Synthesis, stereochemical characterization, and antimicrobial evaluation of a potentially nonnephrotoxic 3′-C-acethydrazide puromycin analog

Abstract

Puromycin is a peptidyl nucleoside endowed with significant antibiotic and anticancer properties, but also with an unfortunate nephrotoxic character that has hampered its use as a chemotherapeutic agent. Since hydrolysis of puromycin's amide to puromycin aminonucleoside is the first metabolic step leading to nephrotoxicity, we designed a 3'-C-hydrazide analog where the nitrogen and carbon functionality around the amide carbonyl of puromycin are inverted. The title compound, synthesized in 11 steps from D-xylose, cannot be metabolized to the nephrotoxic aminonucleoside. Evaluation of the title compound on Staphylococcus epidermidis and multi-drug resistance Staphylococcus aureus did not show significant antimicrobial activity up to a 400 μM concentration.