This Minireview highlights recent advances in the field of aryne and cyclohexyne chemistry that have allowed the extraordinary reactivity of these entities to be harnessed during the course of natural product syntheses. The syntheses presented rely on the use of these reactive species in chemoselective transformations and follow unprecedented synthetic strategies that are inspiring for the practitioners of synthetic organic chemistry.

There is a dichotomy between the increasing utility of aldehydes as tool molecules that bind to “undruggable” protein sites and the designation of the aldehyde functional group as a structural alert by the medicinal chemistry community. Herein we compile information about pharmacologically active aldehydes that are being used in humans. We summarize the learnings from these data, discuss advantages and challenges associated with aldehydes, and derive strategies for the successful development of aldehydes within drug discovery programs.

New antibiotic drugs need to be identified to address rapidly developing resistance of bacterial pathogens to common antibiotics. The natural antibiotic moenomycin A is the prototype for compounds that bind to bacterial peptidoglycan glycosyltransferases (PGTs) and inhibit cell wall biosynthesis, but it cannot be used as a drug. Here we report the chemoenzymatic synthesis of a fluorescently-labeled, truncated analog of moenomycin based on the minimal pharmacophore. This probe, which has optimized enzyme binding properties compared to moenomycin, was designed to identify low micromolar inhibitors that bind to conserved features in PGT active sites. We demonstrate its use in displacement assays using PGTs from S. aureus, E. faecalis, and E. coli. 110,000 compounds were screened against S. aureus SgtB, and we identified a non-carbohydrate based compound that binds to all PGTs tested. We also show that the compound inhibits in vitro formation of peptidoglycan chains by several different PGTs. Thus, this assay enables the identification of small molecules that target PGT active sites, and may provide lead compounds for development of new antibiotics.

No abstract

We present a flexible, modular route to GlcNAc-MurNAc-oligosaccharides that can be readily converted into peptidoglycan (PG) fragments to serve as reagents for the study of bacterial enzymes that are targets for antibiotics. Demonstrating the utility of these synthetic PG substrates, we show that the tetrasaccharide substrate lipid IV (3), but not the disaccharide substrate lipid II (2), significantly increases the concentration of moenomycin A required to inhibit a prototypical PG-glycosyltransferase (PGT). These results imply that lipid IV and moenomycin A bind to the same site on the enzyme. We also show the moenomycin A inhibits the formation of elongated polysaccharide product but does not affect length distribution. We conclude that moenomycin A blocks PG-strand initiation rather than elongation or chain termination. Synthetic access to diphospholipid oligosaccharides will enable further studies of bacterial cell wall synthesis with the long-term goal of identifying novel antibiotics.