Synthesis of gramicidin S and its analogues via an on-resin macrolactamization assisted by a predisposed conformation of the linear precursors

A simple and efficient preparation of gramicidin S and its analogues is described. It involves solid-phase peptide synthesis and on-resin macrolactamization without side chain protection, affording cyclic products in high yield and high purity. The high specificity of the cyclization reaction was shown to originate in the formation of a pre-organized conformation of the linear biosynthetic precursor of gramicidin S. This facile method will provide convenient access to the analogues of the natural product for functional optimization to counter microbial resistance.     

Investigation for the cyclization efficiency of linear tetrapeptides: Synthesis of tentoxin B and dihydrotentoxin

Investigation of the cyclization efficiency of N-methyl linear tetrapeptides using a molecular modeling study and chemical synthesis is described. The linear peptide with two N-methyl groups, MeAla-Leu-MePhe-Gly, forms γ-turn like conformation with the amine at N-terminus and the carbonyl at C-terminus in closer proximity to give the desired cyclic tetrapeptide, dihydrotentoxin. In addition, synthesis of tentoxin B by the combination of Fmoc solid-phase peptide synthesis and cyclization in solution phase has been reported. An unusual amino acid, an L-N-methyl-β-hydroxyphenylalanine derivative, which was assembled on solid support, was prepared from ethyl cinnamate. Cyclic tetrapeptide formation and cleavage of benzyl ether were optimized with DIPCI/HOBt/DIPEA and Et₃SiH/Pd(OH)₂, respectively.     

Facile synthesis of Gramicidin S via cyclication of a linear pentapeptide

Azide and N-hydroxysuccinimide ester of five pentapeptides related to gramicidin S (cyclic decapeptide) were cyclized to determine the ratio of dimer to monomer in the cyclization product, the pentapeptide derivative with D-Phe as C-terminus giving the dimer in good yield.     

Biomimetic synthesis of gramicidin s and analogues by enzymatic cyclization of linear precursors on solid support

[reaction: see text] Gramicidin S is a potent decapeptide antibiotic with high hemolytic activity but is unlikely to provoke microbial resistance. Here we demonstrate that gramicidin thioesterase (GrsB TE) correctly cyclizes immobilized linear decapeptide precursors into head-to-tail products, indicating its suitability for parallel solid-phase synthesis of gramicidin analogues from linear precursors on solid support. This chemoenzymatic method will enable the optimization of the therapeutic index of the natural product to fight microbial resistance.     

Thiazole‐Based γ‐Building Blocks as Reverse‐Turn Mimetic to Design a Gramicidin S Analogue: Conformational and Biological Evaluation

This paper describes the ability of a new class of heterocyclic γ‐amino acids named ATCs (4‐amino(methyl)‐1,3‐thiazole‐5‐carboxylic acids) to induce turns when included in a tetrapeptide template. Both hybrid Ac‐Val‐(R or S)‐ATC‐Ile‐Ala‐NH₂ sequences were synthesized and their conformations were studied by circular dichroism, NMR spectroscopy, MD simulations, and DFT calculations. It was demonstrated that the ATCs induced highly stable C₉ pseudocycles in both compounds promoting a twist turn and a reverse turn conformation depending on their absolute configurations. As a proof of concept, a bioactive analogue of gramicidin S was successfully designed using an ATC building block as a turn inducer. The NMR solution structure of the analogue adopted an antiparallel β‐pleated sheet conformation similar to that of the natural compound. The hybrid α,γ‐cyclopeptide exhibited significant reduced haemotoxicity compared to gramicidin S, while maintaining strong antibacterial activity.     

Synthesis of novel 3,4‐dihydropyrimidinones on water soluble solid support catalyzed by indium triflate

Syntheses of several new 3,4‐dihydropyrimidinones (DHPMs) on sodium sulfate solid support have been reported. The microwave enhanced rapid synthesis of the title compounds yielded a good percentage of the DHPMs. The catalytic activity of indium triflate enables to prepare a wide range of DHPMs. Syntheses of 2‐hydroxyphenyl, 2‐hydroxy‐4‐methoxyphenyl pendant groups on DHPMs scaffold are advantages of the present method, which are rather prone towards cyclization and the presence of free hydroxyl groups on the phenyl ring is confirmed via D₂O exchange study. The mechanism of the reaction is expected to proceed via absorption of substrates on the solid support followed by promotion of the reaction by In(OTf)₃ coupled with microwave irradiation.     

Influence of cationic antibiotics on phase behavior of rough-form lipopolysaccharide

The rough-form lipopolysaccharide (LPS) interacted with cationic antibiotic polymyxin B and gramicidin S in solution, and showed altered thermotropic phase behavior and viscoelasticity. The phase behavior was measured by differential scanning calorimetry and quartz crystal microbalance (QCM). Addition of polymyxin B of up to 0.5 mg/mL to the 5.0 mg/mL LPS solution increased gel-to-liquid crystalline phase transition enthalpy (ΔH) and raised the transition temperature (t_max). The further addition of polymyxin B reduced the ΔH value. Gramicidin S produced a different effect, whereby a minor addition reduced t_max and ΔH value of the LPS. The LPS film on the platinum electrode of the QCM indicated a downward shift of resonant frequency and an upward shift of resonant resistance when in contact with the antibiotic solution. An interpretation of these variations is that the LPS on the QCM electrode changed not only film weight, but also viscoelasticity owing to contact with the antibiotic solution. The different effects between the antibiotics between polymyxin B and gramicidin S on the LPS are induced by the difference of the governing effect. Polymyxin B interacts with the LPS electrostatically, whereas gramicidin S interacts by hydrophobic moieties.     

