Synthesis and biological evaluation of a MraY selective analogue of tunicamycins

Abstract

Tunicamycins, which are nucleoside natural products, inhibit both bacterial phospho-Nacetylmuraminic acid (MurNAc)-pentapeptide translocase (MraY) and human UDP-Nacetylglucosamine (GlcNAc): polyprenol phosphate translocase (GPT). The improved synthesis and detailed biological evaluation of an MraY-selective inhibitor, 2, where the GlcNAc moiety was modified to a MurNAc amide, has been described.

Synthesis of chimera oligopeptide including furanoid β-sugar amino acid derivatives with free OHs: mild but successful removal of the 1,2-O-isopropylidene from the building block

“…Alternative methods for the selective removal of the isopropylidene protection under relatively mild conditions were studied more recently as aqueous tert-butyl hydroperoxide (Maddani and Prabhu 2011), CBr 4 -photoirradiation (Chen et al 2004) and acid zeolites (Rauter et al 2010). The removal of 2,3-O-isopropylidene acetals is also presented in acidic conditions of TFA (Bornaghi et al 2004;Ganapati and Arvind 2020;Ferreira et al 2020;Gelin et al 2020;Pogula et al 2020;Ahmed-Belkacem et al 2020), AcOH (Decultot et al 2020), HCl (Ko et al 2017) or BCl 3 (Yamamoto et al 2019;Yoo et al 2018). For deprotection of 1,2-O-isopropylidene moieties, fewer approaches were mentioned, including H 2 SO 4 (Masamune et al 2001;Yanaisaka et al 1970), HCl (Sorensen et al 2001;Yanaisaka et al 1970), TsOH (Yuan et al 2020;Sukumar et al 1986;Rosenthal and Cliff 1980), aqueous TFA (Piccini et al 2020;Fernandez-Bolanos and Lopez 2007) or cationic exchange resins (e.g.…”

Uridine natural products: Challenging targets and inspiration for novel small molecule inhibitors

“…Recently, total chemical and biochemical syntheses of tunicamycin have been highlighted. 5,6 Unlike A-94964 and tunicamycin, muraymycin (3) lacks a long chain acyl moiety and instead contains a pseudo peptide. 7,8 Significantly, the aforementioned natural products are just a selection of scaffolds that are currently available for inhibitor development and new uridine-containing compounds are continually being isolated, producing new targets for future studies.…”

“…Two examples of UDP-sugar donors (4) involved in this type of transformation are illustrated in Figure 1C, UDP-MurNAc-pentapeptide (4a, Park's nucleotide) and UDP-diNAc-bacillosamine (4b, UDP-diNAcBac). These UDP-sugars (4) donate a glycosylphosphate to a membrane-bound polyprenol phosphate (6), producing uridine monophosphate (UMP, 5) and the glycan-linked polyprenol diphosphate (7). In addition to uridine natural products, uridine nucleotide derivatives have therapeutic applications.…”