Trifluoroacetic Acid Salt Research Articles

Decatungstate-Catalyzed C(sp3)–H Alkylation of a Val Residue Proximal to the N-Terminus Controlled by an Electrostatic Interaction

The decatungstate photocatalyst [W10O32]4- efficiently promoted the C(sp3)-H alkylation of the trifluoroacetic acid salt of valine methyl ester (H-Val-OMe·TFA) with electron-deficient alkenes under UV irradiation. The electrostatic interaction between the cationic ammonium group (+NH3) of the main chain and anionic [W10O32]4- played an important role in this reaction. The influence of various protected amino acids in the C(sp3)-H alkylation was investigated as the model reaction for the alkylation of Val-containing peptides. The introduction of an alkyne moiety into Val through this alkylation was successful, and successive copper-catalyzed azide-alkyne cycloaddition (CuAAC) was demonstrated. The C(sp3)-H bond of a Val residue located at the second from the N-terminus was also successfully converted. C(sp3)-H alkylation of oligopeptides containing two Val residues selectively proceeded proximally to the N-terminus.

Silymarin Protects against Acute Liver Injury Induced by Acetaminophen by Downregulating the Expression and Activity of the CYP2E1 Enzyme.

Previous studies have shown that silymarin protects against various types of drug-induced liver injury, but whether the protective mechanism of silymarin against acetaminophen-induced liver injury is related to the CYP2E1 enzyme remains unclear. In this study, we investigated the effect of silymarin on the activity and expression of CYP2E1 in vitro and in vivo. The results of in vitro studies showed that silymarin not only inhibited the activity of CYP2E1 in human and rat liver microsomes but also reduced the expression of CYP2E1 in HepG2 cells. In vivo studies showed that silymarin pretreatment significantly reduced the conversion of chlorzoxazone to its metabolite 6-OH-CLX and significantly increased the t1/2, area under the curve (AUC) and mean residence time (MRT) of chlorzoxazone. In addition, silymarin pretreatment significantly inhibited the upregulation of Cyp2e1 expression, reduced the production of 3-cysteinylacetaminophen trifluoroacetic acid salt (APAP-CYS), and restored the liver glutathione level. The results of our study show that silymarin plays an important protective role in the early stage of acetaminophen-induced acute liver injury by reducing the activity and expression of CYP2E1, reducing the generation of toxic metabolites, and alleviating liver injury.

An Ornithine-Free Gramicidin S Analogue Using Norleucine, Cyclo(Val-Nle-Leu-D-Phe-Pro)2, Forms Helically Aligned β-Sheets.

The structure of an ornithine (Orn)-free Gramicidin S (GS) analogue, cyclo(Val-Nle-Leu-D-Phe-Pro)2 (NGS), was studied. Its circular dichroism (CD) spectrum showed that NGS has a structure similar to GS, though the value of [θ] indicated smaller β-turn and sheet populations. This is probably because the Nle side chain could not form intramolecular hydrogen bonds stabilizing the sheet structure. The chemical shift perturbation of αH and JNH-αH were similar in GS and NGS. Three independent NGS molecules formed intramolecular β-sheet structures in crystal. The turn structures of D-Phe-Pro moieties were classed as type II' β-turns, but one part was unclassed. The molecules were arranged in a twisting manner, which resulted in the formation of a helical sheet. Similar structural characteristics were observed previously in a Leu-type, Orn-free GS analogue and in GS trifluoroacetic acid salt.

Genetic Engineering in Combination with Semi-Synthesis Leads to a New Route for Gram-Scale Production of the Immunosuppressive Natural Product Brasilicardin A.

Brasilicardin A (1) consists of an unusual anti/syn/anti‐perhydrophenanthrene skeleton with a carbohydrate side chain and an amino acid moiety. It exhibits potent immunosuppressive activity, yet its mode of action differs from standard drugs that are currently in use. Further pre‐clinical evaluation of this promising, biologically active natural product is hampered by restricted access to the ready material, as its synthesis requires both a low‐yielding fermentation process using a pathogenic organism and an elaborate, multi‐step total synthesis. Our semi‐synthetic approach included a) the heterologous expression of the brasilicardin A gene cluster in different non‐pathogenic bacterial strains producing brasilicardin A aglycone (5) in excellent yield and b) the chemical transformation of the aglycone 5 into the trifluoroacetic acid salt of brasilicardin A (1 a) via a short and straightforward five‐steps synthetic route. Additionally, we report the first preclinical data for brasilicardin A.

