Synthesis and in vivo anti- or pro-inflammatory activity of new bisphosphonates and vinylphosphonates

We herein report the synthesis and in vivo anti-inflammatory activity of a series of new bisphosphonate and vinylphosphonate derivatives of pyrrolidine and piperidine through a short route of synthesis. The C-alkylation of tetraethylmethylene diphosphonate with N-(bromoacetyl)pyrrolidine or N-(bromoacetyl)piperidine, respectively, yielded the corresponding -substituted bisphosphonates in excellent yields (82-89%). Next, the Horner-Wadsworth-Emmons reaction of these bisphosphonates with aromatic aldehydes afforded final vinylphosphonates in moderate yields (26-36%). Synthesized bisphosphonates and vinylphosphonates were tested by two models of acute inflammation in male BalB/c mice, founding excellent edema inhibition by topical TPA (12-O-tetradecanoylphorbol-13-acetate) model (67.53-72.10% in comparison with indomethacin=64.89%). However, remarkably pro-inflammatory effect by systematic carrageenan model (-9.78 to -36.18) was observed, probably due to biotransformation. In conclusion, the new vinylphosphonates emerged as attractive topical anti-inflammatory compounds that twist its pharmacological activity to route of administration. Further research is needed to understand the dual effect. [GRAPHICS] .