Spermicidal activity of chelated complexes of bis(cyclopentadienyl)vanadium(IV).
Transition metal complexes containing vanadium IV have been shown to modulate the cellular redox potential and catalyse the generation of reactive oxygen intermediates (ROI). Since sperm function is exquisitely susceptible to ROI, we examined the effects of stable chelate complexes of vanadocenes on human sperm motility. We synthesized seven structurally distinct chelate complexes of bis(cyclopentadienyl)vanadium(IV) with bidentate ligands [i.e. vanadocene acetylacetonato monotriflate (VDacac), vanadocene hexafluoro acetylacetonato monotriflate (VDHfacac), vanadocene N-phenyl benzohydroxamato monotriflate (VDPH), vanadocene acethydroxamato monotriflate (VDH), vanadocene catecholate (VDCAT), vanadocene bipyridino ditriflate (VDBPY), and vanadocene dithiocarbamate monotriflate (VDDTC)], and evaluated their spermicidal activity using computer-assisted sperm analysis (CASA; Hamilton-Thorne). All seven chelate complexes of vanadocene elicited potent spermicidal activity at micromolar concentrations (EC50 values: 3.9-106 microM) without affecting the sperm acrosome integrity. The catecholate and acetylacetonate complexes of vanadocene were the most active and the bipyridyl complex the least active with an order of efficacy VDCAT > VDacac > VDDTC > VDPH > VDH > VDHfacac > VDBPY. The spermicidal activity of chelate complexes of vanadocenes was rapid and irreversible since the treated spermatozoa underwent apoptosis, as determined by the flow cytometric analysis of mitochondrial membrane potential, surface annexin V binding assay, in-situ nick-end labelling of sperm nuclei, and confocal laser scanning microscopy. These results provide unprecedented evidence that chelate complexes of vanadocene with bidentate ligands have spermicidal and apoptosis inducing properties. These vanadocene complexes, especially VDacac, may be useful as contraceptive agents.
Drug Discovery Program, Hughes Institute, St Paul, Minnesota 55113, USA.
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D'Cruz
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Ghosh
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Uckun
D017209:Apoptosis / Q000187:drug effects; D006801:Humans; D007091:Image Processing, Computer-Assisted; D007700:Kinetics; D008024:Ligands; D008297:Male; D018613:Microscopy, Confocal; D008956:Models, Chemical; D009942:Organometallic Compounds / Q000494:pharmacology*; D010084:Oxidation-Reduction; D017382:Reactive Oxygen Species / Q000378:metabolism; D013081:Sperm Motility / Q000187:drug effects; D013089:Spermatocidal Agents / Q000494:pharmacology*; D013090:Spermatocytes / Q000187:drug effects* / Q000378:metabolism
D008024:Ligands; D009942:Organometallic Compounds; D017382:Reactive Oxygen Species; D013089:Spermatocidal Agents; C114984:bis(cyclopentadienyl)vanadium(IV)