A Study of the Bisphosphonic Derivatives from the Pudovik Reaction of Dialkyl α-Oxophosphonates and >P(O)H Reagents: X-ray Structure and Bioactivity
Zsuzsanna Szalai,
Boldizsár Tóth,
Rita Oláhné Szabó,
Szilvia Bősze,
Konstantin Karaghiosoff,
Mátyás Czugler,
László Drahos,
György Keglevich
Affiliations
Zsuzsanna Szalai
Department of Organic Chemistry and Technology, Faculty of Chemical Technology and Biotechnology, Budapest University of Technology and Economics, 1521 Budapest, Hungary
Boldizsár Tóth
Department of Organic Chemistry and Technology, Faculty of Chemical Technology and Biotechnology, Budapest University of Technology and Economics, 1521 Budapest, Hungary
Rita Oláhné Szabó
Eötvös Loránd Research Network (ELKH), Research Group of Peptide Chemistry, Eötvös Loránd University, 1117 Budapest, Hungary
Szilvia Bősze
Eötvös Loránd Research Network (ELKH), Research Group of Peptide Chemistry, Eötvös Loránd University, 1117 Budapest, Hungary
Konstantin Karaghiosoff
Department Chemie, Ludwig-Maximilians-Universitat München, Butenandtstr. 5-13, D-81377 München, Germany
Mátyás Czugler
Department of Organic Chemistry and Technology, Faculty of Chemical Technology and Biotechnology, Budapest University of Technology and Economics, 1521 Budapest, Hungary
László Drahos
MS Proteomics Research Group, Research Centre for Natural Sciences, 1117 Budapest, Hungary
György Keglevich
Department of Organic Chemistry and Technology, Faculty of Chemical Technology and Biotechnology, Budapest University of Technology and Economics, 1521 Budapest, Hungary
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.
