Srinivas Banala, R. Süssmuth
Jul 5, 2010
Citations
0
Influential Citations
62
Citations
Journal
ChemBioChem
Abstract
Thioamides are formed by replacing the carbonyl oxygen in an amide bond with sulfur (HN C=S), and have been considered as an isosteric replacement. Biophysicists and medicinal chemists employ thioamide substitutions in the backbone of peptides and other amide-containing compounds. Several examples have been reported that improve stability in proteolytic degradation and improve the ADME properties of amide-containing compounds. 3] In several cases, the thioamide-modified peptides exhibited improved (bio)activity as well. In addition, thioamides are used in biophysical measurements to investigate the structure, stability and conformations of peptides. This is due to the fact that the larger sulfur atom and, thus, the elongated C=S bond (1.67 ) induce conformational changes and a higher rotation barrier around the C N bond. Apart from this, the propensity for hydrogen bond formation is altered in thioamides, as NH is a better Hdonor but C=S is a weaker H-acceptor than in amides. Finally, the thioamide C=S bond has an UV absorption maximum at 265( 5) nm and an IR stretch at 1120( 20) cm , compared to the 220( 5) nm and 1660( 20) cm , respectively, of a C=O amide bond. Moreover, the C NMR shifts differ by ~30 ppm. Practical and simple routes have been developed for the synthesis of thioamides from amides by using phosphorus pentasulfide and Lawesson’s reagent. Remarkably, until recently, only four thioamide compounds were known out of over 170 000 natural products. Though 2 is believed to be an artefact in isolation, cycasthioamide (1) is of plant origin. Only thioviridamide (3) and apo-methanobactin (4, structure revised), 9] are of bacterial origin, isolated from Streptomyces olivoviridis and Methylosinus trichosporium, respectively. Very little is known about secondary metabolites from anaerobic bacteria. 11] The genus Clostridium, which is known for its pathogenic strains C. botulinum and C. tetani, contains about 150 metabolically diverse anaerobic species wherever organic matter—including soils, aquatic sediments and the intestinal tracts of animals and humans—is present. Clostridium cellulolyticum is an obligate, anaerobic, Gram-positive bacterium and it represents an important industrial strain due to its ability to degrade crystalline cellulose. However, until recently, no C. cellulolyticum secondary metabolites were known from standard laboratory cultures. Upon genomic analysis, Hertweck and colleagues expected that some of these genes could be responsible for secondary metabolites, but that they were in a latent phase in standard cultures. Therefore C. cellulolyticum was grown to activate latent genes by employing external triggers, such as chemical supplements and pH and temperature stress ; however, initially without success. As C. cellulolyticum has as its natural habitat decayed grass or soil compost, natural conditions were induced by adding aqueous soil extracts to the cultures. From these cultures a new all-thioamide compound, named closthioamide (5), has been isolated. Its structure was elucidated by HRMS and NMR spectroscopy and found to contain six thioamides. This seemingly simple, symmetric, twin, drug-like hexathioamide, which is assembled mainly from b-alanine and 4-hydroxy benzoic acid analogues, showed good antibacterial activity (MIC = 0.58 mm) in methillicin-resistant Staphylococcus aureus (MRSA) strains as well as vancomycin-resistant Enterococcus faecalis (VRE) strains. Its antibacterial activity surpassed [a] Dr. S. Banala, Prof. Dr. R. D. S ssmuth Institut f r Chemie Strasse des 17. Juni, 124/TC 2, 10623 Berlin (Germany) Fax: (+ 49) 30-314-79651 E-mail : suessmuth@chem.tu-berlin.de