In vitro and in vivo anticalcification effects of novel bishydroxyiminophosphonates

Some geminal bisphosphonates are used clinically for a number of important bone- and/or calcium-related diseases; however, side effects and lack of selectivity impede their wide use. This work reports the synthesis and evaluation of bishydroxyiminophosphonates (e.g., adipoyl- and suberoylbisphosphonate dioximes). These compounds significantly inhibited hydroxyapatite formation and dissolution in vitro and the calcification of bioprosthetic tissue implanted subdermally in rats. The compounds reported in this paper are less active than the structurally related bisacylphosphonates. The results of this work indicate that the introduction of oxime groups adjacent to the phosphonic function in long-chain bisphosphonates confers calcium interaction capabilities and that complete ionizability of a bisphosphonate may enhance its biological activity.