Synthesis, characterization and biological activity of hydroxyl-bisphosphonic analogs of bile acids

Bisphosphonates (BPs) are now the most widely used drugs for diseases associated with increased bone resorption, such as osteoporosis, and tumor bone diseases. A significant drawback of the BPs is their poor oral absorption that is enhanced by the presence of bile acid substituents in the bisphosphonate framework, with no toxic effects. A straightforward synthesis of bile acid-containing hydroxy-bisphosphonates and a full characterization of these pharmaceutically important molecules, including an evaluation of affinity and the mechanism of binding to hydroxyapatite, is presented. The biological activity of bile acid-containing bisphosphonate salts was determined using the neutral-red assay on the L929 cell line and primary cultures of osteoclasts. The bioactivity of the new compounds was found superior than bisphosphonates of established activity.

A simple and efficient synthesis of bile acid-derived hydroxyl-bisphosphonates is described. The hydroxy-bisphosphonate salt containing the chenodeoxycholic acid structure 4b exhibited a high affinity toward hydroxyapatite and a remarkable biological activity in a comparison with bisphosphonate drug references. In the inhibition of osteoclastogenesis, 4b was found to be more active than neridronate 2 or other bisphosphonates of established activity.Figure optionsDownload as PowerPoint slideHighlights
► New hydroxyl-bisphosphonates substituted with bile acid moieties were synthesized by a simple and direct method.
► The chenodeoxycholic acid-derived hydroxyl-bisphosphonate 4b is significantly less cytotoxic than neridronate 2.
► The biological activity of 4b in inhibition of osteoclastogenesis is much higher than that of other commericial BPs.