latter can then play the role of reducing agent for Cu2+, leading to disulfide formation. Ascorbate will initiate reaction when the free thiolate has initially been reduced to a very low level by the synthesis of RSNO from a large excess of nitrous acid over the thiol. Reaction (b) is interpreted in terms of nucleophilic attack by ascorbate at the nitroso-nitrogen atom, leading to thiol and O-nitrosoascorbate which breaks up, by a free-radical pathway, to give dehydroascorbic acid and NO. A similar pathway is the accepted mechanism in the literature for the nitrosation of ascorbate by nitrous acid and alkyl nitrites. The rate constant for the Cu2+-independent pathway increases sharply with pH and analysis of the variation of the rate constant with pH identifies a reaction pathway via both the mono- and di-anion forms of ascorbate, with the latter being the more reactive. As expected the entropy of activation is large and negative. Some aspects of structure-reactivity trends are discussed.
- Holmes, Anthony J.,Williams, D. Lyn H.
-
p. 1639 - 1644
(2007/10/03)
-
- Potential role of fatty acid initiation in the biosynthesis of the fungal aromatic polyketide aflatoxin B1
-
Earlier work in this laboratory has shown the intact incorporation of [1-13C]hexanoate into averufin (1), a key intermediate in aflatoxin B1 biosynthesis. Parallel experiments with equimolar amounts of [1-13C]butyrate, [1-
- Brobst,Townsend
-
p. 200 - 207
(2007/10/02)
-
- Simplified thioester and isostere analogs of oleoyl coenzyme a as hypocholesterolemic agents
-
New thioester and ester, amide and ketone isostere analogs of oleoyl coenzyme A, useful as antiatherosclerotic agents, are provided. The compounds have the formula: STR1 wherein A is selected from the group consisting of STR2 Y is selected from the group consisting of --S--, --O--, --NH-- and (--CH2 --)n wherein n=1 to 4; and Z is selected from the group consisting of alkyl (C1 -C6), STR3 wherein R=Hydrogen, C1 -C4 alkyl or C1 -C4 acyl, and STR4
- -
-
-
- Antiparasitic agents
-
Antiparasitic compound of formula (I): STR1 The broken line at the 22-23 position representing an optional double bond and either R1 is a H or OH and the double bond is absent or the double bond is present and R1 is absent; R2 is optionally substituted phenyl, or a group of formula (II): STR2 wherein X is O, S or --CH2 --, abc and d are 0-2 and a+b+c+d≤5 R3 is H or Me R4 is H, OH or 4'-(alpha-L-oleandrosyl)-alpha-L-oleandrosyloxy. The compounds are prepared by fermentation of Streptomyces avermitilis in the presence of an N-alkanoyl cysteamine thioester containing R2.
- -
-
-
- Etude de germathiazolidines et de dithioacetals germanies derives de la cysteamine et methylcysteamine N-substituees: synthese et activite radioprotectrice
-
Study of germathiazolidines and germylated dithioacetals derived from N-substituted cysteamine and methylcysteamine: synthesis and radioprotective activity.Synthesis and pharmacological studies (toxicity, radioprotective activity) of new N-substituted ger
- Fatome, Marc,Sentenac-Roumanou, Henri,Lion, Claude,Satge, Jacques,Rima, Ghassoub
-
p. 257 - 266
(2007/10/02)
-
- Additions to Alkenes via Metal Ion-Promoted Oxidation of Dialkyl and Diaryl Disulphides
-
Reactions of alkenes with di-n-propyl, diphenyl, and dibenzyl disulphide in the presence of lead(IV) salts in trifluoroacetic acid-dichloromethane are described.The products, vicinal trifluoroacetoxysulphides, are obtained in higher yields with manganese(III) salts as the oxidant.Alternative reaction conditions with use of iron(III) salts or in the absence of added metal salts are also described.Trifluoroacetoxysulphides derived from diphenyl disulphide react with acetonitrile under Ritter conditions to give acetamidosulphides but trifluoroacetoxysulphides derived from dibenzyl disulphide only give the vicinal acetamidosulphides in poor yield as a result of an alternative reaction pathway affording benzylacetamide.Conversions of acetamidosulphides into aminosulphides and into acetamidothiols are described.
