Andrew D. Abell

Estrogenicity of pyrethroid insecticide metabolites

There is concern that insecticides are able to mimic the action of 17beta-estradiol by interaction with the human estrogen receptor. Pyrethroids are commonly used insecticides and several have been assessed for potential endocrine disrupting activity by various methods. It has been noted that some metabolites of pyrethroids, in particular, permethrin and cypermethrin, have chemical structures that are more likely to interact with the cellular estrogen receptor than the parent pyrethroid. For this study permethrin and cypermethrin metabolites 3-(4-hydroxy-3-phenoxy)benzyl alcohol, 3-(4-hydroxy-3-phenoxy)benzoic acid, and N-3-(phenoxybenzoyl)glycine were synthesised, and together with the commercially available 3-phenoxybenzyl alcohol, 3-phenoxybenzaldehyde, and 3-phenoxybenzoic acid, were studied in a recombinant yeast assay expressing human estrogen receptors (YES). Three metabolites, 3-phenoxybenzyl alcohol, 3-(4-hydroxy-3-phenoxy)benzyl alcohol, and 3-phenoxybenzaldehyde, showed estrogenic activity of approximately 10(5) less than that of 17beta-estradiol. No activity was observed in the yeast assay for 3-phenoxybenzoic acid, 3-(4-hydroxy-3-phenoxy)benzoic acid, and N-3-(phenoxybenzoyl)glycine. The results from this study show that pyrethroid metabolites are capable of interacting with the human estrogen receptor, and so might present a risk to human health and environmental well being. The impact would be expected to be small, but still add to the overall environmental xenoestrogen load.

Calpains: Attractive Targets for the Development of Synthetic Inhibitors

The physiological roles of calpains are discussed, as are the associated pathological disorders that result from their over-activation. We also present practical information for establishing functional inhibition assays and an overview of X-ray crystal structures of calpain-inhibitor complexes to aid inhibitor design. These structures reveal the expected extended beta-strand conformation for the inhibitor backbone, a geometry that has been engineered into inhibitors with the introduction of either an N-terminal heterocycle or a macrocycle that links the P(1) and P(3) residues. The structure and function of all the main classes of inhibitors are reviewed, with most examples being classified according to the nature of the C-terminal reactive warhead group that reacts with the active site cysteine of calpains. These inhibitor classes include epoxysuccinate derivatives, aldehydes, aldehyde prodrugs (hemiacetals) and alpha-keto carbonyl compounds. Inhibitors derived from the endogenous inhibitor calpastatin and examples lacking a warhead, are now known and these are also discussed.

Molecular Modeling, Synthesis, and Biological Evaluation of Macrocyclic Calpain Inhibitors

The design and elaboration of a series of macrocyclic templates that exhibit a propensity to adopt a beta-strand-like peptide-backbone conformation led to potent and selective inhibitors of calpain 2. Macrocycle 1 retarded calcium-induced opacification in an ovine-lens culture assay and is a lead compound for the development of a drug for cataract treatment. Cbz=carbobenzyloxy.

Fluorescence-Based Aluminum Ion Sensing Using a Surface-Functionalized Microstructured Optical Fiber

The first microstructured optical fiber-based sensor platform for aluminum ions using a surface-attached derivative of lumogallion (3), a known fluorescence-based indicator, has been fabricated. These fibers allow for strong evanescent field interactions with the surrounding media because of the small core size while also providing the potential for real-time and distributed measurements. The fluorescence response to aluminum ions was first demonstrated by applying the procedure to glass slides. This was achieved through the covalent attachment of the fluorophore to a polyelectrolyte-coated glass surface and then to the internal holes of a suspended-core microstructured optical fiber to give an effective aluminum sensor. Whereas the sensor platform reported is fabricated for aluminum, the approach is versatile, with applicability to the detection of other ions.

The synthesis and crystal structure of alpha-keto tetrazole-based dipeptide mimics

Abstract— Here we report the synthesis of a cis -dipeptide mimic N -Boc-Phe-[COCN 4 ]-Gly-OBn, 7 , containing the non-hydrolysable -keto tetrazole isostere and an unusual 2,5-disubstituted -keto tetrazole-based peptidomimetic, 8 . The incorpora-tion of the novel cis -amide bond isostere was achieved via direct alkylation of a precursor five-substituted (1 H )-tetrazole. Theassignment of the resulting 1,5- and 2,5-tetrazoyl regiomers was based on the first reported X-ray structure analysis of an -ketotetrazole, compound 8 .

Azobenzene-Containing, Peptidyl α-Ketoesters as Photobiological Switches of α-Chymotrypsin

Abstract Three photoswitchable, peptidomimetic inhibitors of α-chymotrypsin have been synthesised. The compounds comprise an azobenzene, an α-ketoester and l -phenylalanine. The compounds were photoisomerised to give enriched states of the (E) and (Z) isomers and these states were assayed against α-chymotrypsin. The inhibitors were shown to be moderately active with switching ability of between two- and three-fold between the two isomer-enriched states. The behaviour of the inhibitors in solution was examined; specifically, their hydration and configurational stability.

The synthesis of naturally occurring vitamin K and vitamin K analogues

The synthesis of vitamin K and its analogues has been an important goal since the biochemical roles of the K vitamins were elucidated. This review presents a detailed account of syntheses of natural K vitamins and analogues that contain side chain functionality.

New β-Strand Templates Constrained by Huisgen Cycloaddition

New peptidic templates constrained into a β-strand geometry by linking acetylene and azide containing P(1) and P(3) residues of a tripeptide by Huisgen cycloaddition are presented. The conformations of the macrocycles are defined by NMR studies and those that best define a β-strand are shown to be potent inhibitors of the protease calpain. The β-strand templates presented and defined here are prepared under optimized conditions that should be suitable for targeting a range of proteases and other applications requiring such a geometry.

Synthesis of Macrocyclic β-Strand Templates by Ring Closing Metathesis

We report the synthesis of macrocycles 1-6 via ring closing metathesis of dienes 7-12. Addition of chlorodicyclohexylborane to thermal and microwave assisted RCM of dienes 8 and 9 markedly improves the yield. The geometric isomers of macrocycles 1-3 and 5 have been assigned using X-ray crystallography and NMR.

Dual Sensor for Cd(II) and Ca(II): Selective Nanoliter-Scale Sensing of Metal Ions

The first selective, dual sensor for Ca(2+) and Cd(2+) capable of detection at 100 pM concentrations was designed and synthesized. The experimental observations made for the MC-cation complexes and the selectivity of compounds 1 and 2 with Ca(2+) and Cd(2+) ions were further explored using density functional theory. A first step toward a nanoliter-scale dip sensor for the dual sensing of Ca(2+) and Cd(2+) was demonstrated using microstructured optical fiber as the sensing platform which is important for ion sensing in confined spaces such as the medium surrounding cell clusters. In addition, this system displays picomolar sensitivity for these ions, with an added ability to reproducibly turn ion-binding on/off.