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PubMedDate not supplied

Efficient solid-phase synthesis of 1,3,5-trisubstituted 1,3,5-triazine-2,4,6-triones.

The solid-phase synthesis of 1,3-disubstituted and 1,3,5-trisubstituted 1,3,5-triazine-2,4,6-triones from MBHA and Wang resin is described. Reaction of resin-bound amino acids with isocyanates yield resin-bound ureas, which further react with chlorocarbonyl isocyanate in toluene at 65 degrees C to selectively afford the resin-bound 1,3-disubstituted 1,3,5-triazine-2,4,6-triones. Selective alkylation at the N-5 position of the resin-bound 1,3-disubstituted 1,3,5-triazine-2,4,6-triones was accomplished by treatment with alkyl halides in the presence of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU). The desired products were cleaved from their solid support and obtained in good yield and purity. The method can be employed in production of toltrazuril analogue libraries for identification of new anticoccidial agents.

Alkylation↗

PubMedDate not supplied

Safety-catch approach to orthogonal synthesis of a triazine library.

A novel safety-catch method for orthogonal synthesis of highly pure trisubstituted triazines was developed. Since the polymer-support used in this method is not acid-labile, this strategy can be uniquely applied to the synthesis of acid-sensitive triazine library compounds. This method will dramatically increase the diversity of triazine and other related heterocyclic library compounds.

Acylation↗

PubMed2002

Sol-gel glass immunosorbent-based determination of s-triazines in water and soil samples using gas chromatography with a nitrogen phosphorus detection system.

A rapid and efficient method for the selective extraction of s-triazine herbicides in environmental samples was developed using an immunosorbent of monoclonal antiatrazine antibodies, which were encapsulated in a sol-gel glass matrix. The cross-reactivity of the antibody for analytes structurally related with atrazine enabled the simultaneous extraction of several s-triazine herbicides (atrazine, propazine, terbuthylazine, cyanazine, desethyl atrazine). After trace enrichment on the immunoextraction column, the s-triazines were desorbed by means of an acidic buffer (pH 2.5) and further extracted with ethyl acetate before being injected into the GC. Compared to liquid-liquid extraction and solid-phase extraction with a hydrophobic SDB-L support, the GC-NPD chromatograms obtained after immunoaffinity enrichment of surface water (river water) samples or soil extracts and analysis were free from matrix interferences. Nonspecific adsorption of humic acids was not observed. The method allows for the determination of the herbicides in linear ranges up to 1.5 microg/L with correlation coefficients higherthan 0.99 and relative standard deviations between 4% and 7% (n = 5). The LODs for 50-mL water samples were in the range 0.02 microg/L (atrazine, propazine) to 0.1 microg/L (desethyl atrazine) (S/N = 3). In addition to its high selectivity, the immunosorbent proved to be reusable for a significant number of preconcentration runs. However, the composition of samples may influence the lifetime of the column.

Chromatography, Gas↗

PubMed2004

Metabolism and mineralization of hexahydro-1,3,5-trinitro-1,3,5-triazine inside poplar tissues (Populus deltoides x nigra DN-34).

