Todd Ashley Houston

In Vitro Activity of a Novel Antimycobacterial Compound, N-Octanesulfonylacetamide, and Its Effects on Lipid and Mycolic Acid Synthesis

ABSTRACT β-Sulfonyl carboxamides have been proposed to serve as transition-state analogues of the β-ketoacyl synthase reaction involved in fatty acid elongation. We tested the efficacy ofN-octanesulfonylacetamide (OSA) as an inhibitor of fatty acid and mycolic acid biosynthesis in mycobacteria. Using the BACTEC radiometric growth system, we observed that OSA inhibits the growth of several species of slow-growing mycobacteria, includingMycobacterium tuberculosis (H37Rv and clinical isolates), the Mycobacterium avium complex (MAC), Mycobacterium bovis BCG, Mycobacterium kansasii, and others. Nearly all species and strains tested, including isoniazid and multidrug resistant isolates of M. tuberculosis, were susceptible to OSA, with MICs ranging from 6.25 to 12.5 μg/ml. Only three clinical isolates of M. tuberculosis (CSU93, OT2724, and 401296), MAC, and Mycobacterium paratuberculosis required an OSA MIC higher than 25.0 μg/ml. Rapid-growing mycobacterial species, such asMycobacterium smegmatis, Mycobacterium fortuitum, and others, were not susceptible at concentrations of up to 100 μg/ml. A 2-dimensional thin-layer chromatography system showed that OSA treatment resulted in a significant decrease in all species of mycolic acids present in BCG. In contrast, mycolic acids in M. smegmatis were relatively unaffected following exposure to OSA. Other lipids, including polar and nonpolar extractable classes, were unchanged following exposure to OSA in both BCG and M. smegmatis. Transmission electron microscopy of OSA-treated BCG cells revealed a disruption in cell wall synthesis and incomplete septum formation. Our results indicate that OSA inhibits the growth of several species of mycobacteria, including both isoniazid-resistant and multidrug resistant strains of M. tuberculosis. This inhibition may be the result of OSA-mediated effects on mycolic acid synthesis in slow-growing mycobacteria or inhibition via an undescribed mechanism. Our results indicate that OSA may serve as a promising lead compound for future antituberculous drug development.

Boronolectin with divergent fluorescent response specific for free sialic acid

A fluorescent boronate receptor with a unique response to free sialic acid has been developed; this divergent response system may find use in design of other fluorophores to discriminate between structurally similar analytes.

Tapping into Boron/α-Hydroxycarboxylic Acid Interactions in Sensing and Catalysis

Whereas interaction of boron acids (boric and boronic) with diols and neutral sugar ligands has received much global research attention in recent years, the binding of simple α-hydroxycarboxylic and sugar acids by boron has received less attention. Applications of boron-based fluorescent sensors and chemoselective catalysts targeting this functional motif have appeared only in the past 5 years. The present synopsis will focus on rapid developments that have occurred in both areas during this half decade.

A drug targeting motif for glycosidase inhibitors: an iminosugar–boronate shows unexpectedly selective β-galactosidase inhibition

Abstract Boronic acids were tethered to iminosugars in compounds such as 8 and 13 in order to increase their affinity for cell surfaces where glycoprotein processing enzymes are operative. Surprisingly, this modification diminished α-mannosidase inhibition while increasing β-galactosidase inhibitory activity ( 8 : K i =2.0×10 −4 M versus E. coli β-galactosidase). The presence of a boronate in 8 and 13 has a profound impact on the specificity of this inhibition.

Boronate derivatives of bioactive amines: potential neutral receptors for anionic oligosaccharides

Abstract Oligomeric δ-aminoboronates were synthesized via reductive amination of o -formylbenzene boronic acid with several polymines. The process entails the direct addition of o -formylbenzene boronic acid to the polyamine in methanol at room temperature followed by reduction of the resulting imine with NaBH 4 . Di-, tri-, and tetrameric δ-aminoboronates have been prepared in this manner and these are anticipated to have enhanced affinities for certain oligosaccharides. A novel templating method for the synthesis of these compounds is also described.

