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

Abstract

Purine nucleoside phosphorylase (PNP) is a well-known molecular target with potential therapeutic applications in the treatment of Tcell 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 IC 50 values as low as 19 nM (human PNP) and 4 nM (Mycobacterium tuberculosis (Mt) PNP) and highly selective cytotoxicity toward various Tlymphoblastic cell lines with CC 50 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.

N2′‐Branched Acyclic Nucleoside Phosphonates Containing 9‐Deazahypoxanthine as Inhibitors of Plasmodium falciparum 6‐Oxopurine Phosphoribosyltransferase

“…First, aldehyde 9 was prepared as one of the reagents. Treatment of 6-chloro-9-deazapurine (6) with benzyl alcoholate gave 7 (96 %), then iodination and protection of 7 with 2-(trimethylsilyl)ethoxymethyl (SEM) group offered 9-iodo-9-deazapurine 8 (86 %), [24] and then, treatment of 8 with n-BuLi in THF at À 78 °C, followed by DMF addition, gave the desired aldehyde 9.…”