We have used computer-assisted sperm analysis (CASA) to evaluate the spermicidal activity of 8 metallocene dihalides (vanadocene dichloride [VDC], titanocene dichloride [TDC], zirconocene dichloride [ZDC], molybdocene dichloride [MDC], hafnocene dichloride [HDC], vanadocene dibromide [VDB], bis[methylcyclopentadienyl] vanadium dichloride [VMDC], and vanadocene diiodide [VDI]); 5 vanadocene di-pseudohalides (vanadocene diazide [VDA], vanadocene dicyanide [VDCN], vanadocene dioxycyanate [VDOCN], vanadocene dithiocyanate [VDSCN], and vanadocene diselenocyanate [VDSeCN]); and 3 disubstituted derivatives (vanadocene ditriflate [VDT], vanadocene monochloro oxycyanate [VDCO], and vanadocene monochloro acetonitrilo tetrachloro ferrate [VDFe]). Whereas the metallocene complexes containing titanium, zirconium, molybdenum, and hafnodium were inactive, all 12 vanadocene complexes elicited potent spermicidal activity at nano-micromolar concentrations with an order of efficacy VDSeCN > VDSCN > VDB > VMDC > VDCN > VDA > VDC > VDOCN > VDI > VDT > VDFe > VDCO without disrupting the acrosomal membrane, as determined by high-resolution low-voltage scanning electron microscopy. The sperm-immobilizing activity of the vanadocene complexes was rapid and irreversible, since the treated sperm underwent apoptosis as determined by the flow cytometric annexin V binding assay, DNA nick end-labeling, and confocal laser scanning microscopy. These results provide unprecedented evidence that metallocene complexes containing vanadium(IV), especially VDSeCN, may be useful as contraceptive agents.
PIP: Computer-assisted sperm analysis was used to evaluate the spermicidal activity of 8 metallocene dihalides, 5 vanadocene di-pseudohalides, and 3 disubstituted derivatives. The metallocene complexes containing titanium, zirconium, molybdenum, and hafnodium were inactive. However, in high-resolution low-voltage scanning electron microscopy, all 12 vanadocene complexes elicited potent spermicidal activity at nano-micromolar concentrations with the following order of efficacy: vanadocene diselenocyanate vanadocene dithiocyanate vanadocene dibromide vanadium dichloride vanadocene dicyanide vanadocene diazide vanadocene dichloride vanadocene dioxycyanate vanadocene diiodide vanadocene ditriflate vanadocene monochloro acetonitrilo tetrachloro ferrate vanadocene monochloro oxycyanate, without disruption of the acrosomal membrane. The sperm-immobilizing activity of the vanadocene complexes was rapid and irreversible due to induction of apoptosis. The potent spermicidal activity of metallocene complexes containing vanadium may provide the basis for the development of novel vaginal contraceptive agents. Studies are underway to further evaluate the mechanisms involved in the induction of vanadocene-mediated apoptotic pathways.