Genetic Engineering in Combination with Semi‐Synthesis Leads to a New Route for Gram‐Scale Production of the Immunosuppressive Natural Product Brasilicardin A

The development of a heterologous producer strain that enables the sustainable production of the stereochemically complex natural products brasilicardin C and E at excellent rates is presented. The semi-synthetic approach allows an efficient gram-scale conversion of brasilicardin E into the potent immunosuppressant brasilicardin A for which the first preclinical data are reported.

Large-Scale Isolation of Three O-Methyl Anthocyanins from Bilberry (Vaccinium myrtillus L.) Extract.

Three O-methyl anthocyanidin 3-O-β-D-glucopyranosides were isolated from bilberry extract on a large-scale basis together with two non O-methyl analogues. Anthocyanidin 3-O-β-D-galactopyranosides were removed from bilberry extract together with parts of anthocyanidin 3-O-α-L-arabinopyranosides after treatment with β-galactosidase. The remaining arabinopyranosides were removed by applying acid catalytic hydrolysis. The amounts of anthocyanins recovered as flavylium trifluoroacetic acid salt were as follows: 630 mg for petunidin 3-O-β-D-glucopyranoside, 423 mg for peonidin 3-O-β-D-glucopyranoside, 588 mg for malvidin 3-O-β-D-glucopyranoside, 877 mg for delphinidin 3-O-β-D-glucopyranoside, and 742 mg for cyanidin 3-O-β-D-glucopyranoside.

Automated [18F]PSMA-1007 production by a single use cassette-type synthesizer for clinical examination

Background[18F]PSMA-1007, a positron emission tomography (PET) tracer, specifically targets prostate-specific membrane antigen (PSMA), which is highly expressed in prostate cancer. PSMA-PET is effective especially for regional detection of biochemical recurrence, which significantly affects patient management. Herein, we established and optimized a one-step radiolabeling protocol to separate and purify [18F]PSMA-1007 with a CFN-MPS200 synthesizer for clinical application.ResultsA dedicated single use cassette and synthesis program for [18F]PSMA-1007 was generated using a single-step method for direct precursor radiolabeling. In the cassette, three tube types (fluoro-elastomer, PharMed® BPT, silicone) and two different precursor salts (trifluoroacetic acid or acetic acid) were compared for optimization. Furthermore, three-lot tests were performed under optimized conditions for quality confirmation. Activity yields and mean radiochemical purity of [18F]PSMA-1007 were > 5000 MBq and 95%, respectively, at the end of synthesis, and the decay-corrected mean radiochemical yield from all three cassettes was approximately 40% using a trifluoroacetic acid salt precursor. Fluoro-elastomer tubings significantly increased the amount of non-radioactive PSMA-1007 (8.5 ± 3.1 μg/mL) compared to those with other tubings (0.3 μg/mL). This reduced the molar activity of [18F]PSMA-1007 synthesized in the cassette assembled by fluoro-elastomer tubings (46 GBq/μmol) compared to that with PharMed® BPT and silicone tubings (1184 and 1411 GBq/μmol, respectively). Residual tetrabutylammonium, acetonitrile, and dimethyl sulfoxide levels were < 2.6 μg/mL, < 8 ppm, and < 11 ppm, respectively, and ethanol content was 8.0–8.1% in all three cassettes and two different salts. Higher activity yields, radiochemical purities, and decay-corrected radiochemical yields were obtained using an acetic acid salt precursor rather than a trifluoroacetic acid salt precursor (7906 ± 1216 MBq, 97% ± 0%, and 56% ± 4%). In the three-lot tests under conditions optimized with silicone cassettes and acetic acid salt precursor, all quality items passed the specifications required for human use.ConclusionsWe successfully automated the production of [18F]PSMA-1007 for clinical use and optimized synthesis procedures with a CFN-MPS200 synthesizer using a silicone cassette and acetic acid salt precursor. Cassette availability will facilitate a wide spread use of [18F]PSMA-1007-PET, leading to an effective prostate cancer management.

