The role of glutathione S-transferase GliG in gliotoxin biosynthesis in Aspergillus fumigatus

Gliotoxin, a redox-active metabolite, is produced by the opportunistic fungal pathogen Aspergillus fumigatus, and its biosynthesis is directed by the gli gene cluster. Knowledge of the biosynthetic pathway to gliotoxin, which contains a disulfide bridge of unknown origin, is limited, although L-Phe and L-Ser are known biosynthetic precursors. Deletion of gliG from the gli cluster, herein functionally confirmed as a glutathione S-transferase, results in abrogation of gliotoxin biosynthesis and accumulation of 6-benzyl-6-hydroxy-1-methoxy-3-methylenepiperazine-2,5-dione. This putative shunt metabolite from the gliotoxin biosynthetic pathway contains an intriguing hydroxyl group at C-6, consistent with a gliotoxin biosynthetic pathway involving thiolation via addition of the glutathione thiol group to a reactive acyl imine intermediate. Complementation of gliG restored gliotoxin production and, unlike gliT, gliG was found not to be involved in fungal self-protection against gliotoxin.     

An efficient copper-catalyzed carbon-sulfur bond formation protocol in water

An efficient protocol of copper-catalyzed C-S bond formation between aryl halides and potassium thiocyanate leading to diaryl sulfides is reported. A variety of diaryl sulfides can be synthesized in good to excellent yields up to 94%.     

Carbon tetrabromide-mediated carbon-sulfur bond formation via a sulfenyl bromide intermediate

In the presence of carbon tetrabromide, a variety of dithiocarbamates, xanthates, dithioesters, and thioethers were prepared in one pot by reacting the corresponding dithioic acids or thiols with active methylene compounds/indole derivatives under mild conditions. The formation of a sulfenyl bromide intermediate is proposed as the key step, which initiates the C-S bond formation.     

A mild and highly efficient one-pot three-component reaction for carbon-sulfur bond formation catalyzed by potassium tert-butoxide

Potassium tert-butoxide has been found to be a highly efficient catalyst for one-pot,three-component reaction of aryl aldehydes, acetophenones,and thiols via Claisen-Schmidt/Michael addition reactions for the synthesis of thia-Michael adducts in high yields. The reactions are best carried out in tert-butyl alcohol at room temperature.     

A latent oxazoline electrophile for N-O-C bond formation in pseudomonine biosynthesis

Nitrogen-heteroatom bonds figure prominently in the structural, chemical, and functional diversity of natural products. In the case of Pseudomonas siderophore pseudomonine, an N-O hydroxamate linkage is found uncommonly configured in an isoxazolidinone ring. In an effort to understand the biogenesis of this heterocycle, we have characterized the pseudomonine synthetase in vitro and reconstituted the complete biosynthetic pathway. Our results indicate that the isoxazolidinone of pseudomonine arises from spontaneous rearrangement of an oxazoline precursor. To the best of our knowledge, this is a previously uncharacterized mode of post-assembly line heterocyclization. Our results establish the oxygen of the ubiquitous siderophore hydroxamate functionality as a nucleophile and may be indicative of general strategy for N-O-C bond formation in nature.     

Efficient synthesis of 1,3,5-trisubstituted benzenes via three Pd-mediated carbon-sulfur, carbon-nitrogen and carbon-carbon bond formation reactions

An efficient synthesis of 1,3,5-trisubstituted benzenes via a sequential Pd-mediated carbon-sulfur, carbon-nitrogen, and carbon-carbon bond formation reactions is reported. Selective amidation and sulfonamidation reactions are accomplished via Pd-catalyzed reactions between aryl chlorides and an acetamide or a methanesulfonamide.     

