17 e ~- rhenium dicarbonyl CO-releasing molecules on a cobalamin scaffold for biological application

摘要

Cyanocobalamin (B _(12)) offers a biocompatible scaffold for CO-releasing 17-electron dicarbonyl complexes based on the cis-trans-[Re ~(II)(CO) _2Br _2] ~0 core. A Co-CN-Re conjugate is produced in a short time and high yield from the reaction of [Et _4N] _2[Re ~(II)Br _4(CO) _2] (ReCORM-1) with B _(12). The B _(12)-Re II(CO) _2 derivatives show a number of features which make them pharmaceutically acceptable CO-releasing molecules (CORMs). These cobalamin conjugates are characterized by an improved stability in aqueous aerobic media over the metal complex alone, and afford effective therapeutic protection against ischemia-reperfusion injury in cultured cardiomyocytes. The non-toxicity (at μM concentrations) of the resulting metal fragment after CO release is attributed to the oxidation of the metal and formation in solution of the ReO _4 - anion, which is among the least toxic of all of the rare inorganic compounds. Theoretical and experimental studies aimed at elucidating the aqueous chemistry of ReCORM-1 are also described.