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

0572565 - ÚOCHB 2024 RIV US eng J - Journal Article
Skácel, Jan - Djukic, Stefan - Baszczyňski, Ondřej - Kalčic, Filip - Bílek, Tadeáš - Chalupský, Karel - Kozák, Jaroslav - Dvořáková, Alexandra - Tloušťová, Eva - Kráľová, Zuzana - Šmídková, Markéta - Voldřich, Jan - Rumlová, M. - Pachl, Petr - Brynda, Jiří - Vučková, Tereza - Fábry, Milan - Snášel, Jan - Pichová, Iva - Řezáčová, Pavlína - Mertlíková-Kaiserová, Helena - Janeba, Zlatko
Design, Synthesis, Biological Evaluation, and Crystallographic Study of Novel Purine Nucleoside Phosphorylase Inhibitors.
Journal of Medicinal Chemistry. Roč. 66, č. 10 (2023), s. 6652-6681. ISSN 0022-2623. E-ISSN 1520-4804
R&D Projects: GA TA ČR(CZ) TN01000013; GA MŠMT(CZ) EF16_019/0000729; GA MŠMT LX22NPO5102
Institutional support: RVO:61388963
Keywords : multisubstrate analog inhibitors * transition-state analog * human erythrocytes
OECD category: Organic chemistry
Impact factor: 7.3, year: 2022
Method of publishing: Open access
https://doi.org/10.1021/acs.jmedchem.2c02097

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 mu M. 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.
Permanent Link: https://hdl.handle.net/11104/0343213