Synthesis, NMR characterization and in vitro antitumor evaluation of new aminophosphonic acid diesters.
The synthesis of three novel alpha-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 alpha-aminophosphonates have been characterized by elemental analysis, IR and NMR ((1)H, (13)C and (31)P) 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.
Kraicheva
I
I
Institute of Polymers, Bulgarian Academy of Sciences, Sofia, Bulgaria. kraicheva@yahoo.com
Bogomilova
A
A
Tsacheva
I
I
Momekov
G
G
Troev
K
K
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D015195:Drug Design; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D020128:Inhibitory Concentration 50; D009682:Magnetic Resonance Spectroscopy; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000378:metabolism; D063065:Organophosphonates / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*
D000970:Antineoplastic Agents; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D063065:Organophosphonates; C421109:multidrug resistance-associated protein 1