Triazole pyrimidine nucleosides as inhibitors of Ribonuclease A. Synthesis, biochemical, and structural evaluation

Vanessa Parmenopoulou, Demetra S.M. Chatzileontiadou, Stella Manta, Stamatina Bougiatioti, Panagiotis Maragozidis, Dimitra Niki Gkaragkouni, Eleni Kaffesaki, Anastassia L. Kantsadi, Vassiliki T. Skamnaki, Spyridon E. Zographos, Panagiotis Zounpoulakis, Nikolaos A.A. Balatsos, Dimitris Komiotis, Demetres D. Leonidas

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Abstract

Five ribofuranosyl pyrimidine nucleosides and their corresponding 1,2,3-triazole derivatives have been synthesized and characterized. Their inhibitory action to Ribonuclease A has been studied by biochemical analysis and X-ray crystallography. These compounds are potent competitive inhibitors of RNase A with low μM inhibition constant (Ki) values with the ones having a triazolo linker being more potent than the ones without. The most potent of these is 1-[(β-d-ribofuranosyl)-1,2,3-triazol-4-yl]uracil being with Ki = 1.6 μM. The high resolution X-ray crystal structures of the RNase A in complex with three most potent inhibitors of these inhibitors have shown that they bind at the enzyme catalytic cleft with the pyrimidine nucleobase at the B1 subsite while the triazole moiety binds at the main subsite P1, where P-O5′ bond cleavage occurs, and the ribose at the interface between subsites P1 and P0 exploiting interactions with residues from both subsites. The effect of a susbsituent group at the 5-pyrimidine position at the inhibitory potency has been also examined and results show that any addition at this position leads to a less efficient inhibitor. Comparative structural analysis of these RNase A complexes with other similar RNase A - ligand complexes reveals that the triazole moiety interactions with the protein form the structural basis of their increased potency. The insertion of a triazole linker between the pyrimidine base and the ribose forms the starting point for further improvement of these inhibitors in the quest for potent ribonucleolytic inhibitors with pharmaceutical potential.

Original languageEnglish
Pages (from-to)7184-7193
Number of pages10
JournalBioorganic & Medicinal Chemistry
Volume20
Issue number24
DOIs
Publication statusPublished - 15 Dec 2012
Externally publishedYes

Keywords

  • Inhibition
  • Ribonuclease A
  • Structure-assisted inhibitor design
  • Triazole nucleosides
  • X-ray crystallography

Cite this

Parmenopoulou, V., Chatzileontiadou, D. S. M., Manta, S., Bougiatioti, S., Maragozidis, P., Gkaragkouni, D. N., Kaffesaki, E., Kantsadi, A. L., Skamnaki, V. T., Zographos, S. E., Zounpoulakis, P., Balatsos, N. A. A., Komiotis, D., & Leonidas, D. D. (2012). Triazole pyrimidine nucleosides as inhibitors of Ribonuclease A. Synthesis, biochemical, and structural evaluation. Bioorganic & Medicinal Chemistry, 20(24), 7184-7193. https://doi.org/10.1016/j.bmc.2012.09.067