Elucidating the mechanism of cis double bond formation in epothilone biosynthesis

The epothilones, originally isolated from the myxobacterium Sorangium cellulosum, are macrocyclic compounds that are synthesized by a modular polyketide synthase, an enzyme complex composed of six large, multifunctional proteins. The penultimate intermediates in epothilone production, and the products of the PKS-catalyzed reactions, are epothilones D and C, which contain a 12,13-cis-double bond. The 12 and 13 positions of epothilones are generated during the fourth elongation step that is governed by module 4. Module 4 does not contain a dehydratase (DH) domain, which is required for dehydration to create the double bond. A DH domain, present in module 5 and presumed to act in the fifth elongation step at the 10 and 11 positions, was proposed to act as well to generate the 12,13-cis-double bond. Inactivation of the DH domain in module 5 resulted in the production of 10,11-dehydro-13-hydroxyepothilone D as the major product, confirming that DH5 is required for 12,13 dehydration. A mechanistic model based on domain skipping and modular stuttering is presented to explain the basis for the iterative DH5 activity observed.     

A novel crystallization-induced diastereomeric transformation based on a reversible carbon-sulfur bond formation. Application to the synthesis of a gamma-secretase inhibitor

This paper describes a remarkably efficient process for the preparation of gamma-secretase inhibitor 1. The target is synthesized in only five steps with an overall yield of 58%. The key operation is a highly selective and practical, crystallization-driven transformation for the conversion of a mixture of tertiary benzylic alcohols into the desired sulfide diastereomer with 94:6 dr. This unprecedented process is based upon a reversible carbon-sulfur bond formation under acidic conditions.     

Catalytic carbon-sulfur bond formation by amphoteric vanadyl triflate: exploring with thia-Michael addition, thioacetalization, and transthioacetalization reactions

A series of thiols have been examined as protic nucleophiles for Michael-type additions to α,β-unsaturated carbonyls as well as double nucleophilic condensations with aldehydes, ketones, and acetals catalyzed by amphoteric, water-tolerant vanadyl triflate under mild and neutral conditions. The newly developed C-S bond formation protocols were carried out smoothly in good to high yields in a highly chemoselective manner.     

Interaction of glutathione S-transferase with hypericin: A photophysical study

The photophysics of hypericin have been studied in its complex with two different isoforms, A1-1 and P1-1, of the protein glutathione S-transferase (GST). One molecule of hypericin binds to each of the two GST subunits. Comparisons are made with our previous results for the hypericin/human serum albumin complex (Photochem. Photobiol. 1999, 69, 633-645). Hypericin binds with high affinity to the GSTs: 0.65 microM for the A1-1 isoform and 0.51 microM for the P1-1 isoform (Biochemistry 2004, 43, 12761-12769). The photophysics and activity of hypericin are strongly modulated by the binding protein. Intramolecular hydrogen-atom transfer is suppressed in both cases. Most importantly, while there is significant singlet oxygen generation from hypericin bound to GST A1-1, binding to GST P1-1 suppresses singlet oxygen generation to almost negligible levels. The data are rationalized in terms of a simple model in which the hypericin photophysics depends entirely upon the decay of the triplet state by two competing processes, quenching by oxygen to yield singlet oxygen and ionization, the latter of these two are proposed to be modulated by A1-1 and P1-1.     

Vibration assignment of carbon-sulfur bond in 2-thione-1,3-dithiole-4,5-dithiolate derivatives

The higher frequency peak near 1050 cm(-1) of the doublet in the infrared and Raman spectra of 2-thione-1,3-dithiole-4,5-dithiolate (DMIT) derivatives corresponds mainly to the stretching vibration of carbon-sulfur double bond in the terminal S=CS2 fragments of DMIT skeletons while the lower one corresponds mainly to the Fermi resonance peak between overtones of symmetric stretching vibration of two carbon-sulfur single bond in the S=CS2 fragment of DMIT skeletons and the higher frequency. On the other hand, the higher frequency near 500 cm(-1) corresponds mainly to the symmetric stretching vibration of two carbon-sulfur single bond in the S=CS2 fragments of DMIT skeletons while the lower one corresponds mainly to the symmetric stretching vibration of the four carbon-sulfur single bond in the S2C=CS2 fragments of DMIT skeletons.     