- Bewick, Alan,Mellor, John M.,Owton, W. Martin
-
p. 1039 - 1044
(2007/10/02)
-
- Steric Course of the Allylic Rearrangement Catalyzed by β-Hydroxydecanoylthioester Dehydrase. Mechanistic Implications
-
β-Hydroxydecanoylthioester dehydrase, which is the pivotal enzyme in the biosynthesis of unsaturated fatty acids in anaerobic metabolism, catalyses the equilibration of thio esters of (R)-3-hydroxydecanoic acid, (E)-2-decenoic acid, and (Z)-3-decenoic acid.On the basis of evidence available to date, both two-base and one-base mechanisms of action can be envisioned for dehydrase.In an effort to distinguish between these mechanisms, the stereochemical course of the dehydrase-catalyzed allylic rearrangement has been determined.N-Acetylcysteamine (NAC) thio esters of (R)- and (S)-(E)-decanoic acid were synthesized and incubated with dehydrase.The product (Z)-3-decenoyl-NAC was derivatized, and 2H NMR analysis showed that the pro-4R hydrogen had been removed. (E)-2-Decenoyl-NAC and unlabeled (E)-2-decenoyl NAC were incubated with dehydrase in 1H2O and 2H2O, respectively.Analysis of a derivative of the resulting labeled (Z)-3-decenoyl-NAC showed that protonation had occured on the si face at substrate C-2.The overall steric course of the reaction is therefore suprafacial.The significance of this result is discussed in terms of the mechanisms of the "normal" dehydrase-catalysed reactions as well as the "suicide" inactivation of the enzyme.
- Schwab, John M.,Klassen, John B.
-
p. 7217 - 7227
(2007/10/02)
-
- ACTIVATION OF CARBOXYL GROUPS BY DIPHENYL 2-OXO-3-OXAZOLINYLPHOSPHONATE. FACILE PREPARATION OF VERSATILE REAGENTS, 3-ACYL-2-OXAZOLONES
-
Synthetic utility of the 2-oxazolone moiety as an excellent new leaving group is described.Based on such a function of the heterocycles, diphenyl 2-oxo-3-oxazolinylphosphonate has been newly introduced as a carboxyl-activating reagent which permits a facile direct preparation of 3-acyl-2-oxazolones and amides including peptides from a wide variety of carboxylic acids.The 3-acyl-2-oxazolides also serve as versatile reactive agents for highly chemoselective acyl-transfer to the nucleophilic species such as amines, alcohols and thiols, providing convenient and high-yield routes to amides, esters and thiol esters under mild conditions.They are also useful intermediates for ketones and alcohols.
- Kunieda, Takehisa,Higuchi, Tsunehiko,Abe, Yoshihiro,Hirobe, Masaaki
-
p. 3253 - 3260
(2007/10/02)
-
- Transformation of DAEP under Various Oxidative Conditions
-
14C-DAEP was subjected to four different oxidative conditions, and the products were identified.On peracid oxidation in dichloromethane, DAEP gave the oxon (1) predominantly, and 2-acetylaminoethyl dimethoxyphosphinyl disulphide (3), N-acetylcysteamine (10), its oxidized dimer (11) and a further oxidation product of compound (11).This indicates that an unstable phosphorus oxythionate was initially formed, which lost sulfur, was rearranged, and hydrolyzed to give these products.Under other conditions, phosphinyl disulfide 3 was not found.DAEP was metabolized in vitro with a rat liver microsome-NADPH system via oxydation.The aqueous reaction condition prevented the formation of compound 3 from the intermediate, which predominated as well as the oxon formation under anhydrous or close conditions.The formation of various products with sunlight irradiation on glass plates or on bean leaves could be interpreted by oxidation at P=S, C1 and C2 positions, demethylation, and deacetylation, followed by further transformation.The initial formation of phosphorus oxythionate seems to play an important role in the oxidation of the organothionophosphorus compound.