固体催化剂用于二元醇分子内环化制内酯的研究

将钌改性的固体催化剂Ru-Co(OH)₂-CeO₂用于以分子氧作为氧化剂的二元醇的催化氧化内酯化反应中, 发现该催化剂具有很好的催化反应性能. 该催化剂可优先氧化伯碳上的羟基. 对反应机理的研究表明, 活性中心钌首先与反应物形成醇化物, 经β-氧化消除反应使得其中一羟基氧化, 经异构环化、氧化进一步脱氢形成内酯.     

Surface characterization and depth profiling of biological molecules by electrospray droplet impact/SIMS

Electrospray droplet impact (EDI) was applied to the analysis of peptides. The etching rate of bradykinin was estimated to be ~2 nm/min. This value is about one order of magnitude greater than the etching rate for SiO₂ (0.2 nm/min). Considering that the etching rate of argon cluster ions Ar₇₀₀⁺ for organic compounds is more than two orders of magnitude larger than that for inorganic materials, the rather small difference in etching rates of EDI for organic and inorganic materials is unique. When water/ethanol (1/1, vol%) solution of gramicidin S and arginine was dried in air, [gramicidin S + H]⁺ was observed as a predominant signal with little [Arg + H]⁺ right after the EDI irradiation, indicating that EDI is capable of detecting the analytes enriched on the sample surface. Copyright © 2011 John Wiley & Sons, Ltd.     

CF3SO2Na as a Bifunctional Reagent: Electrochemical Trifluoromethylation of Alkenes Accompanied by SO2 Insertion to Access Trifluoromethylated Cyclic N-Sulfonylimines

An unprecedented electrochemical trifluoromethylation/SO₂ insertion/cyclization process has been achieved in an undivided cell in an atom-economic fashion. The protocol relies on tandem cyclization of N-cyanamide alkenes by using Langlois’ reagent as a source of both CF₃ and SO₂ under direct anodically oxidative conditions, in which two C−C bonds, two C−X bonds (N−S and S−C), and two rings were formed in a single operation. This transformation enabled efficient construction of various trifluoromethylated cyclic N-sulfonylimines from readily accessible materials.     

CF3SO2Na as a Bifunctional Reagent: Electrochemical Trifluoromethylation of Alkenes Accompanied by SO2 Insertion to Access Trifluoromethylated Cyclic N‐Sulfonylimines

An unprecedented electrochemical trifluoromethylation/SO₂ insertion/cyclization process has been achieved in an undivided cell in an atom‐economic fashion. The protocol relies on tandem cyclization of N‐cyanamide alkenes by using Langlois’ reagent as a source of both CF₃ and SO₂ under direct anodically oxidative conditions, in which two C?C bonds, two C?X bonds (N?S and S?C), and two rings were formed in a single operation. This transformation enabled efficient construction of various trifluoromethylated cyclic N‐sulfonylimines from readily accessible materials.     

Bacitracin and gramicidin S as inhibitors of carboxylic proteinase

Summary 1. It has been shown that polypeptide antibiotics — bacitracin and gramicidin S — inhibit carboxylic proteinases — porcine and equine pepsins. Bacitracin inhibits pepsin with K_I=2.3 mM, and gramicidin S with K_I2 mM.2. The results obtained permit a theoretical foundation for the use of bacitracin and gramicidin S and also of other polypeptide antibiotics as ligands for the biospecific chromatography of proteinases.M. V. Lomonsov State University. Translated from Khimiya Prirodnykh Soedinenii, No. 3, pp. 385–389, May–June, 1978.     

Synthesis of nitrogen-containing heterocycles using exo- and endo-selective radical cyclizations onto enamides

The effect of positional change of the carbonyl group of enamides on Bu₃SnH-mediated alkyl radical cyclization leading to five-, six-, seven-, and eight-membered nitrogen-containing heterocycles was examined. A 5-exo cyclization is generally preferred over a 6-endo ring closure in systems having an alkyl radical center on the enamide-acyl side chain, whereas enamides having an alkyl radical center opposite to the acyl side chain predominantly gave 6-endo cyclization products. These results suggest that the exo or endo selectivity of radical cyclization onto the alkenic bond of enamides can be controlled by positional change of the carbonyl group. For an understanding of these selectivities, heat of formation for each transition state was calculated. 6-endo-Selective radical cyclization was applied to the radical cascade, enabling a concise synthesis of a cylindricine skeleton. A 7- or 8-endo alkyl radical cyclization, however, predominated over a corresponding 6- or 7-exo ring closure regardless of the positional change of the carbonyl group of enamides.     

