Long-chain functional bisphosphonates: synthesis, anticalcification, and antiresorption activity

Bisacylphosphonates have previously been shown to posses in vitro activity with regard to hydroxyapatite (HAP) formation and dissolution, and in vivo on tissue calcification and bone resorption. This work was aimed at elucidating the role of the keto groups in the biological activity of these compounds. For this purpose, we have synthesized a series of long-chain bisphosphonates possessing different functional groups adjacent to the phosphonic functions and examined them in some in vitro and in vivo models. The functional groups introduced into the newly synthesized biphosphonates (hydroxyl, amide, and difluoromethylene) were chosen as to represent certain isolated aspects of the keto groups in the original compounds. None of the functional groups introduced into the long chain bisphosphonates bestowed higher activity on the molecules than the carbonyl groups. The unique effect of the α-keto groups in rendering long-chain bisphosphonates active is presumably attained through a combination of chelating ability with sufficiently low pKa values of enable the bisacylphosphonate molecules to be fully ionized at physiological pH.