- New Antibacterial Agents Derived from the DNA Gyrase Inhibitor Cyclothialidine
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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.
- 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
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p. 1487 - 1513
(2007/10/03)
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- Detritylation Procedure under Non-Acidic Conditions: Naphthalene Catalysed Reductive Cleavage of Trityl Ethers
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The reaction of primary, secondary, allylic and benzylic trityl ethers 1 with lithium powder and a catalytic amount of naphthalene led to reductive cleavage of the trityl-oxygen bond, affording the corresponding alcohols 2 in good to excellent yields under very mild reaction conditions. The detritylation process could successfully be extended to several hydroxy, alkoxy and amino functionalised trityl ethers. This methodology represents a new and efficient detritylation procedure under non-acidic reaction conditions.
- Yus, Miguel,Behloul, Cherif,Guijarro, David
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p. 2179 - 2184
(2007/10/03)
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- Catalytic enantioselective synthesis of macrolides via asymmetric alkylation
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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
- Jones, Graham B.,Huber, Robert S.,Chapman, Brant J.
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p. 1797 - 1809
(2007/10/03)
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- Catalytic enantioselective macrolide synthesis II: Use of differential deprotection protocols
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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
- Jones,Chapman,Huber,Beaty
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p. 1199 - 1202
(2007/10/02)
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