Rational design of novel glycomimetics: inhibitors of concanavalin A.

A virtual screening approach was used to identify new glycomimetics. The National Cancer Institute Diversity Set was docked into the carbohydrate binding site of the lectin concanavalin A (ConA). The resulting poses were analyzed and 19 molecules were tested for inhibition with an enzyme-linked lectin assay (ELLA). Eight of the 19 molecules inhibited ConA-carbohydrate binding. The two most potent inhibitors have IC(50) values that are an order of magnitude smaller than the monosaccharide methyl alpha-D-mannopyranoside.

Discovery of non-carbohydrate inhibitors of aminoglycoside-modifying enzymes.

Chemical modification and inactivation of aminoglycosides by many different enzymes expressed in pathogenic bacteria are the main mechanisms of bacterial resistance to these antibiotics. In this work, we designed inhibitors that contain the 1,3-diamine pharmacophore shared by all aminoglycoside antibiotics that contain the 2-deoxystreptamine ring. A discovery library of molecules was prepared by attaching different side chains to both sides of the 1,3-diamine motif. Several of these diamines showed inhibitory activity toward two or three different representative aminoglycoside-modifying enzymes (AGMEs). These studies yielded the first non-carbohydrate inhibitor N-cyclohexyl-N'-(3-dimethylamino-propyl)-propane-1,3-diamine (Compound G,H) that is competitive with respect to the aminoglycoside binding to the enzyme aminoglycoside-2''-nucleotidyltransferase-Ia (ANT2''). Another diamine molecule N-[2-(3,4-dimethoxyphenyl)-ethyl]-N'-(3-dimethylamino-propyl)-propane-1,3-diamine (Compound H,I) was shown to be a competitive inhibitor of two separate enzymes (aminoglycoside-3'-phosphotransferase-IIIa (APH3') and ANT2'') with respect to metal-ATP. Thermodynamic and structural-binding properties of the complexes of APH3' with substrates and inhibitor were shown to be similar to each other, as determined by isothermal titration calorimetry and NMR spectroscopy.

An NMR and molecular modeling study of carbosilane-based dendrimers functionalized with phenolic groups or titanium complexes at the periphery.

Dendrimers are modified polymers whose architecture is defined by the presence of a central atom or core with multiple branches. These molecules lend themselves to a variety of architectures and uses, including drug delivery and catalysis. The study of the molecular conformations and shapes of dendritic molecules is necessary but not yet routine. Here we present an NMR and molecular modeling study of a series of carbosilane dendrimers, namely 1G-{(CH2)3[C6H3(OMe)]OH}4 (1), 2G-{(CH2)3[C6H3(OMe)]OH}8 (2), and 2G-{(CH2)3[C6H3(OMe)]O[Ti(C5H5)Cl2]}8 (3). Various two-dimensional NMR techniques were used to completely assign the 1H and 13C resonances of molecules 1-3. This information was used, in conjunction with 1H and 13C spin-lattice relaxation measurements, to assess the chain motion of the molecules. The NMR data were also compared with 1-ns molecular dynamics (MD) simulations of 1 and 2 using the MMFF94 force field. The results indicate that these dendrimers possess a core that is motionally decoupled from the rest of the dendrimer, with flexible arm segments that extend from the core. The addition of eight functionalized titanium groups to the ends of the dendrimer chains of 2 to yield molecule 3 serves to further restrict chain motion.

Analysis and glycosyl composition of the exopolysaccharide isolated from the floc-forming wastewater bacterium Thauera sp. MZ1T.

Conditions were developed for the reproducible production, isolation and characterization of a novel microbial extracellular polysaccharide believed to be involved in transient viscous bulking at an industrial wastewater treatment plant. The exopolysaccharide was extracted from cell-free culture supernatants of Thauera sp. strain MZ1T grown on a minimal medium with succinate. The purified polymer was found to be approximately 260 kDa in size by gel-permeation chromatography. The GC-MS analysis of the alditol acetate and per-O-trimethylsilyl methyl glycoside derivatives revealed that the exopolysaccharide was composed of four monosaccharides including: rhamnose, galacturonic acid, N-acetylglucosamine and N-acetylfucosamine. Glucose, which also appeared at low levels, is most likely from a co-eluting glucan. The FTIR and NMR spectroscopic analyses further revealed the presence of esterified component groups on the polymer. These results represent the first published description of a polysaccharide from a member of the genus Thauera, and lay the foundation for a deeper understanding of the factors potentially involved in zoogloeal cluster formation and viscous bulking.

A quenched molecular dynamics-rotating frame Overhauser spectroscopy study of a series of semibiosynthetically monoacylated anthocyanins.

Quenched molecular dynamics (QMD), in conjunction with NMR (ROESY) studies, was used to investigate the conformational behavior of some semibiosynthetic anthocyanins of the type 6-O-acyl-beta-D-Glcp-(166)-beta-D-Galp-(1-->O(3))-cyanidin, with and without a beta-D-Xylp branch at the 2-O-Gal position. These compounds, which are produced by the addition of selected carboxylic acids to growing tissue cultures of Daucus carota (wild carrot), are of interest as color-stabilized anthocyanins, some of which have potential as useful colorants in the nutraceutical and pharmaceutical industries. The QMD-ROESY studies, performed for the first time on anthocyanins, have led to the identification of families of conformers of these flexible molecules that are of interest in work toward determining the mechanism for stabilization of color among these compounds in solution.