Synthesis, characterization and nitric oxide release profile of nitrosylcobalamin: a potential chemotherapeutic agent.
Nitrosylcobalamin, a vitamin B12-based, non-toxic carrier of nitric oxide (NO), has been synthesized, isolated and characterized in vitro. A UV/Vis analysis was performed confirming the reduction of the cobalt atom of hydroxocobalamin (vitamin B12a) with the binding of NO, causing a shift in the absorption spectra of CO3+ (lambdamax=530) to CO2+ (lambdamax=500) with the formation of nitrosylcobalamin. The extinction coefficient (epsilonmax) of nitrosylcobalamin, as calculated, was 4.8 (mM(-1), cm(-1)). An IR analysis determined the v(NO) vibrational frequency at 1652 cm(-1), supporting the binding of NO and suggesting a bent bonding geometry. NO release was maximized utilizing acidic conditions (pH 4.9, 32 degrees C) with a cumulative release of about 4610 nmol of NO in 675 h (calculated half-life of 210 h), representing 39% NO loading based on 11,890 nmol NO, theoretically possible (one NO per molecule of hydroxocobalamin). The cumulative NO release followed first-order kinetics and was pH dependent. NO release was minimal at pH 6.0 and 7.4 (37 degrees C), and undetected at pH 10 (37 degrees C). The possibility for nitrosylcobalamin to deliver NO (the active chemotherapeutic agent) to neoplastic cells is suggested because tumor cells, specifically leukemia cells, possess surface cell receptors for vitamin B12 which is readily utilized in the cellular proliferation process. Nitrosylcobalamin may offer a 'drug targeting' approach as a potential, biologically compatible and selective chemotherapeutic agent.
Bauer
J A
JA
Department of Chemistry, University of Akron, OH 44325-3601, USA.
D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry*; D007202:Indicators and Reagents; D007700:Kinetics; D008968:Molecular Conformation; D009569:Nitric Oxide; D009603:Nitroso Compounds / Q000138:chemical synthesis / Q000737:chemistry*; D013053:Spectrophotometry; D014805:Vitamin B 12 / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry
D000970:Antineoplastic Agents; D007202:Indicators and Reagents; D009603:Nitroso Compounds; C113298:nitrosylcobalamin; D009569:Nitric Oxide; D014805:Vitamin B 12