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The syntheses of 3-(1-methyl-1 H -imidazol-2-ylthio)acrylic acid and 3-(1-methyl-1 H -imidazol-2-ylthio)propanoic acid, mitochondria-targeted prodrugs of the antioxidant methimazole, are described. The method of Fan et al. (Fan et al., Synthesis 2006 , 2286) for the reaction of phenols with propiolic acid and propiolate esters was modified to synthesize ( E )-3-(1-methyl-1 H -imidazol-2-ylthio)acrylic acid. The intermediate tert -butyl ( E )-3-(1-methyl-1 H -imidazol-2-ylthio)acrylate was prepared by the reaction of tert -butyl propiolate with methimazole; the use of tert -butyl propiolate rather than methyl propiolate gave tert -butyl ( E )-3-(1-methyl-1 H -imidazol-2-ylthio)acrylate as the predominant isomer. Acid hydrolysis of the intermediate ester afforded the target compound. 3-(1-Methyl-1 H -imidazol-2-ylthio)propanoic acid was synthesized from 3-bromopropanoic acid and methimazole under conditions that gave preferential substitution on sulfur and minimized substitution on nitrogen.

The carbazole assay is commonly employed to quantify heparin and other uronic acid-containing polysaccharides. Heparin-derived standard curves are often employed to quantify solutions of various natural and unnatural heparin structures that have different levels of sulfate substitution, different levels of N-sulfo and N-acetyl groups, and other structural changes as a consequence of reducing molecular weight. Recent studies in our laboratory have focused on chemically modified heparin derivatives comprised of structurally diverse N-acyl moieties substituted into heparin in place of N-sulfo groups. We report here that although differing degrees of 2-N-sulfo-, 2-N-acetyl- or 2-amino-d-glucosamine residues within heparin do not affect signal intensity in the carbazole assay, replacing N-sulfo groups in heparin with structurally diverse N-acyl moieties affords products that display significant variation in the assay. The structure of different N-acyl groups, and to a lesser extent the degree of N-acylation by individual N-acyl groups, is shown to variably alter signal intensity in the carbazole assay even though content and structure of uronic acid residues is unaltered.

The glycosaminoglycan heparin is a polyanionic polysaccharide most recognized for its anticoagulant activity. Heparin binds to cationic regions in hundreds of prokaryotic and eukaryotic proteins, termed heparin-binding proteins. The endogenous ligand for many of these heparin-binding proteins is a structurally similar glycosaminoglycan, heparan sulfate (HS). Chemical and biosynthetic modifications of heparin and HS have been employed to discern specific sequences and charge-substitution patterns required for these polysaccharides to bind specific proteins, with the goal of understanding structural requirements for protein binding well enough to elucidate the function of the saccharide-protein interactions and/or to develop new or improved heparin-based pharmaceuticals. The most common modifications to heparin structure have been alteration of sulfate substitution patterns, carboxyl reduction, replacement N-sulfo groups with N-acetyl groups, and chain fragmentation. However, an accumulation of reports over the past 50 years describe semi-synthetic heparin derivatives obtained by incorporating aliphatic, aryl, and heteroaryl moieties into the heparin structure. A primary goal in many of these reports has been to identify heparin-derived structures as new or improved heparin-based therapeutics. Presented here is a perspective on the introduction of non-anionic structural motifs into heparin structure, with a focus on such modifications as a strategy to generate novel reduced-charge heparin-based bind-and-block antagonists of HS-protein interactions. The chemical methods employed to synthesize such derivatives, as well as other unique heparin conjugates, are reviewed.

Quinolones were examined for rapid lethal activity against Mycobacterium smegmatis in the presence and absence of chloramphenicol, an inhibitor of protein synthesis. C-8 methoxy, C-6 fluorine, and particular C-7 ring substituents enhanced rapid killing. With the surprising exception of moxifloxacin, higher quinolone concentrations were required for lethal activity in the presence of chloramphenicol than in its absence. Moxifloxacin was also unusual in lacking the time lag characteristic of fluoroquinolone lethality. Several fluoroquinolone dimers, which represent quinolones with large C-7 substituents, showed modest bacteriostatic activity. Unlike other quinolones, the dimers failed to display lethal activity. The insensitivity of moxifloxacin to chloramphenicol has not been observed with other bacteria and may therefore reflect unique aspects of mycobacterial gyrase.

A series of N-methylated polyarylurea oligomers have been reduced with potassium metal in HMPA. These reductions result in the transient formation of arylurea anion radicals, which undergo reductive elimination of the urea linkages. The aryl moieties appear in the products as the anion radicals of oligoaryl systems. The reaction is intramolecular, and the sequencing in the polyaryl anion radical remains the same as in the polyarylureas due to the urea-enforced pi-pi stacking interactions.

The one-electron reduction of tertiary N,N'-dimethyl-N,N'-diarylureas (aryl = phenyl, beta-naphthyl, alpha-naphthyl), in HMPA, results in anion radicals that undergo novel intramolecular reductive elimination reactions leading to the formation of the anion radicals of the corresponding biaryls. These results are due to face to face pi-pi stacking interactions involving the two aromatic rings in the urea systems. The overlapping p(pi)() orbitals on the ipso carbons of opposing aryl groups evolve into a sigma bond leading to the formation of the biaryl anion radical. In the case of the N,N'-dimethyl-N,N'-di-2-pyrenylurea system, there is a node in the LUMO of the number 2 carbon, and the parent anion radical remains intact.