Kolio Troev

Recent synthesis of aminophosphonic acids as potential biological importance

Aminophosphonic acids are an important group of medicinal compounds, and their synthesis has been a focus of considerable attention in synthetic organic chemistry as well as medicinal chemistry. Although the phosphonic and carboxylic acid groups differ considerably with respect to shape, size, and acidity, α-aminophosphonic acids are considered to be structural analogues of the corresponding amino acids and the transition state mimics peptide hydrolysis. This review summarizes recent developments in the synthesis, characterization and biological activity of α-aminophosphonic acid and N-analogues. An account of both uses will be presented, emphasizing one of the potential future developments, and some implications in medicinal chemistry are also disclosed. In addition, a brief account on the characterization of N-(phosphonomethyl) glycine derivatives will be presented.

Calcium chloride as co-catalyst of onium halides in the cycloaddition of carbon dioxide to oxiranes

The synthesis of 4-substituted 1,3-dioxolan-2-ones from the interaction between carbon dioxide and oxiranes in the presence of a catalytic system composed of tetraalkylammonium or phosphonium halide and calcium chloride has been investigated. It has been established that calcium chloride enhances the catalytic activity of the onium halides used. A mechanism describing the interaction between carbon dioxide and oxiranes has been suggested on the basis of the obtained experimental results. According to the assumed likely mechanism the catalytic system activates the oxirane and the opening of the oxirane ring is the rate-determining stage.

HPLC study on the stability of bendamustine hydrochloride immobilized onto polyphosphoesters.

Novel water soluble polymer complexes of bendamustine hydrochloride, a bifunctional alkylating agent with antimetabolic and cytotoxic activity, were developed using biodegradable polymer carriers-poly(oxyethylene H-phosphonate), poly(methyloxyethylene phosphate) and poly(hydroxyoxyethylene phosphate). Bendamustine hydrochloride was immobilized onto polyphosphoesters via covalent, ionic and hydrogen bonding. The structure of the complexes formed was elucidated by (1)H, (13)C, (31)P NMR and FT-IR spectroscopy. The chemical stability of bendamustine hydrochloride in the novel complexes was studied by HPLC analysis based on a validated method with appointed analytical parameters such as specificity, repeatability, limit of quantitation, limit of detection and linearity. The results from the HPLC indicate that in neutral (pH 7) and alkaline (pH 9) media bendamustine hydrochloride in the polymer complexes is more stable than the pure bendamustine hydrochloride. The enhanced stability of the immobilized drug is explained with the drug interaction with the polymer carriers or their degradation products.

Synthesis of phosphorus‐containing polyurethanes without use of isocyanates

Phosphorus-containing polyurethanes were synthesized by reacting phosphonic acid diesters (RO)2P(O)X (X = H, CH3, Ph) with hydroxycarbamates. These phosphorus-containing polyurethanes were characterized by a combination of molecular-weight determination (GPC) and NMR spectroscopy. The thermal stability of the polymers was evaluated by a combination of TGA and DTA techniques. These polymers are readily soluble in highly polar solvents like DMF and DMSO. The phosphorus-containing polyurethanes are water soluble.

Synthesis, antiproliferative activity and genotoxicity of novel anthracene-containing aminophosphonates and a new anthracene-derived Schiff base.

A new Schiff base, 9-anthrylidene-furfurylamine and three novel anthracene-containing α-aminophosphonates, [N-methyl(dimethoxyphosphonyl)-1-(9-anthryl)]-p-toluidine, [N-methyl(diethoxyphosphonyl)-1-(9-anthryl)]-p-toluidine and [N-methyl(diethoxyphosphonyl)-1-(9-anthryl)]furfurylamine were synthesized. The compounds have been characterized by elemental analysis, TLC, IR, NMR and fluorescent spectra. The aminophosphonates and their synthetic precursors were tested for in vitro antitumor activity on a panel of seven human epithelial cancer cell lines. Safety testing was performed both in vitro (3T3 NRU test) and in vivo on ICR mice for genotoxicity and antiproliferative activity. 9-Anthrylidene-furfurylamine and [N-methyl(diethoxyphosphonyl)-1-(9-anthryl)]furfurylamine were most potent cytotoxic agents towards colon carcinoma cell line HT-29. The latter compound exhibited also antiproliferative activity to HBL-100, MDA-MB-231 and 647-V cells. The aminophosphonate [N-methyl(dimethoxyphosphonyl)-1-(9-anthryl)]-p-toluidine and its synthetic precursor 9-anthrylidene-p-toluidine were found to be cytotoxic to HBL-100 and HT-29 tumor cell lines, respectively. Moderate genotoxic and antiproliferative activity in vivo and low toxicity to Balb/c 3T3 (clone 31) mouse embryo cells were observed for all tested compounds. The subcellular distribution of two tested compounds in a tumor cell culture system was also studied.

