A novel design strategy for stable metal complexes of nitrogen mustards as bioreductive prodrugs.
Parker LL, Lacy SM, Farrugia LJ, Evans C, Robins DJ, O'Hare CC, Hartley JA, Jaffar M, Stratford IJ.
Tumor hypoxia provides a key difference between healthy and cancerous cells. It can be exploited to produce drug selectivity, offering a reductase-rich environment for prodrug activation. Nitrogen mustard drugs are cytotoxic, but usually unselective. Polyamine mustards are candidates for conversion into hypoxia-selective prodrugs via complexation with metals. Reduction to a less stable complex can free the active drug. The novel Cu(II) complexes of N-mustard derivatives of 1,4,7-triazacyclononane (tacn), 1,4,7,10-tetraazacyclododecane (cyclen), and 1,4,8,11-tetraazacyclotetradecane (cyclam) were assessed in vitro as hypoxia-selective cytotoxins. The cyclen mustard complex showed 24-fold selectivity as a hypoxia-selective bioreductive prodrug, with an IC50 value of 2 microM against the lung tumor cell line A549. Reversible redox behavior and stability of the cyclen-Cu(II) complex in aqueous solution correlated with good hypoxia selectivity. The two other related complexes showed irreversible redox behavior and low aqueous stability and were not hypoxia-selective. The use of macrocyclic nitrogen mustard complexes represents a promising new strategy in the design of hypoxia-selective cytotoxins.