In vitro and in vivo evaluations of a novel post-electrospinning treatment to improve the fibrous structure of chitosan membranes for guided bone regeneration

Electrospun chitosan membranes have been investigated for guided bone regeneration but are susceptible to swelling, dissolution, and loss of biomimetic nanofiber structure due to residual acid salts. A novel process was investigated for acidic salt removal from chitosan electrospun in 70% trifluoroacetic acid (TFA) by treating with triethylamine (TEA)/acetone and di-tert-butyl dicarbonate (tBOC) instead of the common Na2CO3 treatment. TFA salt removal and nanofiber structure stabilization were confirmed by EDS, FTIR, 19F NMR and electron microscopy before and after soaking in water. Membrane degradation after 4 weeks in PBS with 100 µg ml−1 lysozyme and osteoblastic proliferation were similar between TEA/tBOC-treated and Na2CO3-treated membranes. A simulated surgical tear test using surgical tacks showed that the peak tensile tear strength of the TEA/tBOC-treated chitosan membranes (62.1 ± 1.9 N mm−1) was significantly greater than a commercial polylactic acid (PLA) membrane (13.4 ± 0.4 N mm−1), similar to one commercial collagen membrane (55.3 ± 7.5 N mm−1) but lower than another commercial collagen membrane (133.9 ± 21.5 N mm−1). Rat 8 mm critical-sized calvarial defects covered with TEA/tBOC-treated chitosan membranes prevented soft tissue infiltration and supported new bone growth (15.76 ± 10.28%) similar to a commercial collagen membrane (16.08 ± 10.69%) at 12 weeks based on microCT analyses. Hence our novel TEA/tBOC process significantly improved nanofiber structure and mechanical strengths of electrospun chitosan membranes as compared to Na2CO3 treated membranes, without affecting in vitro degradation or cytocompatibility, improved membrane mechanical properties to be greater than a commercial PLA membrane and to be in range of commercial collagen membranes and supported calvarial bone defect healing similar to collagen. Thus TEA/tBOC-treated chitosan membranes exhibit many characteristics and properties that strongly support their potential for use in guided bone regeneration.

Asymmetric Diels-Alder Reaction of α-Substituted and β,β-Disubstituted α,β-Enals via Diarylprolinol Silyl Ether for the Construction of All-Carbon Quaternary Stereocenters.

The asymmetric Diels-Alder reaction of α-substituted acrolein proceeds in the presence of the trifluoroacetic acid salt of trifluoromethyl-substituted diarylprolinol silyl ether to afford the exo-isomer with both excellent diastereoselectivity and high enantioselectivity. In the Diels-Alder reaction of a β,β-disubstituted α,β-unsaturated aldehyde, good exo-selectivity and excellent enantioselectivity was obtained when the perchloric acid salt of the bulky triisopropyl silyl ether of trifluoromethyl substituted diarylprolinol was employed as an organocatalyst in the presence of water. In both cases, all-carbon quaternary stereocenters are constructed enantioselectively.

Cation Tuning toward the Inference of the Gelation Behavior of Supramolecular Gels.

We serendipitously discovered that the tripeptide Asp–Phe–Phe trifluoroacetic acid salt (hereafter abbreviated as β-AspFF) formed a reversible thermotropic gel in chloroform solution (at temperatures higher than the boiling point of chloroform), and a stable gel in toluene solution (at equal to or lower than the room temperature). Experimental results indicate that doping metal ions into β-AspFF toluene gels can trigger morphological variations in the gel skeleton, thereby increasing gel volume and inducing the collapse of organogels. Investigation on the cation-tuned gelation behavior of β-AspFF can be used to elucidate heating-induced gel collapse (of normal gel) or reverse thermotropic gelation as well as select carbamide and acetamide as activators of β-AspFF gels in chloroform solution at room temperature.

Crystal structure of (4S)-aminoproline: conformational insight into a pH-responsive proline derivative.

The crystal structure of a (4S)-configured ammoniumproline derivative is presented. The trifluoroacetic acid salt of the acetylated methylester of (4S)-aminoproline (Ac-(4S)Amp-OMe) crystallized as the trans conformer with a C(4)-endo ring pucker. The high-resolution structure shows typical parameters for a transannular H-bond and an n → π* interaction between the adjacent amide and ester groups. The structure corroborates previous findings of solution phase studies on the importance of these two interactions in acidic and neutral aqueous environments for the conformation of this pH-responsive proline derivative.

