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  3. Design, Synthesis, Biological Evaluation, and Crystallographic Study of Novel Purine Nucleoside Phosphorylase Inhibitors

Design, Synthesis, Biological Evaluation, and Crystallographic Study of Novel Purine Nucleoside Phosphorylase Inhibitors

  • J Med Chem. 2023 May 3. doi: 10.1021/acs.jmedchem.2c02097.
Jan Skácel 1,  Stefan Djukic 1,  Ondřej Baszczyňski 1 2,  Filip Kalčic 1,  Tadeáš Bílek 1,  Karel Chalupský 1,  Jaroslav Kozák 1,  Alexandra Dvořáková 1,  Eva Tloušt'ová 1,  Zuzana Král'ová 1 2,  Markéta Šmídková 1,  Jan Voldřich 1 3,  Michaela Rumlová 3,  Petr Pachl 1,  Jiří Brynda 1,  Tereza Vučková 1,  Milan Fábry 1 4,  Jan Snášel 1,  Iva Pichová 1,  Pavlína Řezáčová 1,  Helena Mertlíková-Kaiserová 1,  Zlatko Janeba 1
Affiliations

Affiliations

  • 1 Institute of Organic Chemistry and Biochemistry, The Czech Academy of Sciences, Flemingovo nám. 2, Prague 16610, Czech Republic.
  • 2 Faculty of Science, Charles University in Prague, Hlavova 2030/8, Prague 2 12843, Czech Republic.
  • 3 University of Chemistry and Technology, Technická 5, Prague 16628, Czech Republic.
  • 4 Institute of Molecular Genetics, The Czech Academy of Science, Vídeňská 1083, Prague 14220, Czech Republic.
PMID: 37134237 DOI: 10.1021/acs.jmedchem.2c02097
Abstract

Purine nucleoside phosphorylase (PNP) is a well-known molecular target with potential therapeutic applications in the treatment of T-cell malignancies and/or Bacterial/parasitic infections. Here, we report the design, development of synthetic methodology, and biological evaluation of a series of 30 novel PNP inhibitors based on acyclic nucleoside phosphonates bearing a 9-deazahypoxanthine nucleobase. The strongest inhibitors exhibited IC50 values as low as 19 nM (human PNP) and 4 nM (Mycobacterium tuberculosis (Mt) PNP) and highly selective cytotoxicity toward various T-lymphoblastic cell lines with CC50 values as low as 9 nM. No cytotoxic effect was observed on other Cancer cell lines (HeLa S3, HL60, HepG2) or primary PBMCs for up to 10 μM. We report the first example of the PNP inhibitor exhibiting over 60-fold selectivity for the pathogenic Enzyme (MtPNP) over hPNP. The results are supported by a crystallographic study of eight enzyme-inhibitor complexes and by ADMET profiling in vitro and in vivo.

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