Direct-gradient high-performance liquid chromatographic analysis and preliminary pharmacokinetics of flumequine and flumequine acyl glucuronide in humans: effect of probenecid.

A gradient high-performance liquid chromatographic analysis for the direct measurement of flumequine, with its acyl glucuronide, in plasma and urine of humans has been developed. In order to prevent hydrolysis and isomerization of flumequine acyl glucuronide, the samples were acidified by the oral intake of four 1.2-g amounts of ammonium chloride per day. In contrast to the acyl glucuronides of non-steroidal anti-inflammatory drugs, flumequine and its acyl glucuronide were stable in urine of pH 5.0-8.0. Flumequine acyl glucuronide is unstable at pH 1.5. In acidic urine (pH 5-6), almost no flumequine is excreted unchanged (1%): it is excreted chiefly as acyl glucuronide (84.2%). Probenecid co-medication reduces the renal excretion rate of flumequine acyl glucuronide from 662 to 447 micrograms/min (p = 0.00080), but not the percentage of glucuronidation.     

Bioanalytical challenges and strategies for accurately measuring acyl glucuronide metabolites in biological fluids

Bioanalysis of unstable compounds such as acyl glucuronide metabolites represents a great analytical challenge owing to poor analyte stability in biological matrices. The primary goal for bioanalytical assay development is to minimize the breakdown of acyl glucuronide metabolite into its parent aglycone during sample collection, transportation, storage and analysis. Samples need to be stabilized ex vivo immediately after sample collection to minimize potential breakdown and thus to ensure accurate concentration measurement of both acyl glucuronide metabolite and its parent aglycone. In this review paper, formation of acyl glucuronide metabolites, the importance of establishing acyl glucuronide exposure measurement and safety coverage, optimization of sample pretreatment to stabilize the acyl glucuronide metabolites, current analytical strategy of assaying them as well as considerations for regulatory filings are discussed. It is important to identify acyl glucuronide metabolites that are capable of undergoing hydrolysis and pH-dependent intra-molecular migration as well as covalently binding to plasma and tissue proteins which can cause toxicity in vivo in the early stages of drug development. Carefully planning analytical experiments, identifying structures of acyl glucuronides and monitoring their concentrations in early drug development can help assess the risks associated with their exposures and potentially predict their concentrations in human circulation.     

Synthesis of a series of phenylacetic acid 1-β-O-acyl glucosides and comparison of their acyl migration and hydrolysis kinetics with the corresponding acyl glucuronides

We report the synthesis of the 1-β-O-acyl glucoside conjugates of phenylacetic acid (PAA), R- and S-α-methyl-PAA and α,α'-dimethyl-PAA, and measurement of their transacylation and hydrolysis reactivity by NMR methods. These are analogues of acyl glucuronides, the transacylation kinetics of which could be important in adverse drug effects. One aim of this work was to investigate whether, as previously postulated, the free carboxylate group of the acyl glucuronides plays a part in the mechanism of the internal acyl migration. In addition, such acyl glucosides are known to be endogenous biochemicals in their own right and investigation of their acyl migration propensities is novel. Our previously described selective acylation procedure has proved highly successful for 1-β-O-acyl glucuronide synthesis and when subsequently applied to 6-O-trityl glucose, it gave good yields and excellent anomeric selectivity. Mild acidolysis of the O-trityl intermediates gave the desired acyl glucosides in excellent yield with essentially complete β-selectivity. Measurement of the acyl glucoside transacylation kinetics by (1)H NMR spectroscopy, based simply on the disappearance of the 1-β-isomer in aqueous buffer at pH 7.4, showed marked differences depending on the degree of methyl substitution. Further kinetic modelling of the isomerisation and hydrolysis reactions of the acyl glucosides showed considerable differences in kinetics for the various isomeric reactions. Reactions involving the -CH(2)OH group, presumably via a 6-membered ring ortho-ester intermediate, are facile and the α-glucoside anomers are significantly more reactive than their β-counterparts. By comparison with degradation rates for the corresponding acyl glucuronides, it can be inferred that substitution of the carboxylate by -CH(2)OH in the acyl glucosides has a significant effect on acyl migration for those compounds, especially for rapidly transacylating molecules, and that thus the charged glucuronide carboxylate is a factor in the kinetics.     

