Puromycin based inhibitors of aminopeptidases for the potential treatment of hematologic malignancies

Substantial progress has been described in the study of puromycin and its analogs for antibiotic properties. However, the peptidase inhibitory activity of related analogs has not been explored as extensively. Specifically, inhibiting aminopeptidases for achieving antitumor effect has been sparsely investigated. Herein, we address this challenge by reporting the synthesis of a series of analogs based on the structural template of puromycin. We also present exhaustive biochemical and in vitro analyses in support of our thesis. Analyzing the structure–activity relationship revealed a steric requirement for maximum potency. Effective inhibitors of Puromycin–Sensitive Aminopeptidase (PSA) are disclosed here. These potential therapeutic agents display superior in vitro antitumor potency against two leukemic cell lines, as compared to known inhibitors of aminopeptidases.