Poplar tissue cultures and leaf crude extracts (Populus deltoides x nigra DN-34) were exposed to [U-14C]hexahydro-1,3,5-trinitro-1,3,5-triazine (RDX) and incubated under light and in the dark. Poplar tissue cultures were able to partially reduce RDX to hexahydro-1-nitroso-3,5-dinitro-1,3,5-triazine (MNX) and hexahydro-1,3-dinitroso-5-nitro-1,3,5-triazine (DNX), regardless of the presence or absence of light. However, further transformation of RDX, MNX, and DNX required exposure to light and resulted in the formation of formaldehyde (CH2O), methanol (CH3OH), and carbon dioxide (CO2). Similarly, transformation of RDX by poplar leaf crude extracts required exposure to light. Neither reduction of RDX to MNX and DNX nor mineralization into CO2 were recorded in crude extracts, even when exposed to light, suggesting that both processes were light-independent and required intact plant cells. Control experiments without plant material showed that RDX was partially transformed abiotically, by the sole action of light, but to a lesser extent than in the presence of plant crude extracts, suggesting the intervention of plant subcellular structures through a light-mediated mechanism. Poplar tissue cultures were also shown to mineralize 14CH2O and 14CH3OH, regardless of the presence or absence of light. These results suggest that transformation of [U-14C]RDX by plant tissue cultures may occur through a three-step process, involving (i) a light-independent reduction of RDX to MNX and DNX by intact plant cells; (ii) a plant/light-mediated breakdown of the heterocyclic ring of RDX, MNX, or DNX into C1-labeled metabolites (CH2O and CH3OH); and (iii) a further light-independent mineralization of C1-labeled metabolites by intact plant cells. This is the first time that a significant mineralization of RDX into CO2 by light-exposed plant tissue cultures is reported.

Biodegradation, Environmental↗

PubMed2006

Crystal structures of triazine-3-thione derivatives by reaction with copper and cobalt salts.

The reaction of 5-methoxy-5,6-diphenyl-4,5-dihydro-2H-[1,2,4]triazine-3-thione L1H2OCH3 with copper(II) chloride leads to the formation of an organic molecule L2 containing two triazine rings linked by a new S-S bond. A binuclear copper(II) complex, 1, containing L1 is also isolated. The reaction of L1H2OCH3 with copper(I) chloride yields a hexanuclear cluster of copper(I), 2, in which the copper atoms form a distorted octahedron with the ligand L1 acting as an NS chelate and sulfur bridge, giving to the copper ion a trigonal geometry by one N and two S atoms. In any reaction of the disulfide L2 with metal salts, complexes containing this molecule are isolated. Reactions with copper(I) and copper(II) chloride and nickel(II) and cadmium(II) nitrate produce the S-S bond cleavage, giving complexes containing the triazine L1 behaving as the NS anion, which show spectroscopic characteristics identical with those formed by reaction with L1H2OCH3. However, the reaction with cobalt(II) nitrate gives a low-spin octahedral cobalt(III) complex, in which an asymmetric rupture of the disulfide L2 has been produced, giving an unexpected complex with a new ligand and keeping the S-S bond.

Cadmium Compounds↗

PubMed2000

Oxidative degradation of triazine derivatives in aqueous medium: a radiation and photochemical study.

Pulse and steady state radiolysis techniques have been used to determine the bimolecular rate constants and to investigate the spectral nature of the intermediates and the degradation induced by hydroxyl radicals ((*)OH) with 1,3,5-triazine (T), 2,4, 6-trimethoxy-1,3,5-triazine (TMT), and 2,4-dioxohexahydro-1,3, 5-triazine (DHT) in aqueous medium. A competitive kinetic method with KSCN as the (*)OH scavenger was used to determine the rate constants for the reaction of (*)OH with T, TMT, and DHT. The bimolecular rate constants are 3.4 x 10(9), 2.06 x 10(8), and 1.61 x 10(9) dm(3) mol(-)(1) s(-)(1) respectively, for T, TMT, and DHT at pH approximately 6. The transient absorption spectra obtained from the reaction of (*)OH with T, TMT, and DHT have single absorption maxima at 320, 300, and 300 nm, respectively, and were found to undergo a second-order decay. The formation of TOH(*) [C(6)OH-N(5)-yl radical], TMTOH(*) [N(5)OH-C(6)-yl radical], and DHT(*) [C(6)-yl radical] is proposed from the initial attack of (*)OH with T, TMT, and DHT, respectively. A complete degradation of TMT (10(-3) mol dm(-3)) was obtained after absorbed doses of 5 kGy in N(2)O-saturated solutions and 16 kGy in aerated solutions. A similar degradation pattern was obtained with DHT in N(2)O-saturated solutions. Complete degradation was observed with an absorbed dose of 7 kGy. On the basis of the results from both pulse and steady state radiolysis, a possible reaction mechanism involving (*)OH-mediated oxidative degradation is proposed. A complete photodecomposition of DHT was also observed in the presence of ferric perchlorate using ultraviolet light at low pH. Photoinduced electron transfer between Fe(III) and DHT in the Fe(III)-DHT complex and subsequent formation of DHT(*) are proposed to be the major processes that lead to the complete degradation of DHT at pH 3.

