Mazhar Iqbal

Microwave promoted Pauson–Khand reactions

Abstract The synthesis of various cyclopentenones via the Pauson–Khand reaction, employing for the first time microwave energy to initiate this cycloaddition process is reported.

Total Synthesis and Biological Activity of 13,14‐Dehydro‐12‐Oxo‐Phytodienoic Acids (Deoxy‐J1‐Phytoprostanes)

In plants, almost all abiotic and biotic stresses are associated with enhanced endogenous production of reactive oxygen species and free radicals. Free radicals in turn readily attack unsaturated fatty acids in membrane lipids that can be non-enzymatically oxidised to a variety of products in situ. Eventually oxidised lipids are released from membrane stores. It becomes increasingly clear that several of these oxidised lipids, such as malondialdehyde and the recently discovered phytoprostanes that occur ubiquitously in plants, can be induced by oxidative stress and display potent biological activities. 2] Consequently it has been postulated that oxidised lipids represent archetype mediators of oxidative stress, not only in plants but also in animals. The major metabolites of the phytoprostane pathway are deoxy-J1-phytoprostanes (dPPJ1), which structurally resemble potent, enzymatically formed defence mediators in plants and animals such as 12-oxo-phytodienoic acid (OPDA) and 15deoxy-D-prostaglandin J2 (dPGJ2; Scheme 1). Notably, these cyclopentenone phytoprostanes are more abundant than OPDA even in young and unstressed plants. However, it is not known whether the recently discovered dPPJ1s are merely markers of oxidative stress or are biologically active stress metabolites. It was the aim of this study to systematically prepare and evaluate these cyclopentenone phytoprostanes. In 1976, Pryor and co-workers discovered that a-linolenic acid is prone to undergoing autoxidation to yield a series of prostaglandin-like compounds by a free-radical-catalysed lipidperoxidation process in vitro. This finding remained a laboratory curiosity until 1990, when it was shown that arachidonic acid undergoes a similar radical-catalysed oxidation to yield

Conjugate addition–Peterson olefination reactions: expedient routes to cross conjugated dienones

Abstract The synthesis of 5-alkylidenecyclopent-2-enones is readily achieved in two steps via a one-pot conjugate addition–Peterson olefination sequence, using exo-2-trimethylsilyl-3a,4,7,7a-tetrahydro-4,7-methanoinden-1-one, followed by a retro-Diels–Alder reaction.

High-performance liquid chromatography/mass spectrometric and proton nuclear magnetic resonance spectroscopic studies of the transacylation and hydrolysis of the acyl glucuronides of a series of phenylacetic acids in buffer and human plasma

The use of high-performance liquid chromatography/mass spectrometry (HPLC/MS) and proton nuclear magnetic resonance ((1)H NMR) spectroscopy for the kinetic analysis of acyl glucuronide (AG) isomerisation and hydrolysis of the 1-β-O-acyl glucuronides (1-β-O-AG) of phenylacetic acid, (R)- and (S)-α-methylphenylacetic acid and α,α-dimethylphenylacetic acid is described and compared. Each AG was incubated in both aqueous buffer, at pH 7.4, and control human plasma at 37°C. Aliquots of these incubations, taken throughout the reaction time-course, were analysed by HPLC/MS and (1)H NMR spectroscopy. In buffer, transacylation reactions predominated, with relatively little hydrolysis to the free aglycone observed. In human plasma incubations the calculated rates of reaction were much faster than for buffer and, in contrast to the observations in buffer, hydrolysis to the free aglycone was a significant contributor to the overall reaction.A diagnostic analytical methodology based on differential mass spectrometric fragmentation of 1-β-O-AGs compared to the 2-, 3- and 4-positional isomers, which enables selective determination of the former, was confirmed and applied. These findings show that HPLC/MS offers a viable alternative to the more commonly used NMR spectroscopic approach for the determination of the transacylation and hydrolysis reactions of these AGs, with the major advantage of having the capability to do so in a complex biological matrix such as plasma.

Dissecting the reaction of Phase II metabolites of ibuprofen and other NSAIDS with human plasma protein

Nonsteroidal anti-inflammatory drugs (NSAIDs) are among the most widely used drugs on the market. Whilst they are considered safe, several NSAIDs have been withdrawn from the market as a result of adverse drug reactions. NSAIDs are extensively metabolised to their 1-β-O-acyl glucuronides (AGs), and the risk of NSAID AGs covalently modifying biomacromolecules such as proteins or DNA, leading to immune responses and cellular dysfunction constitutes a major concern in drug discovery and development. The assessment of the degree of protein modification and potential toxicity of individual NSAID AGs is therefore of importance in both drug monitoring and development. Herein, we report the covalent reaction of 1-β-O-acyl glucuronides of ibuprofen and several NSAID analogues with human serum albumin (HSA) protein in vitro under concentrations encountered in therapy. Stable transacylation and glycosylation adducts are formed; the observed protein product ratios can be rationalised by the degree of α-substitution in the acyl group. Structure-based protein reactivity correlations of AGs, such as these, may prove a useful tool in distinguishing between carboxylic acid-containing drugs of similar structure that ultimately prove beneficial (e.g., ibuprofen) from those that prove toxic (e.g., ibufenac).