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)< skeleton was the exclusive component. A similar reaction
of α-oxobenzylphosphonate followed the rearrangement protocol. X-ray crystallography
revealed not only the spatial structures of the three products, but also an intricate
pattern evolving from the interplay of slight chemical differences, solvent inclusion
and disorder as well as 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.
