157730-79-5Relevant academic research and scientific papers
New Antibacterial Agents Derived from the DNA Gyrase Inhibitor Cyclothialidine
Angehrn, Peter,Buchmann, Stefan,Funk, Christoph,Goetschi, Erwin,Gmuender, Hans,Hebeisen, Paul,Kostrewa, Dirk,Link, Helmut,Luebbers, Thomas,Masciadri, Raffaello,Nielsen, Joergen,Reindl, Peter,Ricklin, Fabienne,Schmitt-Hoffmann, Anne,Theil, Frank-Peter
, p. 1487 - 1513 (2007/10/03)
Cyclothialidine (1, Ro 09-1437) is a potent DNA gyrase inhibitor that was isolated from Streptomyces filipinensis NR0484 and is a member of a new family of natural products. It acts by competitively inhibiting the ATPase activity exerted by the B subunit of DNA gyrase but barely exhibits any growth inhibitory activity against intact bacterial cells, presumably due to insufficient permeation of the cytoplasmic membrane. To explore the antibacterial potential of 1, we developed a flexible synthetic route allowing for the systematic modification of its structure. From a first set of analogues, structure-activity relationships (SAR) were established for different substitution patterns, and the 14-hydroxylated, bicyclic core (X) of 1 seemed to be the structural prerequisite for DNA gyrase inhibitory activity. The variation of the lactone ring size, however, revealed that activity can be found among 11- to 16-membered lactones, and even seco-analogues were shown to maintain some enzyme inhibitory properties, thereby reducing the minimal structural requirements to a rather simple, hydroxylated benzyl sulfide (XI). On the basis of these "minimal structures" a modification program afforded a number of inhibitors that showed in vitro activity against Gram-positive bacteria. The best activities were displayed by 14-membered lactones, and representatives of this subclass exhibit excellent and broad in vitro antibacterial activity against Gram-positive pathogens, including Staphylococcus aureus, Streptococcus pyogenes, and Enterococcus faecalis, and overcome resistance against clinically used drugs. By improving the pharmacokinetic properties of the most active compounds (94, 97), in particular by lowering their lipophilic properties, we were able to identify congeners of cyclothialidine (1) that showed efficacy in vivo.
Catalytic enantioselective synthesis of macrolides via asymmetric alkylation
Jones, Graham B.,Huber, Robert S.,Chapman, Brant J.
, p. 1797 - 1809 (2007/10/03)
Catalytic enantioselective syntheses of the macrolides (R)-(-) phoracantholide and (R)-(+) lasiodiplodin have been achieved. Stereochemistry was introduced in using an arene chromium tricarbonyl derived catalyst, which mediated the enantioselective additi
Catalytic enantioselective macrolide synthesis II: Use of differential deprotection protocols
Jones,Chapman,Huber,Beaty
, p. 1199 - 1202 (2007/10/02)
Catalytic enantioselective synthesis of Phorcantholide I has been achieved. Key stereochemistry was introduced using a chiral arene chromium tricarbonyl based catalyst to mediate the addition of dimethyl zinc to a functionalised aldehyde. During the synth
