Low toxicity and unprecedented anti-osteoclast activity of a simple sulfur-containing gem-bisphosphonate: A comparative study

• We prepared five bisphosphonates (BPs) classified into four classes.
• Toxicological screening of BPs was performed comparing to a commercially available BP.
• Cytotoxicity of BPs was measured with neutral-red (NR) assay on the L929 cell line.
• Biological activity of BPs was evaluated on primary cultures of osteoclasts.
• S-containing BPs provides new contributions for more potent and better tolerated BPs.

Bisphosphonates (BPs) are key drugs for the treatment of bone resorption diseases like osteoporosis, Paget's disease and some forms of tumors. Recent findings underlined the importance of lipophilic N-containing BPs to ensure high biological activity. Herein we present some unprecedented results concerning the low toxicity and good anti-osteoclast activity of low molecular weight hydrophilic S-containing BPs. A series of S and N-containing BPs bearing aromatic and aliphatic substitution were prepared through Michael addition reaction between vinylidenebisphosphonate tetraethyl ester and the proper nucleophile under basic catalysis. S-containing BPs showed a generally low toxicity, determined with the neutral-red assay using the L929 cell line, and, in particular for an aliphatic one, a good biological activity assessed on primary cultures of human osteoclasts.

A comparative study on several bisphosphonates showed that aliphatic S-containing species provide low toxicity and good anti-osteoclast activity assessed through primary culture of osteoclasts.Figure optionsDownload as PowerPoint slide