- Miyamoto, Toru,Yamamoto, Izuru
-
p. 1991 - 1998
(2007/10/02)
-
- Rate Constants and Equilibrium Constants for Thiol-Disulphide Interchange Reactions Involving Oxidized Glutathione
-
The rate of reduction of oxidized glutathione (GSSG) to glutathione (GSH) by thiolate (RS-) follows a Broensted relation in pKas of the conjugate thiols (RSH): βnuc ca. 0.5.This value is similar to that for reduction of Ellman's reagent: βnuc ca. 0.4 - 0.5.Analysis of a number of rate and equilibrium data, taken both from this work and from the literature, indicates that rate constants, k, for a range of thiolate-disulphide interchange reactions are correlated well by equations of the form log k = C + βnucpKanuc + βcpKac + βlgpKalg ( nuc = nucleophile, c = central, and lg = leaving group sulfur): eq 36 - 38 give representative values of the Broensted coefficients.The values of these Bronsted coefficients are not sharply defined by the available experimental data, although eq 36 - 38 provide useful kinetic models for rates of thiolate-disulfide interchange reactions.The uncertainty in these parameters is such that their detailed mechanistic interpretation is not worthwhile, but their qualitative interpretation - that all three sulphur atoms experience a significant effective negative charge in the transition state, but that the charge is concentrated on the terminal sulfurs - is justified.Equilibrium constants for reduction of GSSG using α,ω-dithiols have been measured.The reducing potential of the dithiol is strongly influenced by the size of the cyclic disulfide formed on its oxidation: the most strongly reducing dithiols are those which can form six-membered cyclic disulfides.Separate equilibrium constants for thiolate anion-disulphide interchange (KS-) and for thiol-disufide interchange (KSH) have been estimated from literature data: KS- is roughly proportional to 2ΔpKa is the difference between the pKas of the two thiols involved in the interchange.The contributions of thiol pKa values to the observed equilibrium constants for reduction of GSSG with α,ω-dithiols appear to be much smaller than those ascribable to the influence of structure on intramolecular ring formation.These equilibrium and rate constants are helpful in choosing dithiols for use as antioxidants in solutions containing proteines: dithiothreitol (DTT), 1,3-dimercapto-2-propanol (DMP), and 2-mercaptoethanol have especially useful properties.
- Szajewski, Richard P.,Whitesides, George M.
-
p. 2011 - 2026
(2007/10/02)
-
- Antibacterial compounds
-
A thiol acid and esters thereof of formula (II): STR1 wherein R is hydrogen, a salt forming ion or a pharmaceutically acceptable ester-forming radical, have antibacterial and antimycoplasmal activity and are therefore useful in the treatment of human and veterinary bacterial and mycoplasmal infections.
- -
-
-
- Leaving Group Effects in Thiolester Alkaline Hydrolysis. Part 1. A Keten-mediated (E1cB) Pathway for Basic Hydrolysis of S-Acetoacetylcoenzyme A and Analogues
-
The basic hydrolysis of a series of leaving-group substituted acetothiolacetates (CH3COCH2COSR) has been studied in aqueous media.Hydrolysis of N-acetyl-S-acetoacetylcysteinamine follows a kinetic ionisation curve with an inflexion corresponding to the pK of this ester as determined by spectrophotometric and electrometric titrations.The rate constant at high pH was shown to follow a Broensted relationship with βL.G. -1.13, where βL.G. is the slope of a plot of the logarithm of the rate constant versus the pKa of the conjugate acid of the leaving group.This, and other evidence from rate comparisons, activation parameters, and kinetic solvent isotope effects, indicated an E1cB hydrolytic mechanism involving unimolecular collapse of the ester enolate ions via a ketenoid transition-state.S-Acetoacetylcoenzyme-A was also hydrolysed in base by this mechanism.Direct comparison of rates of leaving group expulsion for ArS and ArO was possible by means of this unimolecular process.For a leaving group with pKL.G. 10, the oxyanion departs ca. 1 or 2 orders of magnitude faster than the thiolate anion; for pKL.G. 6.0, the advantage of oxygen over sulphur is 103-104 fold.In a direct structural comparison, PhS departs 32 times as rapidly as PhO.The contribution of steric release in the E1cB transition-state for S-t-butyl acetothiolacetate hydrolysis is discussed.The pKa values of some acetothiolacetates were measured.
