Emil Tashev

Synthesis, characterization, antitumor activity and safety testing of novel polyphosphoesters bearing anthracene-derived aminophosphonate units

Novel polyphosphoesters containing anthracene-derived aminophosphonate units, poly(oxyethylene aminophosphonate)s (4 and 5) and poly[oxyethylene(aminophosphonate-co-H-phosphonate)]s (6 and 7), were synthesized via an addition of poly(oxyethylene H-phosphonate)s to 9-anthrylidene-p-toluidine. The IR, NMR ((1)H, (13)C and (31)P) and fluorescence emission spectral data of the polymers are presented. The copolymers 6 and 7 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. The copolymer 7 showed excellent antiproliferative activity to HBL-100, MDA-MB-231, MCF-7 and HepG2 cell lines. However, the in vitro safety testing revealed significant toxicity to Balb/c 3T3 mouse embryo cells. In contrast, the copolymer 6 showed complete absence of cytotoxicity to Balb/c 3T3 cells, but inhibited the growth of breast cancer cells, cervical carcinoma cells (HeLa) and hepatocellular carcinoma cell cultures after prolonged (72h) exposure. The polymers (4-6) exhibited low (4 and 6) to moderate (5) clastogenicity in vivo and slightly inhibited bone marrow cell division, compared to Mitomycin C. The subcellular distribution of the copolymers 6 and 7 were studied in model cell culture systems. The tested polyphosphoesters are expected to act in vivo as prodrugs of aminophosphonates and could be valuable as a new class of biodegradable polymer drug carriers.

Anthracene-Derived Bis-Aminophosphonates: Crystal Structure, In Vitro Antitumor Activity, and Genotoxicity In Vivo

Abstract The X-ray crystal structures of the anthracene-derived bis-aminophosphonates 4.4′-bis[N-methyl(diethoxyphosphonyl)-1-(9-anthryl)]diaminodiphenylmethane (1) and 1,3-bis [N-methyl(diethoxyphosphonyl)-1-(9-anthryl)]diaminobenzene (3) are reported. The X-ray analyses demonstrated that both compounds crystallize in a centrosymmetric manner containing a meso-form (1) and a pair of enantiomers (3). The cytotoxic potential, genotoxicity, and antiproliferative activity of bis-aminophosphonates 1 and bis[N-methyl(diethoxyphosphonyl)-1-(9-anthryl)]benzidine (2), as well as their subcellular distribution in a tumor cell culture system, are also discussed. Compounds 1 and 2 showed optimal antiproliferative activity to human tumor cells from colon carcinoma line HT-29. In vitro and in vivo safety testing revealed that the compounds exert lower toxicity to normal cells as compared with well-known anticancer and cytotoxic agents. Supplemental materials are available for this article. Go to the publishers online edition ofPhosphorus, Sulfur, and Silicon and the Related Elementsto view the free supplemental file. GRAPHICAL ABSTRACT

Phosphorus containing rigid polyurethane foams

Abstract Rigid polyurethane foams have been synthesized on the basis of industrial raw materials and by use of phosphorus-containing flame retardants, obtained as a result of the interaction between dialkyl phosphites and amino alcohols. The rigid polyurethane foams thus obtained are described and their thermomechanical properties and fire resistance are studied. For a low concentration of phosphorus-containing flame retardant, the rigid polyurethane foams have high fire resistance and retain their physical properties satisfactorily.

Aggregation behavior and in vitro biocompatibility study of octopus-shaped macromolecules based on tert-butylcalix[4]arenes.

