I. Kraicheva

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.

Phosphorus-, nitrogen- and difuryl-containing monomers

Abstract New phosphorus-, nitrogen- and difuryl-containing monomers have been prepared via the addition of dialkyl phosphites (dimethyl, diethyl and diisopropyl) to Schiff bases from furfural and the following amines 4,4′-diaminodiphenyl ether, 4,4′-diaminodiphenylmethane and p-phenylene diamine. The structures of the monomers were determined by i.r. and 1H-NMR spectroscopy. It was found that the phosphorus-, nitrogen- and difuryl-containing compounds react with isocyanates and that they homopolymerize and co-polymerize with difurfurylidene acetone.

ADDITION PRODUCTS OF DIALKYL PHOSPHITES TO A DIFURYL-CONTAINING SCHIFF BASE

Abstract New difuryl-containing diesters of aminophosphonic acids were synthesized through addition of dialkyl phosphites (dimethyl- and diisopropyl phosphite) to bis[4-(furfurylidene amino)-phenyl]methane. The reaction was carried out in the presence of an alkaline catalyst at ambient temperature. The structure of the compounds prepared was confirmed by means of IR, 1H- and 31P-NMR spectroscopy. TLC data are also presented.

Addition products of dialkyl phosphites with a Schiff base as components increasing the combustion resistance of polymers

Abstract New phosphorus- and nitrogen-containing compounds: viz. 4,4′-bis[N-methyl(dimethoxyphosphonyl)-1-phenyl]diaminodiphenylmethane, 4,4′-bis[N-methyl(diethoxyphosphonyl)-1-phenyl]diaminodiphenylmethane and 4,4′-bis[N-methyl(diisopropoxyphosphonyl)-1-phenyl]diaminodiphenylmethane, have been synthesized via the addition of dialkyl phosphites to a Schiff base 4,4′-bis(benzylideneamino)diphenylmethane. It has been shown these addition products can be used as non-reactive additives increasing the combustion resistance of epoxide resin and difurfurylidene acetone polymer.

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

ADDITION PRODUCTS OF MALEIC ANHYDRIDE TO PHOSPHORUS-AND NITROGEN-CONTAINING FURAN DERIVATIVES

Abstract Diels-Alder reaction between maleic anhydride and phosphorus-, nitrogen-and difuryl-containing compounds was carried out giving two new bis-adducts: 1,4-bis{N-methyl(diethoxyphosphonyl)-1-[4,10-dioxa,-3,5-dioxo-tricyclo[5,2,1,0]ec-8-en-1-yl]}diaminobenzene and 4,4′-bis{N-methyl(diethoxyphosphonyl)-1-[4,10-dioxa-3,5-dioxo-tricyclo-[5,2,1,0]ec-8-en-1-yl]}diaminodiphenylmethane. The structure of the compounds was confirmed by Ir-, 1H-and 31P-NMR-spectra. TLC-data are also presented.

SYNTHESIS OF A PHOSPHORUS- AND NITROGEN-CONTAINING BIS-ADDUCT WITH MALEIC ANHYDRIDE

Abstract A new phosphorus- and nitrogen-containing bis-adduct was synthesized through the interaction between maleic anhydride and a phosphorus-, nitrogen- and difuryl-containing compound by the Diels-Alder reaction. The adduct was isolated and characterized through analytical methods. The structure of the compound was studied by means of IR- and 1H-NMR-spectroscopy. The endo-configuration has been established for the bis-adduct.

SYNTHESIS AND NMR SPECTROSCOPIC STUDY OF NEW 5-METHYLFURYL-CONTAINING SCHIFF BASES AND RELATED BIS(AMINOPHOSPHONATES)

The synthesis of three novel 5-methylfuryl-containing Schiff bases: N,N′-bis(5-methylfurfurylidene)-4,4′-diaminodiphenylmethane, N,N′-bis(5-methylfurfurylidene)-1,4-phenylenediamine, and N,N′-bis(5methylfurfurylidene)benzidine and the corresponding bis(aminophosphonates) derived from them, 4,4′-bis{N-methyl(diethoxyphosphonyl)-1-[(5-methyl)-2-furyl]} diaminodiphenylmethane, 1,4-bis { N-methyl(diethoxyphosphonyl)-1-[(5-methyl)-2-furyl]} diaminobenzene, and bis{N-methyl(diethoxyphosphonyl)-1-[(5-methyl)-2-furyl]}- benzidine, is reported. The compounds have been characterized by elemental analysis, TLC, IR, and NMR ( 1 H, 13 C, and 31 P) spectra. For comparison, new 13 C and 31 P NMR data of three furyl-containing analogues of the above bis(aminophosphonates) are also regarded. The NMR studies of the two series of bis(aminophosphonates) reveal the presence of one diastereomer (meso or racemic form).

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