676347-01-6

Upstream product

• 67373-56-2 chlorodimethyl(1,1,2-trimethylpropyl)silane 
• 676346-98-8 4-nitrobenzyl 3-hydroxy-2,6-dimethylbenzoate 
• 100-11-8 1-bromomethyl-4-nitro-benzene 
• 90536-18-8 3-hydroxy-2,6-dimethylbenzoic acid 

Downstream Products

• 676347-07-2 methyl N-(N-tert-butoxycarbonyl-L-seryl)-S-[4-(dimethyl(thexyl)silyloxy)-2-((4-nitrobenzyloxycarbonyl)-3-methylbenzyl)]-L-cysteinate 
• 676347-06-1 methyl N-(N-tert-butoxycarbonyl-L-seryl)-S-[6-(dimethyl(thexyl)silyloxy)-2-((4-nitrobenzyloxycarbonyl)-3-methylbenzyl)]-L-cysteinate 

Relevant academic research and scientific papers

New Antibacterial Agents Derived from the DNA Gyrase Inhibitor Cyclothialidine

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.

Chemical Synthesis of CD52 Glycopeptides Containing the Acid-Labile Fucosyl Linkage

Glycopeptide 1 with the fucosylated trisaccharide, β-D-GlcNAc(1→ 4)[α-L-Fuc(1→6)]-β-D-GlcNAc, linked to the Asn of CD52 peptide was prepared by two methods, both of which used the free glycosyl Asn 12 and glycotripeptide 21 as key intermediates. Thus, after the trisaccharide was prepared and linked to Asn, the carbohydrate moiety was deprotected to give 12. From 12, 21 was constructed in homogeneous NMP solutions by elongating the peptide chain alone the N-terminus. Though the glycopeptides were easily soluble in NMP, they were barely soluble in diethyl ether, because of the free trisaccharide. Consequently, addition of diethyl ether to the reaction mixtures could precipitate the glycopeptides, and the products were conveniently isolated and purified in the solid form. The coupling of 21 with a free nonapeptide 24 in NMP afforded 1. 1 was also prepared by solid-phase synthesis, using the acid-sensitive 2-chlorotrityl resin. In this case, 21 was attached to the nonapeptide on the resin, and the resulting glycopeptide was then released with dilute acetic acid. Deprotection of the peptide under moderate acidic conditions gave 1. The acid-labile α-fucose was not affected in these syntheses.