title: Studies of a cobalt(III) complex of the MMP inhibitor marimastat: a potential hypoxia-activated prodrug.
abstract: We report a potential means of selectively delivering matrix metalloproteinase (MMP) inhibitors to target tumour sites by use of a bioreductively activated Co(III) carrier system. The carrier, comprising a Co(III) complex of the tripodal ligand tris(methylpyridyl)amine (tpa), was investigated with the antimetastatic MMP inhibitor marimastat (mmstH(2)). The X-ray crystal structure of [Co(mmst)(tpa)]ClO(4) x 4H(2)O was determined and two-dimensional NMR revealed the existence of two isomeric forms of the complex in solution. Electrochemical analysis showed that the reduction potential of the complex is suitable for it to be bioreductively activated at hypoxic tumour sites. In vitro assays confirmed the stability of the prodrug in solution prior to reduction and revealed very low cytotoxicity against A2780 cells. In vivo testing in mice showed a higher level of tumour-growth inhibition by the complex than by free marimastat. Both free marimastat and and its Co(III) complex increased metastasis in the model used, with the complex significantly more active.
authors.affiliation: Centre for Heavy Metals Research, School of Chemistry, University of Sydney, NSW 2006, Australia.
authors.forename: Timothy W
authors.initials: TW
authors.lastname: Failes
authors.forename: Carleen
authors.initials: C
authors.lastname: Cullinane
authors.forename: Connie I
authors.initials: CI
authors.lastname: Diakos
authors.forename: Natsuho
authors.initials: N
authors.lastname: Yamamoto
authors.forename: J Guy
authors.initials: JG
authors.lastname: Lyons
authors.forename: Trevor W
authors.initials: TW
authors.lastname: Hambley
mesh_terms: D000588:Amines / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D003035:Cobalt / Q000737:chemistry / Q000494:pharmacology*; D004563:Electrochemistry; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006877:Hydroxamic Acids / Q000494:pharmacology*; D000860:Hypoxia / Q000378:metabolism*; D009682:Magnetic Resonance Spectroscopy; D061965:Matrix Metalloproteinase Inhibitors; D051379:Mice; D009942:Organometallic Compounds / Q000737:chemistry / Q000494:pharmacology*; D011355:Prodrugs / Q000494:pharmacology*; D011725:Pyridines / Q000737:chemistry / Q000494:pharmacology*; D013997:Time Factors; D014407:Tumor Cells, Cultured / Q000187:drug effects; D014961:X-Ray Diffraction
chemical_list: D000588:Amines; D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D006877:Hydroxamic Acids; D061965:Matrix Metalloproteinase Inhibitors; D009942:Organometallic Compounds; D011355:Prodrugs; D011725:Pyridines; C465009:tris((2-(6-methylpyridyl))methyl)amine; D003035:Cobalt; C100342:marimastat