A novel design strategy for stable metal complexes of nitrogen mustards as bioreductive prodrugs.
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.
Parker
Laurie L
LL
Department of Chemistry, University of Glasgow, Glasgow G12 8QQ, UK.
Lacy
Stephen M
SM
Farrugia
Louis J
LJ
Evans
Cameron
C
Robins
David J
DJ
O'Hare
C Caroline
CC
Hartley
John A
JA
Jaffar
Mohammed
M
Stratford
Ian J
IJ
D018906:Antineoplastic Agents, Alkylating / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D003300:Copper; D018360:Crystallography, X-Ray; D015195:Drug Design; D004355:Drug Stability; D006801:Humans; D007700:Kinetics; D008024:Ligands; D015394:Molecular Structure; D009588:Nitrogen Mustard Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D009942:Organometallic Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D010084:Oxidation-Reduction; D011355:Prodrugs / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D012995:Solubility; D013816:Thermodynamics
C494344:(1,4,7,10-tetra(2-chloroethyl)-1,4,7,10-tetraazacyclododecane)copper(II); D018906:Antineoplastic Agents, Alkylating; D008024:Ligands; D009588:Nitrogen Mustard Compounds; D009942:Organometallic Compounds; D011355:Prodrugs; D003300:Copper