A series of products based on tert-butylcalix[4]arene have been synthesized by anionic polymerization of ethylene oxide. The resulting products are amphiphilic octopus-shaped macromolecules, consisting of a hydrophobic calix[4]arene core and four arms of hydrophilic poly(ethylene oxide) chains. In aqueous solutions the polyoxyethylated tert-butylcalix[4]arenes were found to self-associate above certain CMC determined by dye solubilization technique. The light scattering study reveals that the polyoxyethylated tert-butylcalix[4]arenes form aggregates of narrow size distribution and hydrodynamic diameters ranging from about 155 to 245 nm and aggregation numbers from tens to hundreds macromolecules per particle depending on the degree of polymerization of the PEO chains. An in vitro biocompatibility study showed that the tested compounds are practically devoid of intrinsic cytotoxic and hemolytic effects and moreover they failed to modulate the mitogen-induced interleukin-2 release from the human T-lymphocyte cell line Jurkat E6-1. Taken together the excellent in vitro biocompatibility profile and the favorable physicochemical characteristics of the tested polyoxyethylated calix[4]arenes give us reason to consider them as promising for further evaluation as drug delivery platforms.

Synthesis of N,N-diethanolaminoethyl(methylor chloroethyl) phosphites and polyurethane elastomers from them

Abstract Transesterification of dimethyl- or bis(2-chloroethyl) phosphites with triethanolamine yields bifunctional monomers. Phosphorus- and phosphorus and chlorine-containing polyurethanes are prepared, employing N , N -diethanolaminoethyl phosphite or N , N -diethanolaminoethylchloroethyl phosphite as modifiers.

THE REACTION OF DIMETHYL HYDROGEN PHOSPHONATE AND AMINOALCOHOLS

Abstract The interaction between dimethyl hydrogen phosphonate (DMHP) and aminoalcohols was examined. It was found that at the temperature of 80°C the basic reaction is that of alkylation of the aminoalcohols. The structure of the end products was proved by the aid of 1H- and 31P-NMR spectroscopy.

A STUDY ON THE TRANSESTERIFICATION REACTION OF DIMETHYL AND DIETHYL PHOSPHITE WITH 1,3-DICHLOROPROPANOL-2

Abstract The transesterification process of dimethyl and diethyl phosphite with 1,3-dichloropropanol-2 is examined. It is found that the reaction proceeds in the absence of catalyst at a temperature of 155°, whereas in the presence of morpholine as a catalyst it takes place at 126°C. The transesterification of dimethyl phosphite and diethyl phosphite with 1,3-dichloropropanol-2 is accompanied by the evolution of dimethyl and diethyl ethers and alkyl halides (methyl chloride and ethyl chloride).

KINETIC INVESTIGATION OF THE REACTION BETWEEN DIALKYL PHOSPHITES AND AMINE HYDROCHLORIDES

Abstract The kinetics of the reaction between dialkyl phosphites and amine hydrochlorides is reported. It is shown that the reaction is bimolecular and its rate depends on the type of alkyl group of the alkoxyl function of the dialkyl phosphite, as well as on the basicity of the amine.

ON THE INTERACTION BETWEEN DIALKYL PHOSPHITES AND AMINE HYDROCHLORIDES

Abstract The interaction between dialkyl phosphites and amine hydrochlorides is examined. It is found that an alkyl halide is evolved and an ammonium monoalkyl phosphonate, i.e. (R)3NH+O−P(H)(O)(OR), is formed.

Coordination chemistry of a para-tert-octylcalix[4]arene fitted with phosphinoyl pendant arms towards 4f-elements: Extraction, synergism, separation

Abstract The solvent extraction of trivalent lanthanoids (Ln3+) by 5,11,17,23-tetra(para-tert-octyl)-25,26,27,28-tetrakis(dimethylphosphinoylmethoxy)calix[4]arene (S), bearing four phosphine oxide donor groups at the lower rim as synergistic agent in combination with a 4-benzoyl-3-methyl-1-phenyl-2-pyrazolin-5-one (HP) in CHCl3 from chloride medium at µ = 0.1 was quantitatively described in the form of LnP3·S complexes. The role of the synergistic agent on the extraction process was discussed. The values of the separation factors have been evaluated. On the basis of the IR and NMR spectra the stoichiometry and the structure of the solid mixed complex of Eu(III) with HP and S were proposed.