Gamma Rays↗

PubMed1995

Quantitative structure-activity relationships of the inhibition of Pneumocystis carinii dihydrofolate reductase by 4,6-diamino-1,2-dihydro-2,2-dimethyl-1-(X-phenyl)-s-triazines.

The inhibitory activities of 60 4,6-diamino-1,2-dihydro-2,2-dimethyl-1- (X-phenyl)-s-triazines versus purified, recombinant Pneumocystis carinii (Pc) dihydrofolate reductase (DHFR) have been determined at pH 7.0. Utilization of these Kiapp values has led to the formulation of appropriate quantitative structure-activity relationships (QSAR's) for both meta- and parasubstituted derivatives. The QSAR's from Pc are compared with other triazine QSAR's derived versus chicken, murine tumor, Escherichia coli, and particularly human DHFR. Selectivity indices indicate that hydrophobic triazines are particularly effective versus Pc DHFR; they have lower Ki values for Pc DHFR than for human DHFR.

Folic Acid Antagonists↗

PubMed1993

Voronoi modeling: the binding of triazines and pyrimidines to L. casei dihydrofolate reductase.

Vorom is a computer-aided method of drug design which can model a biological receptor given only binding data of known ligands. Using the binding energies of known competitive, reversible ligands of a biological macromolecule, vorom can make predictions about the binding energies and conformations of other small molecules binding to that receptor as well as provide information about the geometry and physicochemical characteristics of the binding site. One such model of L. casei dihydrofolate reductase was made. The model was able to predict the binding energies of 31 pyrimidine and triazine inhibitors out of a total set of 47, using only eight of the molecules (four pyrimidines and four triazines) as input. The binding energy of methotrexate, which is neither a pyrimidine nor a triazine, was correctly predicted. The binding mode of methotrexate predicted by vorom is entirely consistent with known X-ray data. The predicted binding modes of the pyrimidine inhibitors and the geometry of the site model are also consistent with published NMR and crystallographic data.

Amino Acid Sequence↗

PubMed1993

Synthesis and cytotoxicity of potential tumor-inhibitory analogues of trimelamol (2,4,6-tris[(hydroxymethyl)methylamino]-1,3,5-triazine) having electron-withdrawing groups in place of methyl.

In exploring the structural features which determine the antitumor activity of 2,4,6-tris-[(hydroxymethyl)methylamino]-1,3,5-triazine (trimelamol, 1), we have synthesized analogues in which the methyl groups have been replaced by the electron-withdrawing substituents 2,2,2-trifluoroethyl (5), propargyl (13), and cyanomethyl (15) via the respective tris(alkylamino)triazines 3, 12, and 14. Three mono[(hydroxymethyl)amino]triazines (4, 7, and 10) were also prepared. All the new tris(hydroxymethyl) derivatives showed cytotoxicities toward a variety of experimental rodent and human ovarian tumor cell lines similar to those shown by 1, the cyanomethyl analogue (15) having the most favorable profile. Mono(hydroxymethyl) derivatives (4 and 7) were ca. one-third as toxic. The new tris(hydroxymethyl) analogues were more stable to aqueous hydrolysis than was 1. Half-life (pH 7.5) values were, for 1, 120 min, for 5, 690 min, for 13, 450 min, and for 15, 275 min, but at pH 2.0, 15 (t1/2 350 min) was the most stable. This cyanomethyl analogue was also the most water-soluble, being comparable to 1 whereas 5 and 13 were poorly soluble.

