Synthesis, synchrotron X-ray diffraction, and kinetic studies on the formation of a novel thiolatocobalamin of captopril: evidence for cis-trans isomerization in the beta-axial ligand.

The orally administered therapeutic captopril is widely used for treating hypertension, congestive heart failure, and cardiovascular disease. However, a number of undesirable side effects are associated with high doses of captopril. By coordinating a therapeutic to the upper (= beta) axial site of the naturally occurring macrocycle cobalamin (vitamin B(12)), the absorption and cellular uptake of the therapeutic can be significantly enhanced. We report the synthesis of captopril-cobalamin, a derivative of vitamin B(12) in which captopril is bound via its thiol group at the beta-axial site of cobalamin. Characterization of captopril-cobalamin by (1)H NMR spectroscopy and X-ray diffraction shows that captopril-cobalamin exists in both solution and the solid state as a mixture of geometric isomers. Kinetic studies on the formation of captopril-cobalamin have been carried out, and the data fits a model in which the thiol form (RSH, k(1) = 40.9 +/- 1.2 M(-1) s(-1)) and the thiolate form of captopril (RS(-), k(2) = 660 +/- 170 M(-1) s(-1)) react rapidly with aquacobalamin.