ChemInform Abstract: Peptide‐Catalyzed Stereoselective Conjugate Addition Reactions Generating All‐Carbon Quaternary Stereogenic Centers.

AbstractThe diastereomeric mixture (1:1) of the peptide PEP is used as a trifluoroacetic acid salt in all reactions.

CO&lt;sub&gt;2&lt;/sub&gt; Solubility and Physical Properties of Two Containing Fluorine Functional Ionic Liquids

Two containing fluorine functional ionic liquids (ILs) (1-aminoethyl-3-methyl imidazolium trifluoroacetic acid salt ([aemim] [CF3COO]) and 1-aminoethyl-3-methyl imidazolium trifluoromethane sulfonic acid salt ([aemim] [TfO])) were synthesized and the samples were characterized by means of FTIR, 1HNMR respectively. The densities, viscosities, and electrical conductivities of the two samples were measured over the temperature range T = (303.15-333.15) K at atmospheric pressure. The solubility of CO2 in the two samples were investigated at temperature from 303.15 to 333.15 K and pressure from 0 to 7.14 MPa. Results showed that the maximum solubility of CO2 in [aemim] [TfO] was 0.759 (mole fraction) at 7.01 MPa and 323.15K, and the which of [aemim] [CF3COO] was 0.646 at 6.49 MPa and 313.15 K. The influence of the temperature and CO2 partial pressure on the process of CO2 absorption was discussed. The CO2 solubilities in different ILs were also compared. The Henry's constants and infinite dilution partial molar volumes for the ILs+ CO2 systems were obtained.

An efficient method for the synthesis of phenacyl ester‐protected dipeptides using neutral alumina‐supported sodium carbonate ‘Na2CO3/n‐Al2O3’

In the synthesis of dipeptides (Boc-AA(1)-AA(2)-OPac: AA(1) and AA(2) represent amino acids) protected by phenacyl (Pac) ester, amines and solid bases as the base for the conversion of the trifluoroacetic acid (TFA) salt of the amino component (TFA·H-AA(2)-OPac) into the corresponding free amino component (H-AA(2)-OPac) were examined. The synthesis of a dipeptide (Boc-Ala-Gly-OPac) using amines for the conversion afforded an unsatisfactory yield with by-products. On the other hand, the use of neutral alumina-supported Na(2) CO(3) (Na(2)CO(3) /n-Al(2)O(3)) as a solid base for the conversion provided the dipeptide in a quantitative yield without by-products. The application of Na(2)CO(3) /n-Al2 O3 to the synthesis of some dipeptides protected by Pac ester gave the desired peptides in excellent yields.

Synthesis and characterization of novel quick-release propofol prodrug via lactonization

The water-soluble derivatives of propofol have gained attention as a method to increase solubility of propofol. According to the principle of lactonization, the lead compound HX0969 was synthesized first and then the pharmacological features of HX0969 were evaluated in a comparison with those of propofol in the SD rats. Then, HX0969 disodium phosphate monoester (HX0969W) and glycine ester trifluoroacetic acid salt (HX101230) were synthesized, and their pharmacological features were compared with those of Lusedra®, which has been recognized and marketed as a water-soluble prodrug of propofol since 2008. The results showed that HX0969 could produce an anesthetic effect within a few seconds (3.6±3.0s) and its therapeutic index was 4.66 in the SD rat. The pharmacodynamic characteristics of HX0969W were similar to those of the Lusedra®. HX101230 could still produce an anesthetic effect within 60s in the rats though its therapeutic index was not so high (TI=2.96). Therefore, our study has indicated that HX0969 is a potentially useful lead compound of propofol derivative. Its rapid anesthetic effect is probably associated with lactonization.

Synthesis of peptide–cellulose conjugate mediated by a soluble cellulose derivative having β-Ala esters