Protease-catalyzed monoacylation of 2-O-alpha-D-Glucopyranosyl-L-ascorbic acid in pyridine

2-O-alpha-D-Glucopyranosyl-6-O-octanoyl-L-ascorbic acid was enzymatically synthesized from 2-O-alpha-D-glucopyranosyl-L-ascorbic acid (AA-2G) and vinyl octanoate with a protease from Bacillus subtilis in pyridine. Furthermore, with various linear saturated fatty acid vinylesters as acyl donors, AA-2G was also converted to their corresponding 6-O-acyl AA-2G in the same manner. The reactivities of transacylation decreased with increasing length of the acyl groups. Thus, short chain acyl groups were transferred to AA-2G by this protease more efficiently than were long chain acyl groups. This enzymatic method is recommended for the synthesis of 6-Acyl-AA-2G with short or medium length chain acyl groups.     

cis-Tetrahydrofuran-3,4-diol structure as a key skeleton of new protecting groups removable by self-cyclization under oxidative conditions

A variety of carbonate-type acyl groups having a cis-tetrahydrofuran-3,4-diol (1,4-anhydroerythritol) backbone structure and a TrS or MMTrS group have been examined as new "protected" protecting groups of the 5'-hydroxyl group of nucleosides. These acyl groups were designed in a manner where they could be deprotected by I(2)-promoted removal of the TrS or MMTrS group followed by self-cyclization involving an intramolecular attack of the once-generated neighboring hydroxyl group on the acyl carbon. It turned out that these acyl groups could be introduced into the 5'-hydroxyl group of a 3'-O-protected thymidine derivative by use of the corresponding acyl imidazolides or 4-nitrophenyl esters as well as by reaction with carbonyldiimidazole or 4-nitrophenyl chloroformate. Among the acyl groups tested, it was found that the CTFOC group could be easily introduced into the 5'-hydroxyl group of 3'-masked deoxyribonucleoside derivatives and rapidly removed under mild conditions using iodine.     

Deuteration as an aid to the high-temperature gas chromatography—mass spectrometry of steryl fatty acyl esters

A method is presented for reducing degradative losses of steryl fatty acyl esters bearing polyunsaturated fatty acyl moieties during high-temperature gas chromatography (GC) and combined high-temperature GC—mass spectrometry (MS). The method employs selective deuteration of the double bonds in the fatty acyl moiety using a homogeneous catalyst (Wilkinson's catalyst). The Δ⁵ double bond, which occurs in the most commonly occurring plant and animal sterols, is not deuterated under the conditions described. In addition to improving GC behaviour, the method has the advantage of preserving structure information by labelling each double bond present in the original unsaturated fatty acyl moiety. The carbon number and degree of unsaturation of the labelled fatty acyl moiety are readily revealed by combined GC—MS employing negative-ion ammonia chemical ionisation. Two applications of the method are demonstrated in the analysis of steryl fatty acyl esters isolated from a rape seed oil and ovary tissue of the marine prawn Penaeus monodon.     

Synthesis of O‐Acyl Isopeptides

O‐Acyl isopeptides, in which the N‐acyl linkage on the hydroxyamino acid residue (e.g., Ser and Thr) is replaced with an O‐acyl linkage, generally possess superior water‐solubility to their corresponding native peptides, as well as other distinct physicochemical properties. In addition, O‐acyl isopeptides can be rapidly converted into their corresponding native peptide under neutral aqueous conditions through an O‐to‐N acyl migration. By exploiting these characteristics, researchers have applied the O‐acyl isopeptide method to various peptide‐synthesis fields, such as the synthesis of aggregative peptides and convergent peptide synthesis. This O‐acyl‐isopeptide approach also serves as a means to control the biological function of the peptide in question. Herein, we report the synthesis of O‐acyl isopeptides and some of their applications.     

Observation of 1,3-diketones formation in the reaction of bulky acyl chlorides with methyllithium

The formation of 1,3-diketones was observed in the reactions of bulky acyl chlorides with methyllithium. The reaction products depend on the steric hindrance around the carbonyl group of the acyl chloride and the electronic effect of the group(s) linked to the carbonyl. When the steric hindrance around the carbonyl group of the acyl chloride is big enough, the 1,3-diketone is the only product. In the case of the moderate hindrance around the carbonyl group of the acyl chloride, a moderate yield of 1,3-diketone is obtained and some tertiary alcohol is generated. When there is no steric hindrance around the carbonyl group of the acyl chloride, the tertiary alcohol is the only product. When the steric hindrance around the carbonyl group is moderate and an electron-donating group is connected to the carbonyl of the acyl chloride, all three products--ketone, 1,3-diketone and tertiary alcohol--can be isolated from the reaction mixture after long reaction times.     

