Adenosine analogs bearing phosphate isosteres as human MDO1 ligands

Yuezhou Zhang, Mikael Jumppanen, Mirko M. Maksimainen, Samuli Auno, Zulfa Awol, Léo Ghemtio, Harikanth Venkannagari, Lari Lehtiö, Jari Yli-Kauhaluoma, Henri Xhaard, Gustav Boije af Gennäs

Research output: Contribution to journalArticle

Abstract

The human O-acetyl-ADP-ribose deacetylase MDO1 is a mono-ADP-ribosylhydrolase involved in the reversal of post-translational modifications. Until now MDO1 has been poorly characterized, partly since no ligand is known besides adenosine nucleotides. Here, we synthesized thirteen compounds retaining the adenosine moiety and bearing bioisosteric replacements of the phosphate at the ribose 5'-oxygen. These compounds are composed of either a squaryldiamide or an amide group as the bioisosteric replacement and/or as a linker. To these groups a variety of substituents were attached such as phenyl, benzyl, pyridyl, carboxyl, hydroxy and tetrazolyl. Biochemical evaluation showed that two compounds, one from both series, inhibited ADP-ribosyl hydrolysis mediated by MDO1 in high concentrations.

LanguageEnglish (US)
JournalBioorganic and Medicinal Chemistry
DOIs
StateAccepted/In press - Jan 1 2018
Externally publishedYes

Fingerprint

Bearings (structural)
N-Glycosyl Hydrolases
Adenosine Diphosphate Ribose
ADP-ribosylarginine hydrolase
Enzyme Inhibitors
O-Acetyl-ADP-Ribose
Adenosine
Molecular structure
Phosphates
Ligands
Ribose
Amides
Adenosine Diphosphate
Hydrolysis
Nucleotides
Oxygen

Keywords

  • Adenosine analogs
  • Adenosine diphosphate ribose
  • Human macrodomain-containing protein 1
  • Macrodomain
  • MDO1
  • Mono-ADP-ribosylhydrolase
  • Phosphate isosteres

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry

Cite this

Zhang, Y., Jumppanen, M., Maksimainen, M. M., Auno, S., Awol, Z., Ghemtio, L., ... Boije af Gennäs, G. (Accepted/In press). Adenosine analogs bearing phosphate isosteres as human MDO1 ligands. Bioorganic and Medicinal Chemistry. https://doi.org/10.1016/j.bmc.2018.02.006

Adenosine analogs bearing phosphate isosteres as human MDO1 ligands. / Zhang, Yuezhou; Jumppanen, Mikael; Maksimainen, Mirko M.; Auno, Samuli; Awol, Zulfa; Ghemtio, Léo; Venkannagari, Harikanth; Lehtiö, Lari; Yli-Kauhaluoma, Jari; Xhaard, Henri; Boije af Gennäs, Gustav.

In: Bioorganic and Medicinal Chemistry, 01.01.2018.

Research output: Contribution to journalArticle

Zhang, Y, Jumppanen, M, Maksimainen, MM, Auno, S, Awol, Z, Ghemtio, L, Venkannagari, H, Lehtiö, L, Yli-Kauhaluoma, J, Xhaard, H & Boije af Gennäs, G 2018, 'Adenosine analogs bearing phosphate isosteres as human MDO1 ligands' Bioorganic and Medicinal Chemistry. https://doi.org/10.1016/j.bmc.2018.02.006
Zhang, Yuezhou ; Jumppanen, Mikael ; Maksimainen, Mirko M. ; Auno, Samuli ; Awol, Zulfa ; Ghemtio, Léo ; Venkannagari, Harikanth ; Lehtiö, Lari ; Yli-Kauhaluoma, Jari ; Xhaard, Henri ; Boije af Gennäs, Gustav. / Adenosine analogs bearing phosphate isosteres as human MDO1 ligands. In: Bioorganic and Medicinal Chemistry. 2018.
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