The iterative gramicidin s thioesterase catalyzes peptide ligation and cyclization

Here, we present a comprehensive in vitro characterization of the excised iterative, bimodular PCP-TE of the gramicidin S synthetase GrsB, which is able to act both as a ligation and a cyclization catalyst. Using the native pentapeptidyl-thioester substrates, GrsB PCP-TE catalyzes the dimerization and subsequent formation of the decapeptide lactam gramicidin S. Interestingly, the detection of linear decapeptidyl-SNAC as an enzyme-dependent intermediate supports the iterative mechanism in vivo, in which two pentapeptides, one bound as an ester to the active site serine of the TE domain and the second bound as a thioester to the adjacent pan-PCP, are ligated to a decapeptidyl-pan-PCP that subsequently transferred to the adjacent TE domain and cyclized. Moreover, GrsB PCP-TE can handle different substrates length, leading not only to dimerization, but also to trimerization and the formation of different ring sizes.     

Reactions of Aromatic S‐ and O‐Enynes with Two Methyl Substituents on the Olefinic Unit Assisted by a Ruthenium Complex: Tandem Cyclization and Product Selectivity

Ruthenium‐assisted cyclizations of two enynes, HC≡CCH(OH)(C₆H₄)X? CH₂CH?CMe₂ (X=S ( 1a ), O ( 1b )), each of which contains two terminal methyl substituents on the olefinic parts, are explored. The reaction of 1a in CH₂Cl₂ gives the vinylidene complex 2a from the first cyclization and two side products, 3a and the carbene complex 4a with a benzothiophene ligand. The same reaction in the presence of HBF₄ affords 4a exclusively. Air oxidation of 4a in the presence of Et₃N readily gives an aldehyde product. In MeOH, tandem cyclizations of 1a generate a mixture of the benzothiochromene compound 10a and the carbene complex 7a also with a benzothiochromene ligand. First, cyclization of 1b likewise proceeds in CH₂Cl₂ to give 2b . Tandem cyclization of 1b in MeOH yields comparable products 10b and 7b with benzochromene moieties, yet with no other side product. The reaction of [Ru]Cl with HC≡CCH(OH)(C₆H₄)S? CH₂CH?CH₂ ( 1c ), which contains no methyl substituent in the olefinic part, in MeOH gives the carbene complex 15c with an unsubstituted thiochromene by means of a C? S bond formation. Structures of 3a and 15c are confirmed by X‐ray diffraction analysis. The presence of methyl groups of enynes 1a and 1b promotes sequential cyclization reactions that involve C? C bond formation through carbocationic species.     

Solid Phase Synthesis of 3‐Toluenesulfonylglutarimides

A novel route for the synthesis of 3‐toluenesulfonylglutarimides on a solid support is described. The cyclization step involves stepwise [3+3] strategy of Rink Amide resin bound onto an α‐toluenesulfonyl group with various α,β‐unsaturated esters.     

Palladium-catalyzed intramolecular α-arylation of aliphatic ketone, formyl, and nitro groups

Intramolecular arylation of properly designed substrates bearing a ketone, formyl, or nitro terminating group was achieved by use of a PdCl₂(Ph₃P)₂-Cs₂CO₃ reaction system to form a variety of carbocyclic compounds. Arylation in ketone compounds afforded benzene-annulated bridged or spirocycloalkanone derivatives, depending on the structure of the cyclization precursors. Arylation in formyl compounds occurred at the α-position (α-arylation) or at the carbonyl carbon (carbonyl-arylation) depending on the structure of the cyclization precursors and on the reaction solvent. An α-arylated secondary nitro group was partially transformed to ketone in the manner of the Nef reaction, whereas a tertiary nitro group was partially eliminated to afford a styrene-type olefin.     

Efficient solid-phase synthesis of 4,5-dihydro-1,2,4-triazin-6(1H)-ones

A new and easy protocol for the formation of substituted 4,5-dihydro-1,2,4-triazin-6(1H)-ones was developed on solid support. The heterocyclic compounds were formed by nucleophilic reaction of hydrazine on thioamide esters. As cyclization was concomitant with cleavage from the support, substituted 4,5-dihydrotriazinones were obtained in high purity.     

New deprotection method of the 2,2,2-trichloroethoxycarbonyl (Troc) group with (Bu3Sn)2

The 2,2,2-trichloroethoxycarbonyl (Troc) group was efficiently removed in high yields with (Bu₃Sn)₂ in DMF under microwave heating. The present method was applied to deprotection of the Troc group on solid support.     

Synthesis and Controlled Polymerisation of a Novel Gramicidin S Analogue

Summary: The controlled polymerisation of a bulky, peptide‐based monomer was investigated. The cyclic β‐sheet forming decapeptide gramicidin S was modified with a methacrylate handle and subsequently polymerised via atom transfer radical polymerisation (ATRP), to yield a well‐defined gramicidin‐S‐containing polymer. The secondary structure of the peptide moiety was retained within the resulting polymer, as indicated by IR spectroscopy. This is the first example of the use of ATRP to create a synthetic polymer with a cyclic peptide as a side chain.

The gramicidin S based monomers synthesised here were then polymerised by ATRP.