Studies of a cobalt(III) complex of the MMP inhibitor marimastat: a potential hypoxia-activated prodrug.
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.
Failes
Timothy W
TW
Centre for Heavy Metals Research, School of Chemistry, University of Sydney, NSW 2006, Australia.
Cullinane
Carleen
C
Diakos
Connie I
CI
Yamamoto
Natsuho
N
Lyons
J Guy
JG
Hambley
Trevor W
TW
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
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