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

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.