Novel anthracene-containing aminophosphonates and a new anthracene-derived Schiff base were synthesized and tested for antitumor activity and safety. The compounds could be considered promising as a ...novel class antiproliferative agents.
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.
Novel polyphosphoesters containing anthracene-derived aminophosphonate units were synthesized and tested for antitumor activity and safety. The polymers are promising as new antiproliferative agents ...for treatment of breast and liver neoplasms.
Novel polyphosphoesters containing anthracene-derived aminophosphonate units, poly(oxyethylene aminophosphonate)s (4 and 5) and polyoxyethylene(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 (1H, 13C and 31P) 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.
The X-ray crystal structures of the anthracene-derived bis-aminophosphonates 4.4′-bisN-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 bisN-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 publisher's online edition ofPhosphorus, Sulfur, and Silicon and the Related Elementsto view the free supplemental file.
The synthesis of two novel bis-aminophosphonates bearing anthracene rings - bisN- methyl(diethoxyphosphonyl)-1-(9-anthryl)benzidine (3) and ...4,4′-bisN-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 (
1
H,
13
C,
31
P) 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 publisher's online edition of Phosphorus, Sulfur, and Silicon and the Related Elements to view the free supplemental file.
Most
in vivo studies demonstrating decreased activities of hepatic cytochromes P450 with inflammation have used Gram-negative bacterial lipopolysaccharide (LPS) as the inflammatory stimulant. But ...products of Gram-positive bacteria, such as staphylococcal enterotoxin B (SEB), also stimulate inflammatory mediators, albeit with a different pattern than LPS. Therefore, effects of SEB on the regulation of murine constitutive P450s were determined in this study and compared with those of LPS. LPS-responsive C3H/HeN and LPS-unresponsive C3H/HeJ mice were injected with either LPS (0.5 mg/kg) or SEB (0.66 to 6.6 mg/kg), and hepatic cytochromes P450 and serum tumor necrosis factor-α, interleukin-6, nitrate/nitrite, and serum amyloid A concentrations were determined up to 24 hr. HeJ mice were generally less responsive than HeN mice to both stimuli, with lower cytokine, nitrate/nitrite, and serum amyloid A responses. However, in both mouse strains SEB caused more prolonged cytokine, higher nitrate/nitrite, and lower serum amyloid A concentrations than LPS. Despite these differences, in HeN mice, after both SEB and LPS administration, total P450 concentrations were equally depressed by 40%. Both SEB and LPS depressed CYP1A1 and 1A2 microsomal protein concentrations by 45 and 30%, respectively; CYP2E1 by 64%; and CYP3A by 70%. There was comparable inhibition of enzymatic activities. In HeJ mice, SEB was only slightly more effective in depressing P450s than LPS, as might be expected. These data showed that the Gram-positive bacterial inflammatory stimulant SEB caused effects on murine hepatic cytochromes P450 similar to those of LPS, even though the pattern of inflammatory mediators induced after SEB exposure was different.
Inflammation induced by Escherichia coli lipopolysaccharide alters the clearance of several hepatically eliminated drugs. Extensive rat liver research has shown CYP2E1 down-regulation after ...lipopolysaccharide administration. To further investigate this phenomenon in humans, lipopolysaccharide was administered to healthy male volunteers and chlorzoxazone was used as a CYP2E1 probe drug.
Twelve healthy men were given 500 mg oral chlorzoxazone after two daily lipopolysaccharide doses (20 endotoxin units/kg/day) and again after administration of saline solution in this balanced crossover study. Serum and urine chlorzoxazone and 6-hydroxychlorzoxazone were quantified, as well as cytokine and C-reactive protein levels.
Lipopolysaccharide produced the expected induction of the acute-phase response shown by elevations in tumor necrosis factor, interleukin-6, C-reactive protein, and temperature. Lipopolysaccharide treatment failed to produce a significant change in the chlorzoxazone oral clearance (4.4 +/- 0.9 mL/min/kg for lipopolysaccharide versus 4.2 +/- 1.4 mL/min/kg for control) or the 6-hydroxychlorzoxazone formation clearance (2.8 +/- 0.65 mL/min/kg for lipopolysaccharide versus 2.5 +/- 0.9 mL/min/kg for control). The high intersubject variabilities in oral clearance and formation clearance were not accounted for by changes in protein binding, cytokine, or C-reactive protein values. In contrast, a significant increase in the 6-hydroxychlorzoxazone glucuronide renal clearance was observed (7.5 +/- 1.37 mL/min/kg for lipopolysaccharide versus 6.1 +/- 1.7 mL/min/kg for control).
This study showed that the inflammatory response to lipopolysaccharide (20 endotoxin units/kg/day for 2 days) in humans does not consistently alter chlorzoxazone hepatic metabolism. However, the significant increase in renal clearance of the glucuronidated metabolite suggests that renal tubular secretion may be increased in humans with acute endotoxemia.
Vibrational study of new Pt(II) and Pd(II) complexes of functionalized nitrogen-containing tertiary phosphine oxides, namely
ortho-,
meta- and
para-dimethylphosphinylmethyleneoxyaniline (
o-,
m- and
...p-dpmoa), (CH
3)
2P(O)CH
2OC
6H
4NH
2, have been presented. Geometry optimization of the ligands was performed at HF/6-31G* and B3LYP/6-31G* levels of the theory. Harmonic frequencies were calculated at HF/6-31G* optimized geometries. Relative gas-phase and solution-phase (H
2O and CH
3CN) basicities of
o-,
m- and
p-dpmoa ligands have been determined by ab initio calculations at STO-3G level with the Onsager reaction field model. On the basis of the vibrational study, physical and analytical data it was suggested that the ligands in the complexes studied coordinate through the amino group and form square-planar platinum and palladium complexes of the general formula ML
2Cl
2 (M=Pt, Pd, L=
o-,
m- and
p-dpmoa).
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,
H and
P{
H} NMR spectroscopy, mass spectrometry and in two cases by X-ray diffraction.
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.