Acyl Fluorides in Late‐Transition‐Metal Catalysis

In this Review, we summarize the current state of the art in late‐transition‐metal‐catalyzed reactions of acyl fluorides, covering both their synthesis and further transformations. In organic reactions, the relationship between stability and reactivity of the starting substrates is usually characterized by a trade‐off. Yet, acyl fluorides display a very good balance between these properties, which is mostly due to their moderate electrophilicity. Thus, acyl fluorides (RCOF) can be used as versatile building blocks in transition‐metal‐catalyzed reactions, for example, as an “RCO” source in acyl coupling reactions, as an “R” source in decarbonylative coupling reactions, and as an “F” source in fluorination reactions. Starting from the cleavage of the acyl C?F bond in acyl fluorides, various transformations are accessible, including C?C, C?H, C?B, and C?F bond‐forming reactions that are catalyzed by transition‐metal catalysts that contain the Group 9–11 metals Co, Rh, Ir, Ni, Pd, or Cu.     

Visible-Light Photoredox-Catalyzed Acyl Lactonization of Alkenes with Acyl Chlorides

A photocatalytic acyl lactonization of unsaturated carboxylic acids using simple and inexpensive acyl chlorides has been developed for a modular synthesis of acyl lactones. Significantly, the simple protocol could allow an efficient construction of biologically important phthalide framework. The transformation could be extended to a wide variety of unsaturated carboxylic acids, including substituted 2-vinyl benzoic acids and different types of alkenoic acids. Moreover, a series of aroyl, heteroaroyl chlorides could serve as coupling partners. Notably, functional groups including MeO, F, Cl and Br could survive. It is believed that acyl radicals generated from acyl chlorides under photoredox catalysis reacted with alkenes via atom-transfer radical addition (ATRA) and triggered subsequent lactonization in the process. Preliminary mechanistic investigations revealed that the transformation probably proceeded through a free radical pathway.     

The Preparation of Acylselenourea and Selenocarbamate Using Isoselenocyanate

Acyl isoselenocyanates were prepared by a reaction of acyl chloride with KSeCN. The acyl isoselenocyanates formed in situ were ready for further reaction without concentration. N-Acyl selenoureas were obtained by a reaction of acyl isoselenocyanates with amines. The reaction of acyl isoselenocyanates with nucleophiles gave the corresponding selenocarbamate. All the compounds were well characterized by using spectral data, such as ¹³C and ⁷⁷Se NMR and X-ray diffraction.     

Palladium-Catalyzed Annulation of Acyl Fluorides with Norbornene via Decarbonylation and CO Reinsertion

A palladium-catalyzed annulation of acyl fluorides with norbornene is described. This study reports the first example of an annulation of acyl fluorides in the presence of a transition-metal catalyst. Polycyclic ketones are obtained from the cleavage of the C−F and C−H bonds of the acyl fluoride and the rearrangement of the carbonyl moiety by decarbonylation and CO reinsertion.     

度洛西汀酰基衍生物的合成

抗抑郁药度洛西汀与取代酰氯反应合成了四个新的度洛西汀酰基衍生物——N-取代酰基-N-甲基-3-(1-萘氧基)-3-(2-噻吩基)丙胺,其结构经1H NMR,IR和MS表征。     

Acyl Group Migration in Pyranosides as Studied by Experimental and Computational Methods

Acyl group migration affects the synthesis, isolation, manipulation and purification of all acylated organic compounds containing free hydroxyl groups, in particular carbohydrates. While several isolated studies on the migration phenomenon in different buffers have been reported, comprehensive insights into the overall migration process in different monosaccharides under similar conditions have been lacking. Here, we have studied the acyl migration in different monosaccharides using five different acyl groups by a combination of experimental, kinetic and theoretical tools. The results show that the anomeric configuration in the monosaccharide has a major influence on the migration rate, together with the relative configurations of the other hydroxyl groups and the nature of the migrating acyl group. Full mechanistic model, based on computations, demonstrates that the acyl migration proceeds through an anionic stepwise mechanism with linear dependence on the [OH⁻] and the pK_a of the hydroxyl group toward which the acyl group is migrating.     

