Martin D. Smith

Targeting C-reactive protein for the treatment of cardiovascular disease

Complement-mediated inflammation exacerbates the tissue injury of ischaemic necrosis in heart attacks and strokes, the most common causes of death in developed countries. Large infarct size increases immediate morbidity and mortality and, in survivors of the acute event, larger non-functional scars adversely affect long-term prognosis. There is thus an important unmet medical need for new cardioprotective and neuroprotective treatments. We have previously shown that human C-reactive protein (CRP), the classical acute-phase protein that binds to ligands exposed in damaged tissue and then activates complement, increases myocardial and cerebral infarct size in rats subjected to coronary or cerebral artery ligation, respectively. Rat CRP does not activate rat complement, whereas human CRP activates both rat and human complement. Administration of human CRP to rats is thus an excellent model for the actions of endogenous human CRP. Here we report the design, synthesis and efficacy of 1,6-bis(phosphocholine)-hexane as a specific small-molecule inhibitor of CRP. Five molecules of this palindromic compound are bound by two pentameric CRP molecules, crosslinking and occluding the ligand-binding B-face of CRP and blocking its functions. Administration of 1,6-bis(phosphocholine)-hexane to rats undergoing acute myocardial infarction abrogated the increase in infarct size and cardiac dysfunction produced by injection of human CRP. Therapeutic inhibition of CRP is thus a promising new approach to cardioprotection in acute myocardial infarction, and may also provide neuroprotection in stroke. Potential wider applications include other inflammatory, infective and tissue-damaging conditions characterized by increased CRP production, in which binding of CRP to exposed ligands in damaged cells may lead to complement-mediated exacerbation of tissue injury.

Polyurea-encapsulated palladium(ii) acetate: a robust and recyclable catalyst for use in conventional and supercritical mediaElectronic supplementary information (ESI) available: representative experimental procedures. See http://www.rsc.org/suppdata/cc/b2/b200677b/

Palladium(II) acetate microencapsulated in polyurea (MC-[Pd]) is an economical and versatile heterogeneous catalyst for a range of phosphine-free cross-coupling reactions in both conventional solvents and supercritical carbon dioxide (scCO2); the catalyst can be recovered by a simple filtration and recycled up to four times.

Inhibition of UDP-Gal Mutase and Mycobacterial Galactan Biosynthesis by Pyrrolidine Analogues of Galactofuranose

Abstract Some pyrrolidine analogues of galactofuranose - synthesised from carbohydrate lactones - are the first known inhibitors of E. coli K12 UDP-Gal mutase and mycobacterial galactan biosynthesis. This inhibition may form a new chemotherapeutic strategy for the treatment of human pathogens which contain integral galactofuranosyl structures such as tuberculosis and leprosy.

Can a C–H···O Interaction Be a Determinant of Conformation?

Whether nonconventional hydrogen bonds, such as the C-H···O interaction, are a consequence or a determinant of conformation is a long-running and unresolved issue. Here we outline a solid-state and quantum mechanical study designed to investigate whether a C-H···O interaction can override the significant trans-planar conformational preferences of α-fluoroamide substituents. A profound change in dihedral angle from trans-planar((OCCF)) to cis-planar((OCCF)) observed on introducing an acceptor group for a C-H···O hydrogen bond is consistent with this interaction functioning as a determinant of conformation in certain systems. This testifies to the potential influence of the C-H···O hydrogen bond and is consistent with the assignment of this interaction as a contributor to overall conformation in both model and natural systems.

An octameric carbopeptoid; secondary structure in octameric and tetrameric 5-aminomethyl-tetrahydrofuran-2-carboxylates

Abstract The efficient synthesis of an octameric furanose carbopeptoid, readily purified by chromatography in ethyl acetate:hexane (2:1), is reported. Extensive NMR studies suggest that two tetrameric 5-aminomethyltetrahydrofuran-2-carboxylates are prone to adopt solution conformations reminiscent of a repeating β-turn, a third tetramer and the corresponding octamer may tend towards a left-handed α-helix.

Palladium-containing perovskites: recoverable and reuseable catalysts for Suzuki couplingsElectronic supplementary information (ESI) available: experimental details. See http://www.rsc.org/suppdata/cc/b3/b308465e/

Palladium-containing perovskites (LaFe0.57Co0.38Pd0.05O3) have been exploited as recoverable and reuseable catalysts in Suzuki coupling reactions; residual levels of Pd after removal of the catalyst by filtration are low (2 ppm) despite evidence that the reaction is occurring via a homogeneous process.

Catalytic Asymmetric 6π Electrocyclization: Enantioselective Synthesis of Functionalized Indolines

(figure represented) How to close a ring: An approach to catalytic asymmetric 6π electrocyclization leads to a highly enantioselective process that was used in the synthesis of chiral indolines (see scheme). Treatment of N-aryl imines under phase transfer conditions in the presence of N-benzyl cinchonidinium chloride generates a delocalized 2-aza-pentadienyl anion system that cyclizes in up to 99% yield and 98% ee.

Glycosylation Catalyzed by a Chiral Brønsted Acid

The use of a chiral Brønsted acid catalyst for the activation of trichloroacetimidate glycosyl donors has been demonstrated for the first time. In toluene the chirality of the acid catalyst is seen to influence the stereochemical outcome of the glycosylation processes, hinting that perhaps diastereocontrol of glycosylation processes may become achievable through the judicious use of chiral organic catalysts.

From sequencamers to foldamers? Tetrameric furanose carbopeptoids from cis- and trans-5-aminomethyl-tetrahydrofuran-2-carboxylates

Abstract The synthesis of three stereoisomeric cis - and trans -5-azidomethyl-tetrahydrofuran-2-carboxylates in which a ketal-protected cis -diol unit is present is described. The monomers undergo efficient oligomerisation to tetrameric carbopeptoids in which the diol protection facilitates ready purification by chromatography which augurs well for the formation of homogeneous higher polymers.

Catalytic enantioselective synthesis of atropisomeric biaryls: a cation-directed nucleophilic aromatic substitution reaction.

A catalytic enantioselective nucleophilic aromatic substitution reaction which yields axially chiral biaryl derivatives in excellent yields with e.r. values of up to 97:3 has been developed. This process uses a chiral counterion to direct the addition of thiophenolate to a prochiral dichloropyrimidine by a tandem desymmetrization/kinetic resolution mechanism. The products can be derivatized to a range of atropisomeric structures without any reduction in enantioenrichment, thus offering access to unexplored chiral biaryl architectures.