Conformationally rigid aromatic amino acids as potential building blocks for abiotic foldamers

This communication describes the development of conformationally constrained unnatural aromatic amino acids, constructed on rigid backbone wherein the carboxyl and amino groups project in two dimensions (planes) on the aromatic framework. Such a feature offers the possibility of design and development of conformationally ordered synthetic oligomers with intriguing structural architectures distinct from those classically observed. Furthermore, such amino acids will have the potential to extend the conformational space available for foldamer design with diverse backbone conformation and structural architectures.     

Separation of lead sulphate from barium sulphate in their determination in glass

The conventional method for separation of lead from a combined lead and barium sulphate precipitate by extraction with ammonium acetate has been critically studied. The results show that quantitative separation of lead is possible only when the molar concentration ratio of barium to lead is 4.2 or above, but at ratios below 4.2 the method fails because of the formation of a solid solution of lead and barium sulphates which is maximal at initial mole-ratio 0.42. The lead in the solid solution, however, forms a strong soluble complex with EDTA and can be quantitatively separated. Based on this, a gravimetric method has been worked out for determination of lead and barium in glass.     

Grafting of monosaccharide derivatives to cellulose acetate

Grafting of 1,2-O-isopropylidene-α-D -xylofuranose to commercial cellulose diacetate has been accomplished by using a boron trifluoride catalyst. The reaction proceeds quickly at 25 and 40°C, resulting in degrees of molar substitution (MS) of 0.37 and 0.34, respectively. If monomer and catalyst are added over an extended period of time to maintain low concentrations, MS values as high as 0.89 and 0.85 are obtained at 25 and 40°C, respectively. Major side reactions are depolymerization of the cellulose acetate backbone and grafted D -xylose and the homopolymerization of the monomer. These side reactions may be minimized by conducting the reaction at 40°C for a short time or by adding monomer and catalyst over an extended period of time. Grafting has also been accomplished by using D -xylose derivatives with various reactive groups at the anomeric carbon atom. The grafted material of MS greater than 0.7 is insoluble in acetone and after deacetylation is soluble in water under alkaline, neutral and acidic conditions. Oxalic acid hydrolysis of the deacetylated material indicates that most of the grafted D -xylose units are in the furanose form. Methylation and hydrolysis of the methylated material shows that 75% of the D -xylose residues are terminal units and indicates the presence of many singly grafted D -xylose residues and a few di-and trisaccharide grafts.     

Molecular dynamics of 5-HT1A and 5-HT2A serotonin receptors with methylated buspirone analogues

In the present study experimentally determined ligand selectivity of three methylated buspirone analogues (denoted as MM2, MM5 and P55) towards 5-HT_1A and 5-HT_2A serotonin receptors was theoretically investigated on a molecular level. The relationships between the ligand structure and 5-HT_1A and 5-HT_2A receptor affinities were studied and the results were found to be in agreement with the available site-directed mutagenesis and binding affinity data. Molecular dynamics (MD) simulations of ligand-receptor complexes were performed for each investigated analogue, docked twice into the central cavity of 5-HT_1A/5-HT_2A, each time in a different orientation. Present results were compared with our previous theoretical results, obtained for buspirone and its non-methylated analogues. It was found that due to the presence of the methyl group in the piperazine ring the ligand position alters and the structure of the ligand-receptor complex is modified. Further, the positions of derivatives with pyrimidinyl aromatic moiety and quinolinyl moiety are significantly different at the 5-HT_2A receptor. Thus, methylation of such derivatives alters the 3D structures of ligand-receptor complexes in different ways. The ligand-induced changes of the receptor structures were also analysed. The obtained results suggest, that helical domains of both receptors have different dynamical behaviour. Moreover, both location and topography of putative binding sites for buspirone analogues are different at 5-HT_1A and 5-HT_2A receptors.     

