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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; ... Stratford, IJ; + view all (2004) A novel design strategy for stable metal complexes of nitrogen mustards as bioreductive prodrugs. J MED CHEM , 47 (23) 5683 - 5689. 10.1021/jm0449866w.

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Abstract

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 muM 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.

Type: Article
Title: A novel design strategy for stable metal complexes of nitrogen mustards as bioreductive prodrugs
DOI: 10.1021/jm0449866w
Keywords: CROSS-LINKING, ANTITUMOR AGENTS, TUMOR HYPOXIA, CYTO-TOXICITY, DNA-SEQUENCE, MACROCYCLES, DERIVATIVES, SELECTIVITY, MECHANISM, ALKYLATION
UCL classification: UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute > Research Department of Oncology
UCL > Provost and Vice Provost Offices > UCL BEAMS
UCL > Provost and Vice Provost Offices > UCL BEAMS > Faculty of Engineering Science
UCL > Provost and Vice Provost Offices > UCL BEAMS > Faculty of Engineering Science > Dept of Biochemical Engineering
URI: http://discovery.ucl.ac.uk/id/eprint/109042
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