Inhibitory Evaluation of αPMM/PGM from Pseudomonas aeruginosa: Chemical Synthesis, Enzyme Kinetics, and Protein Crystallographic Study.

α-Phosphomannomutase/phosphoglucomutase (αPMM/PGM) from P. aeruginosa is involved in bacterial cell wall assembly and is implicated in P. aeruginosa virulence, yet few studies have addressed αPMM/PGM inhibition from this important Gram-negative bacterial human pathogen. Four structurally different α-d-glucopyranose 1-phosphate (αG1P) derivatives including 1-C-fluoromethylated analogues (1-3), 1,2-cyclic phosph(on)ate analogues (4-6), isosteric methylene phosphono analogues (7 and 8), and 6-fluoro-αG1P (9), were synthesized and assessed as potential time-dependent or reversible αPMM/PGM inhibitors. The resulting kinetic data were consistent with the crystallographic structures of the highly homologous Xanthomonas citri αPGM with inhibitors 3 and 7-9 binding to the enzyme active site (1.65-1.9 Å). These structural and kinetic insights will enhance the design of future αPMM/PGM inhibitors.

A step-wise synthetic approach is necessary to access γ-conjugates of folate: folate-conjugated prodigiosenes.

Despite the vast literature that describes reacting folic acid with a pharmacophore, this route is ineffective in providing the correct regioisomer of the resulting conjugate. We herein present a step-wise route to the preparation of nine folate conjugates of the tripyrrolic prodigiosene skeleton. The strict requirement for step-wise construction of the folate core is demonstrated, so as to achieve conjugation at only the desired γ-carboxylic acid and thus maintain the α-carboxylic site for folate receptor (FRα) recognition. Linkages via ethylenediamine, polyethylene glycol and glutathione are demonstrated.

Deuteration and tautomeric reactivity of the 1-methyl functionality of free-base dipyrrins.

Regioselective reactivity of the 1-methyl group of free-base dipyrrins is explored, including discussion of tautomerism to provide exocyclic alkenyl reactivity. Deuterium is installed so as to generate dipyrrins substituted with deuterated methyl groups. Furthermore, the 1-methyl group reacts to become involved in C-C bonds involving only sp3-hybridised carbon atoms. The isolation of an elusive framework featuring a dipyrrin substituted with a pyrrole in a non-vinylogous fashion is also reported. The use of asymmetric dipyrrins featuring an electron-withdrawing group on one of the pyrrolic units results in regioselective reaction of the alpha-methyl group distal to the electron-withdrawing group.

Chiral induction at octahedral Ru(II) via the disassembly of diruthenium(II,III) tetracarboxylates using a variety of chiral diphosphine ligands.

Achiral [Ru2(µ-O2CR)4(MeOH)2](PF6) (R = CH3 or C6H5) reacts with the chiral diphosphines R,R- and S,S-Chiraphos (two chiral centers on ligand between the coordinating P atoms) and R-Prophos (one chiral center on ligand between the coordinating P atoms) leading to a disassembly of the paddlewheel core and the highly diastereoselective production of Λ-[Ru(η(2)-O2CC6H5)(η(2)-R,R-Chiraphos)2](PF6) (Λ-R,R-III), Δ-[Ru(η(2)-O2CC6H5)(η(2)-S,S-Chiraphos)2](PF6) (Δ-S,S-III) (the R = CH3 complexes of Chiraphos were reported in a earlier communication in this journal), and Λ-[Ru(η(2)-O2CCH3)(η(2)-R-Prophos)2](PF6) (Λ-R,R-VI), respectively, in high yield and purity. Reactions of the same starting material with R,R- and S,S-o-tolyl-Dipamp (chiral centers are the coordinating P-atoms) lead to an inversion in the chirality-at-metal producing Λ-[Ru(η(2)-O2CC6H5)(η(2)-S,S-o-tolyl-Dipamp)2](PF6) (Λ-S,S-IV), Δ-[Ru(η(2)-O2CC6H5)(η(2)-R,R-o-tolyl-Dipamp)2](PF6) (Δ-R,R-IV), Λ-[Ru(η(2)-O2CCH3)(η(2)-S,S-o-tolyl-Dipamp)2](PF6) (Λ-S,S-V), and Δ-[Ru(η(2)-O2CCH3)(η(2)-R,R-o-tolyl-Dipamp)2](PF6) (Δ-R,R-V). X-ray crystallography of all but Λ-S,S-V and Δ-R,R-V and solid-state circular dichroism (CD) show that only the indicated diastereomers are present in the solid-state. Solution CD measurements and (31)P NMR also indicate their predominance in solution.

Synthetic prodigiosenes and the influence of C-ring substitution on DNA cleavage, transmembrane chloride transport and basicity.

Analogues of the tripyrrolic natural product prodigiosin bearing an additional methyl and a carbonyl group at the C-ring were synthesised and evaluated. In vitro anticancer activity screening (NCI) and the study of modes of action (copper-mediated cleavage of double-stranded DNA and transmembrane transport of chloride anions) showed that the presence of the methyl group is not detrimental to activity. Furthermore, although the presence of an ester conjugated to the prodigiosene C-ring seems to decrease both pK(a) and chloride transport efficiency compared to the natural product, these analogues still exhibit a high rate of chloride transport. All analogues exhibit good in vitro anticancer activity and reduced toxicity compared to the natural product: compare an acute systemic toxicity of 100 mg kg(-1) in mice vs. 4 mg kg(-1) for prodigiosin, pointing towards a larger therapeutic window than for the natural product.

Synthesis and characterisation of the unsubstituted dipyrrin and 4,4-dichloro-4-bora-3a,4a-diaza-s-indacene: improved synthesis and functionalisation of the simplest BODIPY framework.

An improved and scalable synthesis of the unsubstituted 4,4-difluoro-4-bora-3a,4a-diaza-s-indacene framework facilitates access to the previously unreported parent dipyrrin HCl salt, as well as 4,4-dichloro-4-bora-3a,4a-diaza-s-indacene.