Chemical degradation of polyurethanes. Degradation of microporous polyurethane elastomer by dimethyl phosphonate

Abstract The primary aim of these studies is to develop a new method for converting polyurethane waste materials and used polyurethanes into reusable products which can be used in the preparation of polymers with reduced flammability. Microporous polyurethane elastomer based on diphenylmethane diisocyanate (MDI) and polyester polyol-Bayflex 2003E has been degraded by dimethyl phosphonate. The reaction has been run without any catalysts at 142°C. The structure of degraded products has been studied by 1H, 13C and 31P NMR spectroscopy. The likely reaction mechanism of the chemical degradation of microporous polyurethane elastomer is presented.

Chemical degradation of polyurethanes 3. Degradation of microporous polyurethane elastomer by diethyl phosphonate and tris(1-methyl-2-chloroethyl) phosphate

Abstract Microporous polyurethane elastomer, based on diphenylmethane diisocyanate (MDI) and polyester polyol-Bayflex 2003E has been converted into a liquid by treatment with diethyl phosphonate and tris(1-methyl-2-chloroethyl) phosphate. The structure of the degraded products has been studied by 1 H, 13 C and 31 P NMR spectroscopy. The degraded products are phosphorus- or phosphorus and chlorine-containing oligomers.

Chemical degradation of polyurethanes2. Degradation of flexible polyether foam by dimethyl phosphonate

Abstract Flexible polyether polyurethane foam based on toluene diisocyanate and polyether polyol has been liquefied by dimethyl phosphonate (CH 3 O) 2 P(O)H at 160°C. The degraded products have been studied by 1 H, 13 C and 31 P NMR spectroscopy and shown to be phosphorus-containing oligomers.

Polyphosphoester conjugates of dinuclear platinum complex: synthesis and evaluation of cytotoxic and the proapoptotic activity.

Macromolecular conjugates of a dinuclear platinum complex with a spermidine bridge were synthesized using poly(oxyethylene H-phosphonate)s as precursor polymer. The complex species were attached to the polymer chain via a phosphoramide bond resulting from the reaction between the H-phosphonate groups and the middle amino group of the spermidine moiety. (1)H and (31)P{H} DOSY NMR spectral data were used to prove the conjugation reaction and to characterize the new species. The conjugates exhibited profound cytotoxicity in a panel of five chemosensitive human tumor cell lines and one cisplatin-resistant model (HL-60/CDDP), and were found to induce apoptotic cell death. A flow cytometric analysis encountered a cisplatin-dissimilar modulation of the cell cycle progression in KG-1 leukemic cells, following exposure to the dinuclear agents. Moreover, the novel compounds displayed less pronounced inhibitory activity against cultured murine renal epithelial cells, as compared to cisplatin.

A novel depolymerization route to phosphorus-containing oligocarbonates

Abstract The interaction of poly[2,2-bis(4-hydroxyphenyl)propanecarbonate] (PC) with phosphonic acid dialkyl esters [(RO) 2 P(O)H, where R CH 3 or CH 3 CH 2 ] or with phosphoric acid triethyl ester (CH 3 CH 2 O) 3 P(O) was studied. Treatment of PC pellets with phosphonic acid dialkyl esters at 160°C or with triethyl phosphate at 180°C yielded phosphorus-containing oligocarbonates. The structure of the phosphorus-containing oligocarbonates was studied by 31 P NMR, 1 H NMR and 13 C NMR spectroscopy.