Towards bioreductively activated prodrugs: Fe(III) complexes of hydroxamic acids and the MMP inhibitor marimastat.
Fe(III)-salen (N,N-bis(salicylidene)-ethane-1,2-diimine) complexes of simple hydroxamic acids and the MMP (matrix metalloproteinase) inhibitor marimastat have been evaluated as hypoxia activated drug carriers. The aceto- (aha), propion- (pha), benzohydroxamato (bha), and marimastat complexes were prepared and characterised by single crystal X-ray diffraction and electrochemical analysis. The hydroxamato ligands form a bidentate chelate to Fe(III) with the remaining octahedral coordination sites occupied by the tetradentate salen ligand. Bonding of the hydroxamato ligands is in the typical motif of the majority of Fe(III) complexes in the literature. The reduction potentials of the complexes are of the order of -1300 mV (vs ferrocene/ferrocenium) and show partial reversibility in the re-oxidation waveforms of the cyclic voltammetry scans. This suggests that the Fe-salen carrier system would provide a suitably redox inert framework yet would release the ligands at hypoxic tumour sites upon reduction to the more labile Fe(II) oxidation state. Furthermore, biological testing of the marimastat complex established that these carriers are stable in non-reducing biological environments and would serve to deliver MMP inhibitors to tumour sites intact.
Failes
Timothy W
TW
Centre for Heavy Metals Research, School of Chemistry, University of Sydney, NSW 2006, Australia. t.failes@chem.usyd.edu.au
Hambley
Trevor W
TW
D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics; D001711:Biotransformation; D015687:Cell Hypoxia; D004337:Drug Carriers / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics; D005290:Ferric Compounds / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics; D006877:Hydroxamic Acids / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics; D020128:Inhibitory Concentration 50; D061965:Matrix Metalloproteinase Inhibitors; D009942:Organometallic Compounds / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics; D010084:Oxidation-Reduction; D011355:Prodrugs / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics; D013329:Structure-Activity Relationship
C520126:(N,N-bis(salicylidene)ethane-1,2-diimine)(marimastat)iron(III); C520127:(marimastat)(tris(2-methylpyridine)amine)cobalt(III); D000970:Antineoplastic Agents; D004337:Drug Carriers; D005290:Ferric Compounds; D006877:Hydroxamic Acids; D061965:Matrix Metalloproteinase Inhibitors; D009942:Organometallic Compounds; D011355:Prodrugs; C100342:marimastat