AI Article Synopsis
- Researchers investigated cyclic and acyclic nitroaryl phosphoramide mustard analogues, which were activated by the E. coli nitroreductase enzyme, for potential use in Gene-Directed Enzyme Prodrug Therapy (GDEPT).
- The acyclic variant, 4-nitrobenzyl phosphoramide mustard, demonstrated remarkable selective cytotoxicity (167,500x) toward specific V79 cells, with a very low IC(50) of 0.4 nM, significantly outperforming the comparison drug, CB1954.
- The enhanced effectiveness of this compound was linked to its superior substrate activity and the potent cytotoxic effects of the phosphoramide mustard it releases.
Article Abstract
Cyclic and acyclic nitroaryl phosphoramide mustard analogues were activated by E. coli nitroreductase, an enzyme explored in GDEPT. The more active acyclic 4-nitrobenzyl phosphoramide mustard (7) showed 167 500x selective cytotoxicity toward nitroreductase-expressing V79 cells with an IC(50) as low as 0.4 nM. This is about 100x more active and 27x more selective than CB1954 (1). The superior activity was attributed to its better substrate activity (k(cat)/K(m) 19x better than 1) and/or excellent cytotoxicity of phosphoramide mustard released.
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