An asymmetric synthesis of the tubulin polymerisation inhibitor (S)-(-)-N-acetylcolchinol is reported based on an intramolecular biaryl oxidative coupling of a 1,3-diarylpropyl acetamide intermediate using phenyliodonium bis(trifluoroacetate) as the final step. Three syntheses of the penultimate 1,3-diarylpropyl acetamide intermediate (S)-(-)-N-[1-[3-(tert-butyldimethylsilyloxy)phenyl)]-3-(3,4,5-trimethoxyphenyl)propyl] acetamide are described which differ in the means by which the stereogenic centre was introduced.
Peptidoglycan is an essential component of the bacterial cell wall and provides the structural integrity necessary to resist internal osmotic pressure and to prevent cell lysis.[1] It is a covalent linear glycan polymer that consists of alternating Nacetylglucosamine (GlcNAc) and N-acetylmuramic acid (MurNAc) residues, the latter of which have an appended pentapeptide chain. In addition to the transglycosylase and transpeptidase enzyme families, the biosynthesis of peptidoglycan involves a number of ATP-dependant ligases (namely the Mur ligases). These catalyze the assembly of the pentapeptide moiety through the successive addition of lAla, d-Glu, m-dpm or l-Lys, and d-Ala-d-Ala to UDPMurNac by MurC, MurD, MurE, and MurF enzymes, respectively (m-dpm = meso-diaminopimelic acid; UDP = uridine-5'-diphosphoryl). An additional ATP-dependant enzyme, d-Ala-d-Ala ligase (dd-ligase) is responsible for supplying the d-Ala-d-Ala dipeptide, which is the substrate for MurF. Inhibition of any of these essential enzymes in either Gram-positive or Gram-negative organisms leads to the loss of cell shape and integrity followed by bacterial death.[2-4] The emergence of bacterial strains that are resistant to all antibiotics in current clinical use has created an urgent need for the development of new inhibitors of peptidoglycan biosynthesis enzymes and, in particular, those that act on targets that have not been previously exploited.As part of a structure-based design and synthesis program for the discovery of new enzyme inhibitors, we previously described the computer-aided molecular design, synthesis, and biological evaluation of novel inhibitors of the ligase responsible for d-Glu attachment, MurD.[5] Other research groups, using either library-screening methods or substrateinspired approaches, have also reported useful inhibitors of the MurC [6][7][8] and MurD [6,9,10] ligases. A phosphinate-based transition-state isostere of dd-ligase has also been reported.[10]The structure-based design of small-molecule enzyme inhibitors is a powerful tool in drug discovery, particularly if an X-ray crystal structure of the target enzyme is available. For cases in which the X-ray crystal structure includes a substrate or a known inhibitor, a substrate-inspired approach can be adopted; classical molecular modeling techniques can be used to alter the structure of the co-crystallized substrate, and a new molecule with enhanced enzyme-binding affinity can be produced. To identify different inhibitor structure types, the technique of virtual high-throughput screening (VHTS) can also be applied to the crystal structure of the enzyme in an attempt to identify new "hits" by docking the 3D structures of molecules contained in a database. [11] However, both techniques have a number of drawbacks. The substrate-inspired approach requires a suitable enzymesubstrate co-crystal structure. Furthermore, the structures of the designed molecules will necessarily be biased toward that of the original co-crystallized small molecule, which, as is the case for man...
Peptidoglycan is an essential component of the bacterial cell wall and provides the structural integrity necessary to resist internal osmotic pressure and to prevent cell lysis.[1] It is a covalent linear glycan polymer that consists of alternating Nacetylglucosamine (GlcNAc) and N-acetylmuramic acid (MurNAc) residues, the latter of which have an appended pentapeptide chain. In addition to the transglycosylase and transpeptidase enzyme families, the biosynthesis of peptidoglycan involves a number of ATP-dependant ligases (namely the Mur ligases). These catalyze the assembly of the pentapeptide moiety through the successive addition of lAla, d-Glu, m-dpm or l-Lys, and d-Ala-d-Ala to UDPMurNac by MurC, MurD, MurE, and MurF enzymes, respectively (m-dpm = meso-diaminopimelic acid; UDP = uridine-5'-diphosphoryl). An additional ATP-dependant enzyme, d-Ala-d-Ala ligase (dd-ligase) is responsible for supplying the d-Ala-d-Ala dipeptide, which is the substrate for MurF. Inhibition of any of these essential enzymes in either Gram-positive or Gram-negative organisms leads to the loss of cell shape and integrity followed by bacterial death.[2-4] The emergence of bacterial strains that are resistant to all antibiotics in current clinical use has created an urgent need for the development of new inhibitors of peptidoglycan biosynthesis enzymes and, in particular, those that act on targets that have not been previously exploited.As part of a structure-based design and synthesis program for the discovery of new enzyme inhibitors, we previously described the computer-aided molecular design, synthesis, and biological evaluation of novel inhibitors of the ligase responsible for d-Glu attachment, MurD.[5] Other research groups, using either library-screening methods or substrateinspired approaches, have also reported useful inhibitors of the MurC [6][7][8] and MurD [6,9,10] ligases. A phosphinate-based transition-state isostere of dd-ligase has also been reported.[10]The structure-based design of small-molecule enzyme inhibitors is a powerful tool in drug discovery, particularly if an X-ray crystal structure of the target enzyme is available. For cases in which the X-ray crystal structure includes a substrate or a known inhibitor, a substrate-inspired approach can be adopted; classical molecular modeling techniques can be used to alter the structure of the co-crystallized substrate, and a new molecule with enhanced enzyme-binding affinity can be produced. To identify different inhibitor structure types, the technique of virtual high-throughput screening (VHTS) can also be applied to the crystal structure of the enzyme in an attempt to identify new "hits" by docking the 3D structures of molecules contained in a database. [11] However, both techniques have a number of drawbacks. The substrate-inspired approach requires a suitable enzymesubstrate co-crystal structure. Furthermore, the structures of the designed molecules will necessarily be biased toward that of the original co-crystallized small molecule, which, as is the case for man...
We report the design, synthesis and biological evaluation of simplified analogues of the herbicidal natural product (+)‐cornexistin. Guided by an X‐Ray co‐crystal structure of cornexistin bound to transketolase from Zea mays, we attempted to identify the key interactions that are necessary for cornexistin to maintain its herbicidal profile. This resulted in the preparation of three novel analogues investigating the importance of substituents that are located on the nine‐membered ring of cornexistin. One analogue maintained a good level of biological activity and could provide researchers insights in how to further optimize the structure of cornexistin for commercialization in the future.
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