ABSTRACT
The synthesis of four novel poly(oxyethylene aminophosphonate)s through an addition of poly(oxyethylene H-phosphonate)s to N-(4-dimethylaminobenzylidene)-p-toluidine or N-furfurylidene-p-toluidine is reported. The IR and 1H, 13C and 31P NMR data of the poly(aminophosphonate)s are given. The polymers consist of aminophosphonate and poly(ethylene glycol) (PEG) units only. They are expected to act in vivo as prodrugs of the aminophosphonates and will be interesting as a new class of biodegradable polymer drug carriers. The cytotoxicity of the synthesized poly(aminophosphonate)s and two previously described analogues, was tested against a panel of human tumor cell lines, using cisplatin as reference cytotoxic agent. The presence of 2-furyl-p-toluidino moiety with a longer PEG (13 units) chain were identified as structural prerequisites affording superior activity, while the analogues originating from the Schiff bases N-(4-dimethylaminobenzylidene)-p-toluidine and N,N-dimethyl-N'-furfurylidene-1,3-diaminopropane were generally less active. In all sub-series of polymers the reduction of the PEG chain length from 13 to 4 units led to a significant reduction in relative potency. The established cytotoxicity, which in most of the polymers was comparable to that of cisplatin give us reason to consider the presented polymers as a novel class of aminophosphonate-based cytotoxic agents.
Subject(s)
Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacology , Organophosphonates/chemical synthesis , Organophosphonates/pharmacology , Polyethylene Glycols/chemical synthesis , Polyethylene Glycols/pharmacology , Antineoplastic Agents/chemistry , Cell Line, Tumor , Cell Proliferation/drug effects , Drug Screening Assays, Antitumor , HL-60 Cells , Humans , Magnetic Resonance Spectroscopy , Molecular Structure , Organophosphonates/chemistry , Polyethylene Glycols/chemistry , Stereoisomerism , Structure-Activity RelationshipABSTRACT
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.