Back to (non)-Basics: Recent developments in neutral and charge-balanced glycosidase inhibitors

Certain glycosidase inhibitors possess potent antiviral, antitumour and antidiabetic properties. Glyconic acid lactones, the earliest glycosidase inhibitors identified, have planar anomeric carbons that mimic the transition state of glycoside hydrolysis. Other classes include lactams, glycals, epoxides, halides and sulfonium ions, the latter based on the natural product salacinol from an antidiabetic herb.

Selective Monoesterification of Malonic Acid Catalyzed by Boric Acid

Boric acid catalyzes the monoesterification of malonic acid, likely through a chelation mechanism that is not available to the monoester product. Under more forcing conditions, diesters form to some extent, but conditions can be optimized to favour the monoester product (56-80%). With the easily handled solid acid catalyst, these reactions can be run with excess alcohol as solvent or with stoichiometric amounts of alcohol in acetonitrile with moderate heating.

Boron-Carbohydrate Interactions

Boron-polyol interactions are of fundamental importance to human health [1], plant growth [2] and quorum sensing among certain bacteria [3]. Such diversity is perhaps not surprising when one considers boron is one of the ten most abundant elements in sea water and carbohydrates make up the planet’s most abundant class of biomass. Several boronic acids matrices are commercially available for the purification of glycoproteins by affinity chromatography [4], and boronic acids are also useful carbohydrate protecting groups.[5,6] Recently, complexes between boron and sugars have become a lynchpin for the development of synthetic carbohydrate receptors.[7] These complexes involve covalent interactions that are reversible in aqueous solution. This chapter reviews current understanding of these processes, provides a historical perspective on their discovery, identifies methods for studying these complexes and classifies these interactions by carbohydrate type. Such information is key to the design and synthesis of synthetic lectins, also termed “boronolectins” when containing boron [7].

Developing High-Affinity Boron-Based Receptors for Cell-Surface Carbohydrates

Humans have sought inspiration from nature since the beginning of recorded history. For today’s scientists, biological systems are replete with molecular recognition events of awe-inspiring specificity. Contrary to amino and nucleic acids, carbohydrates tend to behave as elusive ligands toward their natural receptors, such as the lectin family. Nature has overcome the generally modest affinity of proteins for monosaccharides through multivalent binding mechanisms. Not only does this provide an increase in the association constant of binding, but it also amplifies selectivity among structurally similar carbohydrates. The design of synthetic receptors for specific sugar structures presents a daunting challenge that we have yet to master.

Redox state influence on human galectin-1 function

Intracellular and extracellular functions of human galectin-1 are influenced by its redox surroundings due to the presence of six cysteines within its amino acid sequence. Galectin-1 recognises intracellular-membrane-anchored Ras proteins that act as molecular switches regulating multiple signal transduction pathways. Human tumours frequently express Ras proteins that have become continuously activated due to point mutations, and this typically leads to deregulation of tumour cell growth, angiogenesis and invasion of metastatic cancer cells. Of significance is that galectin-1 preferably recognises H-Ras, one of the human Ras isoforms, and in particular galectin-1 recognition of the H-Ras farnesyl moiety is paramount to H-Ras membrane anchorage, a prerequisite step for H-Ras-mediated signal transduction regulating normal cell growth and malignant transformation. Herein the impact of the redox state on galectin-1s ability to interact with farnesyl analogues is explored. We demonstrate for the first time that reduced galectin-1 directly binds farnesyl and does so in a carbohydrate-independent manner. A K28T mutation abolishes farnesyl recognition by reduced dimeric galectin-1 whilst its carbohydrate-binding activity is retained, thus demonstrating the presence of an independent region on galectin-1 pertaining to growth inhibitory activity. Intriguingly, oxidised galectin-1 also recognises farnesyl, the biological implication of this novel finding is yet to be elucidated. Further, the redox effect on galectin-1 extracellular function was investigated and we discover that oxidised galectin-1 demonstrates a protective effect upon acute lymphoblastic leukaemia cells challenged by oxidative stress.