Animals↗

PubMed1992

Syntheses and 5-HT2 antagonist activity of bicyclic 1,2,4-triazol-3(2H)-one and 1,3,5-triazine-2,4(3H)-dione derivatives.

A series of bicyclic 1,2,4-triazol-3(2H)-one and 1,3,5-triazine-2,4(3H)-dione derivatives with a 4-[bis(4-fluoro-phenyl)methylene]piperidine or 4-(4-fluorobenzoyl)piperidine group has been prepared and tested for 5-HT2 and alpha 1 receptor antagonist activity. Among the compounds prepared, 2-[2-[4-[bis(4-fluorophenyl)methylene]-piperidin-1-yl]ethyl]- 5,6,7,8-tetrahydro-1,2,4-triazolo[4,3-a]pyridin-3(2H)-one (7b) had the most potent 5-HT2 antagonist activity, which was greater than ritanserin (2), while 7b did not show alpha 1 antagonist activity in vivo. The central 5-HT2 receptor antagonism was approximately 1/30 that of 2 when tested for the ability to block head twitches induced by 5-hydroxytryptophan. Compound 21b, 3-[2-[4-(4-fluorobenzoyl)piperidin-1-yl]ethyl]-6,7,8,9-tetrahydro- 2H- pyrido[1,2-a]-1,3,5-triazine-2,4(3H)-dione also displayed potent 5-HT2 antagonist activity. The compound had moderate alpha 1 receptor antagonism, and the potency inhibiting head twitches was about one-third that of ketanserin (1). These results indicate that 5,6,7,8-tetrahydro-1,2,4-triazolo[4,3-a]pyrimidin-3(2H)-one and 6,7,8,9-tetrahydro-2H-pyrido-[1,2-a]-1,3,5-triazine-2,4(3H)-dione ring systems are useful components of 5-HT2 antagonists.

Animals↗

PubMed1992

Comparative molecular field analysis of anticoccidial triazines.

Comparative molecular field analysis (CoMFA) of 2-(substituted phenyl)-1,2,4-triazine-3,5(2H,4H)-diones (triazines henceforth) resulted in an excellent correlation of their anticoccidial potencies with their physical properties. Two items about this work are notable: (i) the biological data are from a whole animal infectious disease model; and (ii) for the best results CoMFA required columns of measured "lipophilicity" and "acidity" data in addition to the calculated data in the steric field and electrostatic field columns. CoMFA resulted in a quantitative description of the major steric and electrostatic field effects, and gave significant new insights to factors governing potency. The model was used to "predict" the potencies of diverse triazines not used in making the model itself.

Coccidiostats↗

PubMed1980

Inhibition of dihydrofolate reductase. 3. 4.6-Diamino-1,2-dihydro-2,2-dimethyl-1-(2-substituted-phenyl)-s-triazine inhibition of bovine liver and mouse tumor enzymes.

Inhibition of dihydrofolate reductase from bovine liver and murine L5178YR-C3 tumor cells has been examined for a series of 4,6-diamino-1,2-dihydro-2,2-dimethyl-1-(2-X-phenyl)-s-triazines. For both enzymes all 2-X substituents cause a decrease in inhibitory activity relative to X = H, with the notable exception of X = SH which is 7.4-12 times as active as X = H. Although there is a high correlation between the activities of these compounds vs. these two enzymes, significant deviations from this correlation for three of the triazines (X = CF3, CH2CN, and Cl) suggest that (a) there may exist significant differences in the two enzymes and their interactions with these triazines and (b) exploitation of such differences might allow for the selective inhibition of enzyme from tumor cells.

Animals↗

PubMed1975

Nucleosides of 2-azapurines. 7 H-Imidazo[4,5-d]-1,2,3-triazines. 2.