A Desulfonylative Approach in Oxidative Gold Catalysis: Regiospecific Access to Donor‐Substituted Acyl Gold Carbenes

Donor‐substituted acyl gold carbenes are challenging to access selectively by gold‐promoted intermolecular oxidation of internal alkynes as the opposite regioisomers frequently predominate. By using alkynyl sulfones or sulfonates as substrates, the oxidative gold catalysis in the presence of substituted pyridine N‐oxides offers regiospecific access to acyl/aryl, acyl/alkenyl, and acyl/alkoxy gold carbenes by in situ expulsion of sulfur dioxide. The intermediacies of these reactive species are established by their reactivities, including undergoing further oxidation by the same oxidant, cyclopropanation of styrenes, engaging in a [3+2] cycloaddition with α‐methylstyrene, and conversion into dienones.     

Mechanistic studies of carbonate macrocyclization

The kinetics of phenylchloroformate (PCF) reactions have been used to model some of the key chemical events in carbonate macrocyclization. Three reactions have been studied using stopped-flow FT-IR spectroscopy: formation of acyl ammonium salt from PCF and three different trialkylamines, the conversion of acyl ammonium salt to urethane, and the condensation reaction between acyl ammonium salt and 4-isopropylphenol. The rate dependence was studied for triethylamine (TEA), diethylmethylamine (DEMA) and tri-n-butylamine (TBA) at 0°C in anhydrous CH₂Cl₂. The reactivity order for acyl ammonium salt formation for TBA: TEA: DEMA is 1 : 2.7 : >444. By contrast, condensation and urethane formation are not sensitive to the structure of the amine. The rate of condensation is comparable to the rate of acyl ammonium salt formation for TEA and TBA, while the rate of urethane formation is the slowest process for all three amines. These results are consistent with the view that the yield of macrocyclic polycarbonates is related to the concentration of the acyl ammonium salt. The optimum amine concentration for obtaining high yields of cyclics varies with the amine structure and parallels the difference in the rates of acyl ammonium salt formation. © 1994 John & Sons, Inc.     

Biosynthesis of lovastatin analogs with a broadly specific acyltransferase

The natural product lovastatin and its semisynthetic, more effective derivative, simvastatin, are important drugs for the treatment of hypercholesterolemia. Here, we report the biochemical characterization of a dedicated acyltransferase, LovD, encoded in the lovastatin biosynthetic pathway. We demonstrate that LovD has broad substrate specificity towards the acyl carrier, the acyl substrate, and the decalin acyl acceptor. LovD can efficiently catalyze the acyl transfer from coenzyme A thioesters or N-acetylcysteamine (SNAC) thioesters to monacolin J. When alpha-dimethylbutyryl-SNAC was used as the acyl donor, LovD was able to convert monacolin J and 6-hydroxyl-6-desmethylmonacolin J into simvastatin and huvastatin, respectively. Using the Escherichia coli LovD overexpression strain as a whole-cell biocatalyst, preparative amounts of simvastatin were synthesized in a single fermentation step. Our results demonstrate LovD is an attractive enzyme for engineered biosynthesis of pharmaceutically important cholesterol-lowering drugs.     

Equilibrium of acyl transfer between pyridine N-oxides and their acylonium salts

Transfer of acyl groups from N-acyloxypyridinium salts to pyridine N-oxides in acetonitrile was studied. The equilibrium constants of acyl exchange were determined. These quantities vary in the range covering eight orders of magnitude, depending on the structure of the reagents, and are independent of the structure of the acyl group.     

Synthesis of acyl pyrroles via palladium-catalyzed carbonylative amination of aryl and alkenyl iodides

A palladium-catalyzed synthesis of acyl pyrroles from aryl and alkenyl iodides is reported. This carbonylative amination requires only atmospheric (balloon) pressure of carbon monoxide and proceeds with Pd(PPh(3))(4) and Pd-NHC catalysts. Aryl and heteroaryl iodides give the corresponding acyl pyrroles in good to excellent yields, while alkenyl iodides provide the corresponding acyl pyrroles in low to moderate yields.     

氯化镍催化的醚的酰化开裂反应

在某些金属盐存在下,醚可与酰氯反应生成酯,早期文献中对于此类反应曾有过报道,其中所用的金属盐有三氯化铁或氯化锌,其相对用量较大,酯的得率较差。其后,Alper等提出用第五族金属羰基化合物和酰氯,如Mo(CO)_4-RCOCl为试剂,进行醚的开裂;近期则有Pri-Bar等用Pd(Ⅱ)-R_3SnX-