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

Eur J Med Chem. 2013 Jul:65:448-55. doi: 10.1016/j.ejmech.2013.04.032. Epub 2013 May 11.

Abstract

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.

Keywords: Apoptosis; Bisphosphonates; Cytotoxicity; Osteoclast; S-containing drugs.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / drug effects
  • Cells, Cultured
  • Collagen / antagonists & inhibitors
  • Collagen / metabolism
  • Diphosphonates / chemical synthesis
  • Diphosphonates / chemistry
  • Diphosphonates / pharmacology*
  • Dose-Response Relationship, Drug
  • Mice
  • Molecular Structure
  • Molecular Weight
  • Osteoclasts / cytology
  • Osteoclasts / drug effects*
  • Structure-Activity Relationship
  • Sulfur / chemistry*

Substances

  • Diphosphonates
  • Sulfur
  • Collagen