Tania Tosheva

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

Urea and Thiourea Derivatives of Bis(dimethyl-phosphinoylmethyl)-amine

A group of hitherto unknown 1-aryl-3,3-bis(dimethyl-phosphinoylmethyl)-, 1-benzyl-3,3-bis(dimethyl-phosphinoylmethyl)- and 1-cyclohexyl-3,3-bis(dimethyl-phosphinoylmethyl) ureas and thioureas 1-10 have been synthesized, characterized, and are reported in this article. The compounds were prepared via reaction of corresponding isocyanates or isothiocyanates with the secondary phosporus-containing amine: bis(dimethyl-phosphinoylmethyl)-amine. The composition of the novel compounds was proved by elemental analysis, corresponding structures were confirmed by IR, 1 H-, 31 P-, 31 P{ 1 H}-NMR spectroscopy and by mass spectrometry.

Synthesis and NMR Characterization of Two Novel Anthracene-Derived BIS-Aminophosphonates. Basic Hydrolysis of Some Aminophosphonate Derivatives

Abstract The synthesis of two novel bis-aminophosphonates bearing anthracene rings – bis[N- methyl(diethoxyphosphonyl)-1-(9-anthryl)]benzidine (3) and 4,4′-bis[N-methyl(diethoxy-phosphonyl)-1-(9-anthryl)]diaminodiphenylmethane (4) – via the Kabachnik–Fields reaction is reported. The compounds have been characterized by elemental analysis, TLC, IR, NMR (1H, 13C, 31P) and fluorescent spectra. The reaction leads to a mixture of the two possible forms (meso and racemic), with predominant formation of one of the diastereomers. The recrystallized compounds 3 and 4 consist of only one diastereomer. A racemization at the chiral centers and a cleavage of the C-P bond are observed in the alkaline hydrolysis of the new compound 4 and three previously described aminophosphonate derivatives 5–7. Supplemental materials are available for this article. Go to the publishers online edition of Phosphorus, Sulfur, and Silicon and the Related Elements to view the free supplemental file. GRAPHICAL ABSTRACT

CARBAMOYL AND THIOCARBAMOYL DERIVATIVES OF AMINOMETHYL-DIMETYL-PHOSPHINE OXIDE

Abstract A group of N-substituted carbamoyl-and thiocarbamoyl-aminomethyl-dimethyl-phosphine oxides 1–9 have been synthesized. These compounds were prepared via reaction of aminomethyl-dimethyl-phosphine oxide with the corresponding isocyanates and isothiocyanates. The composition of the new compounds was proved by elemental analysis of nitrogen and their structure was confirmed by IR, 1H and 31P{H} MNR spectroscopy and mass spectrometry.

Synthesis and Characterization of Partially Substituted at Lower Rim Phosphorus Containing Calix(4)arenes

The synthesis and characterization of several new phosphorus-containing partially lower rim substituted derivatives of 5,11,17,23-tetra(t-butyl) calix(4)arene (I) and 5,11,17,23-tetra(t-octyl)calix(4)arene (II), namely 5,11,17,23-tetra(t-butyl)-25,27-dihydroxy-26,28-bis(diphenylphosphinoyl-oxy) calix(4)arene (IV); 5,11,17,23-tetra(t-butyl)-25-hydroxy-26,27,28-tris(tetramethyldiamido-phosphinoyl-oxy) calix(4)arene (Vb); 5,11,17,23-tetra(t-butyl)-25,27-dihydroxy-26,28-bis(dimethyl-phosphinoyl-methoxy) calix(4)arene (VI); 5,11,17,23-tetra (t-octyl)-25,27-dihydroxy-26,28-bis(dimethyl-phosphinoyl-methoxy) calix(4)arene (VII) are reported. The structure of the synthesized calix(4)arene derivatives are identified and confirmed by elemental analysis, IR, 1H, 13C, 31P{1H} NMR spectroscopy and mass spectrometry as and X-ray crystallographic analysis of 5,11,17,23-tetra(t-butyl)-25,27-dihydroxy-26,28-bis(dimethyl-phosphinoyl-methoxy) calix(4)arene VI. According to the NMR spectra, all calix(4)arenes are in cone conformation.

NEW DIMETHYL(METHYLENEOXYARYL)-PHOSPHINE OXIDES

Abstract From dimethyl-chloromethyl-phosphine oxides and sodium phenolates of the corresponding mono-, di-and triphenols are prepared by the Williamson reaction new dimethyl(methyleneoxyaryl)phosphine oxides containing one, two or three phosphoryl groups.

(CARBAMOYLAMINOPHENOXYMETHYL)-DIMETHYLPHOSPHINE OXIDES AND CORRESPONDING THIOCARBAMOYL DERIVATIVES

Abstract A group of (carbamoylaminophenoxymethyl)-dimethylphosphine oxides 1–13 and corresponding thiocarbarnoyl derivatives 14–26 were prepared via reaction of 2-, 3-and 4-(dimeth-ylphosphinylmethoxy)-phenylamines with isocyanates and isothiocyanates resp., The composition of the new compounds was confirmed by elemental analysis, IR, 1H and 31P{1HJ} MNR spectroscopy.

In vitro antitumour activity, safety testing and subcellular distribution of two poly[oxyethylene(aminophosphonate-co-H-phosphonate)]s in Ehrlich ascites carcinoma and BALB/c 3T3 cell culture systems

ABSTRACT Two polyphosphoesters containing anthracene-derived aminophosphonate and hydrophilic H-phosphonate repeating units, poly[oxyethylene(aminophosphonate-co-H-phosphonate)]s (1 and 2), were tested for the in vitro antitumour activity on cell cultures derived from ascitic form of Ehrlich mammary adenocarcinoma by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT)-dye reduction assay. The in vitro safety testing of the copolymers was performed by BALB/c 3T3 neutral red uptake assay. A study on their uptake and subcellular distribution in non-tumourigenic and tumour cells was performed by means of fluorescence microscopy. Both copolymers showed significant antitumour activity towards Ehrlich ascites carcinoma (EAC) cells. However, the in vitro safety testing revealed significant toxicity of polymer 2 to BALB/c 3T3 mouse embryo cells. In contrast, polymer 1 showed complete absence of cytotoxicity to BALB/c 3T3 cells. The fluorescent studies showed that the substances were diffusely distributed in the cytoplasm in both cell culture systems. As opposed to BALB/c 3T3 cells, in EAC cells, intense fluorescent signal was observed in the nuclei and in the perinuclear region. The tested polyphosphoesters are expected to act under physiological conditions as prodrugs of aminophosphonates.

Synthesis of Dimethylphosphinoyl Substituted α-Aminoarylmethanephosphonates

New dimethylphosphinoyl-substituted α-aminoarylmethanephosphonates 1a - f have been synthesized via addition of dimethyl or diethyl phosphites to Schiff bases and via Kabachnik-Fields reaction. The structure of the compounds was confirmed by elemental analysis, IR, 1H and 31P{1H} NMR spectroscopy, mass spectrometry and in two cases by X-ray diffraction.