PR-104A

PR-104A (SN 27858) is the alcohol metabolite of phosphate proagent PR-104. PR-104A is a hypoxia-selective DNA cross-linking agent/DNA-damaging agent and cytotoxin. Antitumor Activity^[1]. PR-104A is metabolized under hypoxia by the 1-electron NADPH:cytochrome P450 oxidoreductase. PR-104A can be used for the research of relapsed/refractory T-lineage acute lymphoblastic leukemia (T-ALL)^[2]. In Vitro: PR-104A (1-100 uM) shows antiproliferative potency in a panel of 10 human carcinoma cell lines following 4 hours exposures under aerobic and hypoxic conditions with the lowest IC₅₀ (0.51 μM) in H460 non-small cell lung cancer cells and highest (7.3 μM) in PC3 prostate cells^[1].
The phosphate ester PR-104 is rapidly converted in vivo to the alcohol PR-104A, a nitrogen mustard prodrug that is metabolised to hydroxylamine (PR-104H) and amine (PR-104M) DNA crosslinking agents by one-electron reductases in hypoxic cells and by aldo-keto reductase 1C3 independently of oxygen^[3]. In Vivo: The phosphate ester "pre-prodrug" PR-104 is well tolerated in mice and converted rapidly to the corresponding prodrug PR-104A. H460 xenografts shows significant sensitivity to PR-104 (total dose 3.2 mmol/kg)^[1].