Synthesis, NMR characterization and in vitro antitumor evaluation of new aminophosphonic acid diesters

The synthesis of three novel α-aminophosphonic acid diesters N,N-dimethyl-[N′-methyl(diethoxyphosphonyl)-(2-furyl)]-1,3-diaminopropane, p-[N-methyl(diethoxyphosphonyl)-(2-furyl)]toluidine and p-[N-methyl(diethoxyphosphonyl)-(4-dimethylaminophenyl)]toluidine through an addition of diethyl phosphite to N,N-dimethyl-N′-furfurylidene-1,3-diaminopropane, N-furfurylidene-p-toluidine and N-(4-dimethylaminobenzylidene)-p-toluidine, respectively, is reported. The α-aminophosphonates have been characterized by elemental analysis, IR and NMR (1H, 13C and 31P) spectra. The compounds were tested for antiproliferative effects against 4 human leukemic cell lines, namely LAMA-84, K-562 (chronic myeloid leukemias), HL-60 (acute promyelocyte leukemia) and HL-60/Dox (multi-drug-resistant sub-line, characterized by overexpression of MRP-1 (ABC-C1)) and were found to exert concentration-dependent cytotoxic effects. A representative aminophosphonate compound was shown to induce oligonucleosomal DNA fragmentation which implies that the induction of cell death through apoptosis plays an important role for its cytotoxicity mode of action.

Graphical abstractNovel α-aminophosphonates were synthesized and tested for antiproliferative effects against four human leukemic cell lines. The assays revealed that the compounds are quite promising new class of cytostatic agents.Figure optionsDownload full-size imageDownload as PowerPoint slide