A derivatization of cellulose was investigated for gaining up the solubility for subsequent conjugation reaction. Nβ-Boc-β-Ala, was introduced to the parent cellulose using carbonyl diimidazole. Degree of substitution towards the cellulose hydroxyls was 49%. Subsequent removal of Boc in trifluoroacetic acid (TFA) yielded β-Ala-cellulose·TFA salt. A protected hexapeptide, Boc-Ser(Bzl)-Gly-Tyr(Bzl)-Ser(Bzl)-Gly-Lys(Z) was synthesized via 9 steps of peptide elongation, and the C-end carboxyl groups of the peptide was coupled with the β-Ala-cellulose in a homogenous dimethyl sulfoxide solution, using 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide monohydrochloride to ensure the Nβ-selective acylation. The degree of substitution of the protected peptide towards the β-amino groups of β-Ala-cellulose (DS%(/NH2)) was 52% for 1.0eq.mol of the protected peptide feed, and in the presence of N-hydroxysuccinimide, DS%(/NH2) was increased to 61%. At 4.0eq.mol feed, almost quantitative conjugation was observed as DS%(/NH2)=98–99%. Deprotection of the conjugate using thioanisole–TFA resulted in complete removal of Boc, Bzl on Tyr, and Z on Lys, while a very trace amount of Bzl on Ser seemed to be left uncleaved.

ChemInform Abstract: Morpholine Catalyzed Direct C3 Alkenylation of Indoles with α,β‐Unsaturated Aldehydes.

Organocatalytic direct C3 alkenylation of indoles has been developed. Simple and readily available morpholine trifluoroacetic acid salt is employed as an efficient catalyst in this oxidative dehydrogenative reaction. Simplicity and practicality constitute the most attractive advantages of this reaction.

An in-depth in situ IR study of the thermal decomposition of yttrium trifluoroacetate hydrate

The pyrolysis of Y(CF3COO)3·nH2O at temperatures up to 1,000 °C, under flowing pure Ar, O2 and O2 saturated with water vapour, was extensively analysed. The formation of HF is observed directly and the existence of a :CF2 diradical is inferred during a trifluoroacetic acid salt decomposition. High resolution thermogravimetry, differential scanning calorimetry, X-ray diffractometry and scanning electron microscopy indicated that the exothermic one-stage decomposition of the anhydrate salt occurs at 267 °C, forming YF3. Fourier transform infrared spectroscopy identified (CF3CO)2O, CF3COF, COF2, CO2 and CO as the principal volatile species; and revealed the influence of water on the reactions liberating gaseous CF3COOH, CHF3, HF, and SiF4 (from reactions with glass or quartz components). NO2 and N2O evolution suggested that traces of CH3NO2 were present in the starting material. Thermogravimetry and X-ray diffractometry indicated that the slow hydrolysis of the fluoride occurs between 630 and 655 °C, forming a mixture of Y2O3, YOF, Y7O6F9, and YF3. The decomposition and hydrolysis temperatures are significantly lower than previously reported, which has implications for sol–gel processing.

Strategies in Functional Poly(ester amide) Syntheses to Study Human Coronary Artery Smooth Muscle Cell Interactions

The design of new generation cardiovascular biomaterials focuses on biomimetic properties that are capable of eliciting specific cellular responses and directing new tissue formation. Synthetic poly(ester amide)s (PEAs) containing α-amino acid residues have the potential to elicit favorable cellular responses. Furthermore, they are biodegradable owing to the incorporation of naturally occurring amino acids. In this study, a family of PEAs was synthesized from selected α-amino acids using both solution and interfacial polymerization approaches to optimize their properties for vascular tissue engineering applications. By careful selection of the monomers and the polymerization approach, high-molecular-weight PEAs with low glass-transition temperatures were obtained. Human coronary artery smooth muscle cells (HCASMCs) cultured directly on bare PEA films attached and spread well up to 7 days of culture. Moreover, cell viability was significantly enhanced on all nonfunctional PEAs compared with tissue culture polystyrene controls. The trifluoroacetic acid salt of the lysine-containing functional PEAs was found to retard cell growth but still supported cell viability up to 5 days of culture. Immunostaining of HCASMCs revealed strong vinculin expression, suggesting that the HCASMCs initiated cellular processes for focal adhesion contacts with all PEA surfaces. Conversely, smooth muscle α-actin expression was not abundant on the PEA surfaces, suggesting a proliferative smooth muscle cell phenotype. Altogether, our results indicate that these PEAs are promising materials for vascular tissue engineering scaffolds.

Morpholine catalyzed direct C3 alkenylation of indoles with α,β-unsaturated aldehydes

Organocatalytic direct C3 alkenylation of indoles has been developed. Simple and readily available morpholine trifluoroacetic acid salt is employed as an efficient catalyst in this oxidative dehydrogenative reaction. Simplicity and practicality constitute the most attractive advantages of this reaction.