A Modular Approach to the Total Synthesis of Tunicamycins

Li, Jiakun; Yu, Biao

doi:10.1002/ange.201501890

Cited by 24 publications

(3 citation statements)

References 78 publications

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“…Examples of antimicrobial pyrimidine derivatives are the uracil-based tunicamycins 4 , corynetoxins 5 and liposidomycins 6 that inhibit uridyl translocase I and block peptidoglycan biosynthesis. The purine-based family contains antibiotics such as the S-adenosylhomocysteine nucleosidase inhibitor aristeromycin 7 and aminoacyl-tRNA synthetase (aaRS) inhibitors agrocin 84 and microcin C (McC) 8 .…”

Section: Introductionmentioning

confidence: 99%

Structural Insights into the Binding of Natural Pyrimidine-Based Inhibitors of Class II Aminoacyl-tRNA Synthetases

et al. 2019

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The pyrimidine-containing Trojan horse antibiotics albomycin and a recently discovered cytidinecontaining microcin C analog target the class II seryl-and aspartyl-tRNA synthetases (serRS and aspRS), respectively. The active component of these compounds are competitive inhibitors that mimic the aminoacyl-adenylate intermediate. How they effectively substitute for the interactions mediated by the canonical purine group is unknown. Employing non-hydrolysable aminoacyl-sulfamoyl nucleosides substituting the base with cytosine, uracil and N3-methyluracil the structure-activity relationship of the natural compounds was evaluated. In vitro using E. coli serRS and aspRS, the best compounds demonstrated IC 50 values in the low nanomolar range, with a clear preference for cytosine or N3methyluracil over uracil. X-ray crystallographic structures of K. pneumoniae serRS and T. thermophilus aspRS in complex with the compounds showed the contribution of structured waters and residues in the conserved motif-2 loop in defining base preference. Utilizing the N3-methyluracil bound serRS structure, MD simulations of the fully modified albomycin base were performed to identify the interacting network that drives stable association. This analysis pointed to key interactions with a methionine in the motif-2 loop. Interestingly, this residue is mutated to a glycine in a second serRS (serRS2) found in albomycin-producing actinobacteria possessing self-immunity to this antibiotic. A comparative study demonstrated that serRS2 is poorly inhibited by the pyrimidine-containing intermediate analogs, and an equivalent mutation in E. coli serRS significantly decreased the affinity of the cytosine congener. These findings highlight the crucial role of dynamics and solvation of the motif-2 loop in modulating the binding of the natural antibiotics.

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Section: Introductionmentioning

confidence: 99%

Structural Insights into the Binding of Natural Pyrimidine-Based Inhibitors of Class II Aminoacyl-tRNA Synthetases

et al. 2019

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“…[ 22‐26 ] Especially, the gold(I)‐catalyzed glycosylation protocol using glycosyl ortho ‐alkynylbenzoates (Abz) as donors has been successfully applied to the synthesis of highly complex natural nucleoside antibiotics, including A201A, tunicamycins, and amipurimycin. [ 27‐30 ] With this method, we also achieved total synthesis of the largest congener of the amicetin family, streptcytosine A, together with the smaller fragments plicacetin ( 2 ) and cytosamine ( 3 ). [ 18 ] However, the synthesis of amicetin was not successful due to failure in the final amidation and deprotection.…”

Section: Background and Originality Contentmentioning

confidence: 99%

Total Synthesis of Nucleoside Antibiotics Amicetin, Plicacetin, and Cytosaminomycin A—D

2021

Chin. J. Chem.

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Main observation and conclusion Amicetin and congeners constitute a small family of complex pyrimidine nucleosides, which exhibit strong antibiotic activities against Gram‐positive bacteria and notably against strains of Mycobacterium tuberculosis. Herein, we report chemical synthesis of a series of disaccharide congeners of the amicetin family, including amicetin, plicacetin, and cytosaminomycin A—D. It is the first time for successful synthesis of amicetin, the prototypical member, and cytosaminomycins. The synthetic approach employs glycosyl N‐phenyltrifluoroacetimidate and thioglycoside donors to construct the characteristic aminodeoxydisaccharides consisting of α‐(1→4)‐glycosidic linkage, uses gold(I)‐catalyzed N‐glycosylation to furnish 2‐deoxy‐β‐nucleosides, and finally exploits amidation and global deprotection to complete the syntheses. It is noteworthy that the 3‐O‐protecting group in the 2‐deoxydisaccharide donors is found to be crucial for a successful N‐glycosylation to assemble the cytosaminomycin disaccharide nucleosides.

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“…Chemical synthesis has played a large role in understanding the binding modes of these compounds by generating derivatives to test in inhibition experiments. Because of the complex chemical structures of all classes of natural product-based nucleoside antibiotics, only few reports describe efforts towards the total synthesis of nucleoside antibiotics, including muraymycin (Tanino et al 2010;, tunicamycin (Suami et al 1983(Suami et al , 1984Myers et al 1991, 1993a, 1993b, Li and Yu 2015, and pacidamycin (Okamoto et al 2012b). Rather, chemists have started with the minimal scaffolds needed to obtain binding, and have elaborated on these using various methods.…”

Section: Chemical Approaches To Analogs Of Nucleoside Antibioticsmentioning

confidence: 99%

Bacterial phosphoglycosyl transferases: initiators of glycan biosynthesis at the membrane interface

2017

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Phosphoglycosyl transferases (PGTs) initiate the biosynthesis of both essential and virulence-associated bacterial glycoconjugates including lipopolysaccharide, peptidoglycan and glycoproteins. PGTs catalyze the transfer of a phosphosugar moiety from a nucleoside diphosphate sugar to a polyprenol phosphate, to form a membrane-bound polyprenol diphosphosugar product. PGTs are integral membrane proteins, which include between 1 and 11 predicted transmembrane domains. Despite this variation, common motifs have been identified in PGT families through bioinformatics and mutagenesis studies. Bacterial PGTs represent important antibacterial and virulence targets due to their significant role in initiating the biosynthesis of key bacterial glycoconjugates. Considerable effort has gone into mechanistic and inhibition studies for this class of enzymes, both of which depend on reliable, high-throughput assays for easy quantification of activity. This review summarizes recent advances made in the characterization of this challenging but important class of enzymes.

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A Modular Approach to the Total Synthesis of Tunicamycins

Cited by 24 publications

References 78 publications

Structural Insights into the Binding of Natural Pyrimidine-Based Inhibitors of Class II Aminoacyl-tRNA Synthetases

Structural Insights into the Binding of Natural Pyrimidine-Based Inhibitors of Class II Aminoacyl-tRNA Synthetases

Total Synthesis of Nucleoside Antibiotics Amicetin, Plicacetin, and Cytosaminomycin A—D

Bacterial phosphoglycosyl transferases: initiators of glycan biosynthesis at the membrane interface

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