A Study of the Bisphosphonic Derivatives from the Pudovik Reaction of Dialkyl α-Oxophosphonates and >P(O)H Reagents: X-ray Structure and Bioactivity

Abstract

New hydroxy-methylenebisphosphonic derivatives were prepared with different P-functions. The outcome of the reaction of α-oxophosphonates (YC(O)P(O)(OR)2) and dialkyl phosphites or diarylphosphine oxides depended on the Y substituent of the oxo-compound, the nature of the P-reagent and the amount of the diethylamine catalyst. Starting from dimethyl α-oxoethylphosphonate, in the presence of 5% of diethylamine, the corresponding Pudovik adduct was the single product. While using 40% of the catalyst, the rearranged species with the >P(O)–O–CH–P(O)H-bridge patterns, which invite further investigation. In vitro activity of the compounds was assessed on different tumor cell cultures using end-point-type cell tetrazolium-based measurements. These structure–activity studies revealed a cytostatic effect for four rearranged derivatives containing aromatic units. One of them had a pronounced effect on MDA-MB 231 and Ebc-1 cells, showing IC50 = 37.8 and 25.9 µM, respectively.

Keywords

• hydroxy-methylenebisphosphonic derivatives
• α-oxophosphonates
• dialkyl phosphites
• secondary phosphine oxides
• Pudovik reaction
• rearrangement