硫醚中碳硫键室温选择性断裂反应的研究

本文研究了在四氟硼酸银存在下, 硫醚与碘甲烷室温下发生碳硫键选择性断裂反应。研究结果表明: 只有当二苄基硫醚的苯环对位连有强的供电子基团甲氧基时, 方可发生碳硫键的断裂。提出了一个离子型反应机理且碳硫键的断裂分三步完成。首先, 硫醚与甲基化试剂反应生成甲基锍盐; 继而, 此锍离子离解成由苄基碳正离子和硫醚组成的离子-偶极集合物; 最后, 甲基化试剂再进攻集合物中的硫醚, 从而导致碳硫键的断裂。     

Enantioselection in peptide bond formation

Selectivity in abiotic condensations of amino acids remains controversial and stereochemically little explored. We find that competitive activated couplings of N-acyl derivatives of glycine, alanine, valine, proline and phenylalanine with binary, ternary and quaternary mixtures of amides and esters of the same group of amino acids show little selectivity among the reactants, except with respect to configuration, where a consistent and significant preference for heterochiral outcomes, mostly > 80%, is observed. One possible explanation of this selectivity predicts a predisposition to homochiral coupling under conditions that would require the two carboxyl functions to be co-facial in the activated complex.     

A molecular orbital explanation of bond distance variation caused by hydrogen bond formation

For hydrogen bond systems X–D–HA–Y, a simple molecular orbital model is proposed to understand the mechanism of the bond distance variations caused by the hydrogen bond formation. This model explains the bond distance variations for X–D and A–Y as follows. Electrostatic potential that the electrons in a molecule receive from other molecules causes the changes in atomic orbital energy differences between the bonded atoms. Then, the changes in the orbital energy differences make the bond orders larger or smaller and consequently the bond distances vary. The validity of this model has been confirmed by the effective fragment potential method, using the test systems of (HCOOH)₂, HCONH₂ (formamide) crystal and BF₃·2H₂O crystal.     

Asymmetric catalysis in carbon-phosphorus bond formation

o-Nitrobenzaldehyde reacts smoothly with dialkylphosphonates in the presence of catalytic quantities of cinchona alkaloids (e.g. quinine) to produce the -hydroxy phosphate esters in excellent chemical yields, with excellent enantiomeric enrichment.     

Intramolecular AR--O--AR bond formation in calixarenes

The formal dehydration of two vicinal phenol moieties of p-tert-butylcalix[6]arene was achieved in two steps by mild oxidation of the calixarene followed by treatment of the resulting monospirodienone derivative (9c) with an ionic hydrogenation mixture (Et(3)SiH/CF(3)COOH). Reaction of 9c yielded the unsubstituted xanthenocalix[6]arene 11d, while treatment of the monospirodienone derivative of a spherand-type calixarene (13) with Et(3)SiH/CF(3)COOH afforded the dibenzofuran derivative 15. The formation of the latter product indicates that, at least for 13, the rings forming the Ar--O--Ar bond in the product are not those connected by the spiro bond in the starting material. Methylation of the phenolic hydroxyl groups of 11d with methyl p-toluenesulfonate/K(2)CO(3) or dimethyl sulfate/base afforded its dimethyl and tetramethyl ether derivatives. The parent xanthone calix[6]arene derivative 17b was prepared by O-methylation of the phenol groups followed by CrO(3) oxidation of the xanthene methylene group and deprotection of the OH groups. McMurry coupling of calixanthone 17a afforded the dixanthylene 18. Calixarenes 11d and 15 (which possess a xanthene and dibenzofuran group, respectively) were structurally characterized by X-ray crystallography.     

A novel C-C bond formation reaction with 1-methoxymethylindolylborate

The reaction of 1-methoxymethylindolylborates 2 with electrophiles in the presence of benzaldehyde enabled the novel construction of tri-substituted indoles in a 'one-pot' procedure.     

A carbon-carbon bond formation using endoperoxides of 1,2-dihydropyridines

A novel type of a nucleophilic substitution on the piperidine ring was achieved by a stannous chloride-effected reaction of endoperoxides of N-alkoxycarbonyl-1,2-dihydropyridines with various kinds of carbon nucleophiles.