A Polyketide Synthase Component for Oxygen Insertion into Polyketide Backbones

Enzymatic core components from trans‐acyltransferase polyketide synthases (trans‐AT PKSs) catalyze exceptionally diverse biosynthetic transformations to generate structurally complex bioactive compounds. Here we focus on a group of oxygenases identified in various trans‐AT PKS pathways, including those for pederin, oocydins, and toblerols. Using the oocydin pathway homologue (OocK) from Serratia plymuthica 4Rx13 and N‐acetylcysteamine (SNAC) thioesters as test surrogates for acyl carrier protein (ACP)‐tethered intermediates, we show that the enzyme inserts oxygen into β‐ketoacyl moieties to yield malonyl ester SNAC products. Based on these data and the identification of a non‐hydrolyzed oocydin congener with retained ester moiety, we propose a unified biosynthetic pathway of oocydins, haterumalides, and biselides. By providing access to internal ester, carboxylate pseudostarter, and terminal hydroxyl functions, oxygen insertion into polyketide backbones greatly expands the biosynthetic scope of PKSs.     

Calcium Alginate Bead-mediated Enhancement of the Selective Recovery of a Lead Novel Antifungal Bacillomycin Variant

In the pursuit of new antifungal compounds, five coproduced lipopeptide variants (AF₁ to AF₅) from wild-type Bacillus subtilis RLID 12.1 were identified in our previous study. Out of five, AF₄ was identified as a novel lead molecule belonging to the bacillomycin family showing less cytotoxicity at its respective minimum inhibitory concentrations (MIC) evaluated against 81 strains of Candida and Cryptococcus species (including clinical isolates); besides this, AF₄ purified in the present study exhibited encouraging MIC values against 10 clinical mycelial fungi. Aiming for a selective production augmentation of AF₄ lipopeptide variant, a new fermentation media comprising malt extract (1.01%), dextrose (0.55%), peptone (1.79%), MnSO₄ (2 mM), and NaCl (0.5%) was formulated. Maximum production of 954.8?±?10.8 mg/L was achieved with 44% selectivity at 30 °C compared to unoptimized conditions (186.4?±?6.1 mg/L). Use of calcium alginate beads in the formulated media during the onset of lipopeptide production resulted in an augmentation in the selectivity of the most efficacious AF₄ variant to about 72% presumably due to attenuation of other coproduced lipopeptide variants AF₁ and AF₂. Difference in yield of lipopeptides varied with bead size, bead preparation ratios, and sodium alginate concentrations. Use of Ca-alginate beads in the upstream production process of the lead AF₄ variant may be considered as a novel strategy to address the potential challenge that may arise during the scale-up and downstream processing steps. Another significant finding derived from the study is that the proportion of bacillomycin variants of B. subtilis RLID 12.1 could be controlled by temperature and metal ions under static and shaking conditions.     

Synthesis of conjugated diacetylene, metal-chelating monomers for polymerizable monolayer assemblies

[see structure]. Self-assembled monolayers (SAMs) of thiols on gold have been used for numerous applications. For protein targeting applications, one successful strategy is to use a metal-chelating SAM. It has also been demonstrated that polymerized SAMs are much more stable than non-polymerized counterparts. We report herein, the synthesis of several polymerizable, metal-chelating thiols capable of complexing luminescent lanthanide ions.     

New Factorial Designs to Evaluate Chemisorption of Divalent Metals on Aminated Silicas

Adsorption processes of Cu(II), Co(II), and Hg(II) on two aminated silica gel surfaces with immobilized ethylenediamine and diethylenediamine groups were studied by a new 2(3) full factorial design. Two metal quantity levels, temperatures of 25 and 50 degrees C, and silica amounts of 100 and 200 mg were employed. Our study indicates that higher factorial design levels increase adsorption for all metals evaluated, with the exception of the mass parameter. Adsorption is also significantly affected by important antagonistic and synergistic effects involving all factors. Both functionalized silica gel surfaces present higher interactions and good perspectives in preconcentration studies for mercury. The factorial design results are also discussed in terms of some solvation properties for each of the metals studied. Copyright 2001 Academic Press.