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.

Graphical abstractA 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 full-size imageDownload 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.