A novel mercapto-bisphosphonate as an efficient anticalcification agent for bioprosthetic tissues

The synthesis of 2-(2-mercaptoethylamino)ethylidene-1,1-bisphosphonic acid (2) is reported (overall yield >90%), via nucleophilic addition of cystamine to vinylidene-bisphosphonic acid (1) followed by reduction of disulfide bonds with Me₃P. Reaction of 1 with cysteamine forms the isomeric 2-(2-aminoethylthio)ethylidene-1,1-bisphosphonate (3) in an almost quantitative yield. Thiol groups of 2 in water at pH 7 react with epoxy rings more than 30 times faster compared to the known 2-mercaptoethylidene-1,1-bisphosphonate. Elimination of the thiol group is observed as a side-reaction in the reduction of disulfides with phosphines. Stabilization of bioprosthetic tissues with triglycidylamine in the presence of 2 results in covalent immobilization of 2 via an epoxy-SH reaction; this inhibits the long-term calcification of bioprosthetic heart valve tissues to almost undetectable levels.