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

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

doi:https://dx.doi.org/10.1021/acs.jmedchem.2c02097

Number of the records: 1

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

1.

SYSNO ASEP	0572565
Document Type	J - Journal Article
R&D Document Type	Journal Article
Subsidiary J	Článek ve WOS
Title	Design, Synthesis, Biological Evaluation, and Crystallographic Study of Novel Purine Nucleoside Phosphorylase Inhibitors
Author(s)	Skácel, Jan (UOCHB-X)_{ORCID, RID} Djukic, Stefan (UOCHB-X)_ORCID Baszczyňski, Ondřej (UOCHB-X)_{RID, ORCID} Kalčic, Filip (UOCHB-X)_{RID, ORCID} Bílek, Tadeáš (UOCHB-X) Chalupský, Karel (UOCHB-X) Kozák, Jaroslav (UOCHB-X)_{RID, ORCID} Dvořáková, Alexandra (UOCHB-X) Tloušťová, Eva (UOCHB-X)_{RID, ORCID} Kráľová, Zuzana (UOCHB-X) Šmídková, Markéta (UOCHB-X)_{RID, ORCID} Voldřich, Jan (UOCHB-X) Rumlová, M. (CZ) Pachl, Petr (UOCHB-X)_{RID, ORCID} Brynda, Jiří (UOCHB-X)_{RID, ORCID} Vučková, Tereza (UOCHB-X) Fábry, Milan (UOCHB-X) Snášel, Jan (UOCHB-X)_RID Pichová, Iva (UOCHB-X)_{RID, ORCID} Řezáčová, Pavlína (UOCHB-X)_{RID, ORCID} Mertlíková-Kaiserová, Helena (UOCHB-X)_{RID, ORCID} Janeba, Zlatko (UOCHB-X)_{RID, ORCID}
Source Title	Journal of Medicinal Chemistry. - : American Chemical Society - ISSN 0022-2623 Roč. 66, č. 10 (2023), s. 6652-6681
Number of pages	30 s.
Language	eng - English
Country	US - United States
Keywords	multisubstrate analog inhibitors ; transition-state analog ; human erythrocytes
OECD category	Organic chemistry
R&D Projects	TN01000013 GA TA ČR - Technology Agency of the Czech Republic (TA ČR)
	EF16_019/0000729 GA MŠMT - Ministry of Education, Youth and Sports (MEYS)
	LX22NPO5102 GA MŠMT - Ministry of Education, Youth and Sports (MEYS)
Method of publishing	Open access
Institutional support	UOCHB-X - RVO:61388963
UT WOS	000985510500001
EID SCOPUS	85159615141
DOI	10.1021/acs.jmedchem.2c02097
Annotation	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.
Workplace	Institute of Organic Chemistry and Biochemistry
Contact	asep@uochb.cas.cz ; Kateřina Šperková, Tel.: 232 002 584 ; Viktorie Chládková, Tel.: 232 002 434
Year of Publishing	2024
Electronic address	https://doi.org/10.1021/acs.jmedchem.2c02097

Number of the records: 1