Synthesis of 2- and 3-aminonucleoside analogs as inhibitors of asp-tRNAAsn

Name: Withsakorn Sangsuwan.

LCSH: Kasetsart University -- Theses. M.S. (Chemistry) 2017.

Classification :.LCCS: QD262

LCSH: Kasetsart University. -- Department of Chemistry -- Theses.

LCSH: Asymmetric synthesis.

LCSH: Heterocyclic compounds.

LCSH: Mannose.

Abstract: Glu-tRNAGln/Asp-tRNAAsn amidotransferase (GatCAB) is a heteromeric tRNA-dependent amidotransferase found in several pathogenic bacteria, including Helicobacter pylori, Staphylococcus aureus, and Pseudomonas aeruginosa. These bacteria, all archaea, and some organelles, lack the glutaminyltRNA synthetase (GlnRS) and/or asparaginyl-tRNA synthetase (AsnRS) and cannot directly synthesize Gln-tRNAGln and/or Asn-tRNAAsn. For faithful protein synthesis, these organisms rely on the indirect aminoacylation pathway involving the formation of misacylated Asp-tRNAAsn and/or Glu-tRNAGln, catalyzed by non-discriminating aminoacyl-tRNA synthetases (ND-aaRSs), followed by the conversion to the correctly charged Asn-tRNAAsn and/or Gln-tRNAGln, catalyzed by GatCAB. Because of its indispensability, this enzyme is a promising target for antibacterial drug development. In this work, 2́- and 3́-aminonucleoside analogs as GatCAB inhibitors were designed and synthesized. These analogs structurally mimic the last base of the acceptor stem of the related aminoacyl-tRNA substrates. Various sulfone-containing amino acid residues were integrated into the inhibitors, imitating the transition state of transamidation catalyzed by GatCAB. Phosphoryl, morpholinyl, Nethylpiperazinyl, and piperidinyl moieties were also incorporated to increase the structural similarity to the key intermediates of the transamidation reaction. The synthesis of the inhibitors mentioned above started from commercially available adenosine. The non-hydrolyzable aminoacyl-adenosine analogs were successfully synthesized in 3–11% overall yields through a series of selective protection of the hydroxyl groups of the ribose ring, followed by functionalization and amide coupling reaction. Furthermore, the 5́-modifications involving the introduction of fatty acids and a Fe(III)-siderophore were explored to enhance the antibacterial efficiency by increasing the cellular uptake. The in vivo antibacterial activity evaluation by the disc diffusion method revealed that incorporating the fatty acid chain at the 5́-position increased the inhibitory activity of the methionine-sulfone containing aminonucleoside compared to the analogs without the fatty acid conjugation. The results reported herein pave the road for the development of antimicrobial agents with a novel mechanism of action to combat emerging antibacterial resistance.

Kasetsart University. Office of the University Library

Address: Bangkok

Email: tdckulib@ku.ac.th

Name: Boonsong Kongkathip.

Role: Thesis Advisor

Name: Pitak Chuawong.

Role: Thesis Co-Advisor

Created: 2023

Modified: 2025-06-24

Issued: 2025-06-24

วิทยานิพนธ์/Thesis

วิทยานิพนธ์/Thesis

application/pdf

URL: http://www.lib.ku.ac.th/KUthesis/2566/withsakorn-sang-all.pdf

CallNumber: QD262.W58

eng

DegreeName: Doctor of Philosophy

Level: Doctoral Degraee

Descipline: Chemistry

Grantor: Kasetsart University

©copyrights Kasetsart University

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