Designing new drugs that inhibit the biosynthesis of the D-arabinan moiety of the mycobacterial cell wall arabinogalactan is one important basic approach for treatment of mycobacterial diseases. However, the biosynthetic origin of the D-arabinosyl monosaccharide residues themselves is not known. To obtain information on this issue, mycobacteria growing in culture were fed glucose labeled with 14 C or 3 H in specific positions. The resulting radiolabeled cell walls were isolated and hydrolyzed, the arabinose and galactose were separated by high-pressure liquid chromatography, and the radioactivity in each sugar was determined. [U- H]glucose were shown to be C-1 and H-5, respectively. These results demonstrated that the arabinose carbon skeleton is formed via the nonoxidative pentose shunt and not via hexose decarboxylation or via triose condensations. Since the pentose shunt product, ribulose-5-phosphate, is converted to arabinose-5-phosphate as the first step in 3-keto-D-manno-octulosonic acid biosynthesis by gram-negative bacteria, such a conversion was then searched for in mycobacteria. However, cell-free enzymatic analysis using both phosphorous nuclear magnetic resonance spectrometry and colorimetric methods failed to detect the conversion. Thus, the conversion of the pentose shunt intermediates to the D-arabino stereochemistry is not via the expected isomerase but rather must occur via novel metabolic transformations.The structure (Fig. 1) of the mycobacterial cell wall arabinan moiety of the arabinogalactan (henceforth referred to simply as arabinan) reveals that it is a very complex branched polysaccharide of arabinofuranosyl (Araf) resides (1). It provides a key structural connection between the peptidoglycan and the mycolic acids (9). Thus, the mycolic acids are attached in a specific fashion to a nonreducing end pentaarabinofuranosideThe reducing end of the arabinan is attached to a galactofuran (1) which is finally attached to the peptidoglycan via the actinomycete-specific linker disaccharide [34-Rha-(133)-GlcNAc-(13phosphate)] (10). This structural information suggests that arabinan is essential for cell wall integrity, and the antimycobacterial activity of ethambutol, an inhibitor of arabinan formation (3, 14), confirms this expectation.In parallel with what is known about the biosynthesis of other polysaccharides (12), it is expected that the arabinan is synthesized via arabinosyltransferases. These enzymes should utilize a 1-phosphorylated arabinose (either an arabinosyl sugar nucleotide or an arabinosyl polyprenyl phosphate) as the donor and the incomplete growing arabinan as the acceptor. Indeed, -D-Araf-monophosphodecaprenol has been isolated and characterized from a variety of mycobacteria (18,19), and it has been demonstrated to function as an arabinosyl donor (7a, 21). It remains unknown if -D-Araf-monophosphodecaprenol is the sole donor of arabinosyl residues or if there is an aqueous soluble arabinosyl nucleotide donor as well. In this regard, a preliminary report of a partially purifie...
A series of 5,5-disubstituted hydantoin derivatives was synthesized by alkylating 5,5-bis(mercaptomethyl)-2,4-imidazolidinedione (3) with various halomethylaromatic or halomethylheteroaromatic precursors, or by using the Buchener-Berg procedure on the required ketone. When evaluated for their ability to inhibit HIV-induced cell killing and virus production in CEM or MT-2 cells only compounds 2, 4n, 4o, and 4i demonstrated modest activity, the latter with an IC50 = 53 microM.
The reactions of levopimaric acid (1) with the activated dienophiles methyl cyanodithioformate (2) and jV-benzoyl-N-phenylcyanothioformamide (3) are reported. The resulting Diels-Alder adducts were then subjected to various reaction conditions, including acid and/or base hydrolysis, permanganate oxidation, and catalytic hydrogenation, where applicable.After reinvestigating the fundamental chemistry of the especially interested in a group of analogous heteroatomic model formaldehyde-levopimaric acid adduct,11 became dienophiles, the activated thiocarbonyls. First of all, these
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