- Douglas, Kenneth T.,Yaggi, Norbert F.
-
p. 1037 - 1044
(2007/10/02)
-
- Kinetics and Mechanism of the Thiolytic Removal of the Dithiasuccinoyl (Dts) Amino Protecting Group
-
The dithiasuccinoyl (Dts) amino protecting group is removed by thiols through the intermediacy of open-chain carbamoyl disulfides.The elucidation of practical and effective conditions for carrying out the reductive deprotection was facilitated by a rapid, convenient, and quantitative method to directly measure starting materials, intermediates, and products on a standard amino acid analyzer.The apparent pseudo-first-order rate constants were determined as a function of thiol, base, and solvent composition and concentration.Both steps of the mechanism were first order in thiol.In anhydrous solutions, the rate of the second step, k2, varied directly with tertiary amine concentration, suggesting that the active species is an association complex of the thiol and the base.In contrast, a more complex explanation is required to account for the fact that plots of log k1 against log had a slope of only 0.7-0.8.The ratio of rates, k = k2/k1, was generally between 0.1 and 5 for neutral monofunctional aliphatic thiols, but with bifunctional thiols, where the second step can proceed intramolecularly because a cyclic disulfide is formed, k 100 and consequently carbamoyl disulfide intermediates could not be observed.Intermediates were also never observed for thiophenol, the most acidic thiol tested, nor for 2-mercaptopyridine, a compound existing primarily as its thione tautomer.For these two cases, k was estimated, by indirect means, as ca. 105 and 109, respectively.The fastest overall rates were observed with thiols of intermediate acidity (pKa = 8.0-9.5) in polar aprotic media of high dielectric constant.In aqueous solutions, the first step of the mechanism was rate limiting (k ca. 375 based on an independent measurement).The observed rates k1 were directly proportional to the thiol anion concentration and the data for monofunctional thiols fit a Broensted correlation of thiol anion reactivity against pKa with slope βnuc ca. 0.9.The two steps in the mechanism of thiolytic deprotection of dithiasuccinoyl amines have strikingly different electronic requirements, meaning that the transition states are different.The driving force for the first step appears to be relief of the ring strain of the Dts heterocycle, while the rate of the second step correlates with the ease of ionization of the thiocarbamate leaving group.Suitable conditions for the quantitative removal of the Dts protecting group from any amino acid residue at 25 deg C include (1) β-mercaptoethanol (0.2 M) - triethylamine (0.5 M) in benzene for 5 min; (2) N-methylmercaptoacetamide or dithiothreitol (0.1 M) in neat pyridine for 5 min; (3) N-methylmercaptoacetamide or N-acetyl-β-mercaptoethylamine (0.1 M) - N-methylmorpholine (0.5 M) in acetonitrile for 1 min; (4) β-mercaptoethanol (0.1 M) and 2-mercaptopyridine or thiophenol (1.1 equiv over Dtc amine) in N,N-dimethylformamide - pyridine (9:1) for 1 min; (5) N-methylmercaptoacetamide (0.2 M) in N,N-dimethylformamide - acetic acid (9:1) for 2 min; (6) dithiothreitol...
- Barany, George,Merrifield, R. B.
-
p. 3084 - 3095
(2007/10/02)
-
- N-(2-mercapto-ethyl)alkanamides from H2 S and 2-H-2-oxazolines or 2-alkyl-2-oxazolines
-
N-(2-mercaptoethyl)alkanamides are produced by reacting hydrogen sulfide with 2-H-2-oxazolines or 2-alkyl-2-oxazolines. For example, N-(2-mercaptoethyl)acetamide was prepared in excellent yields by incrementally adding 2-methyl-2-oxazoline to a stirred solution of hydrogen sulfide in methanol under autogeneous pressure at about 100° C.
- -
-
-