A number of nucleosides of 2-azaadenine (4-amino-7H-imidazo[4,5-d]-1,2,3-triazine) were prepared by a previously described route, and some of these were deaminated by means of adenosine deaminase. Alternatively, nucleosides of 2-azahypoxanthine (7H-imidazo[4,5-d]-1,2,3-triazin-4(3h)-one) were prepared from hypoxanthine nucleosides by a 2-azahypoxanthine (7H imidazo[4,5]-1,2,3-triazin-4(3H)-one) were prepared from hypoxanthine nucleosides by a ring-opening and reclosure sequence. The cytotoxicity of these compounds to human epidermoid carcinoma No. 2 cells in culture and to certain resistant sublines thereof was determined. 2-Azaadenine nucleosides chan be metabolized to nucleotides, the cytotoxic agents, by two pathways, but the activity of the 2-azahypoxanthine nucleosides appears to result only from cleavage back to 2-azahypoxanthine.

Aza Compounds↗

PubMed1982

A comparison of the inhibition of growth of methotrexate-resistant and -sensitive leukemia cells in culture by triazines. Evidence for a new mechanism of cell resistance to methotrexate.

Forty-five 4,6-diamino-1,2-dihydro-2,2-dimethyl-1-(3-X-phenyl)-s-triazine inhibitors of dihydrofolate reductase (DHFR) and methotrexate (MTX) were tested on L5178Y/R murine tumor cell culture. The concentration of inhibitor causing a 50% decrease in growth rate was determined, and from these results a quantitative structure-activity relationship (QSAR) was developed. This QSAR is compared with QSAR for the same inhibitors acting on isolated DHFR and on L5178Y cell culture sensitive to MTX. The results show that very potent triazine inhibitors of resistant tumor cell growth can easily be made by making the triazines strongly hydrophobic. The optimum pi value for inhibition of MTX-sensitive cell culture is 0.8, while pi 0 for the resistant cell culture is about 6.0. The QSAR for MTX-sensitive and -resistant tumor cell culture inhibition is compared with the corresponding QSAR for Lactobacillus casei cells. Both the mammalian and bacterial cells appear to protect themselves from the highly hydrophilic MTX by erecting lipophilic barriers.

Animals↗

PubMed1983

Combined distance geometry analysis of dihydrofolate reductase inhibition by quinazolines and triazines.

Guided by the success of distance geometry in explaining the inhibition of dihydrofolate reductase by 68 quinazolines, we have made a combined analysis on the inhibition of rat liver dihydrofolate reductase by 33 triazines and 15 quinazolines. The model gave a fit having the correlation coefficient 0.892 and root mean square (rms) deviation 0.596 in log (1/C50) units. The model was applied to predict the biological activity of 91 compounds. The predicted values showed an rms deviation of 0.907 and a correlation coefficient of 0.790. The present study suggested the synthesis of some triazines as possible potent dihydrofolate inhibitors. The site geometry was compared with the crystal structure of a triazine bound to chicken liver dihydrofolate reductase, and a good correlation has been found.

Chemical Phenomena↗

PubMed1984

Comparative structure-activity relationships of antifolate triazines inhibiting murine tumor cells sensitive and resistant to methotrexate.

The inhibitory effect of 108 4,6-diamino-1,2-dihydro-2,2-dimethyl-1-(substituted-phenyl)-s-triazines on murine L5178Y tumor cells, resistant and sensitive to methotrexate (MTX), has been studied. From the pI50 values, quantitative structure-activity relationships have been formulated which show that the lipophilic triazines are much more inhibitory against resistant cells than methotrexate or hydrophilic triazines. The results are compared with the behavior of other antifolate drugs that have been used in chemotherapy, as well as with eight antitumor drugs that are not antifolates. The acquired resistance of these cells toward hydrophilic antifolates may be attributed to the combined effect of an impaired active-transport system, a change in the conformation of dihydrofolate reductase in the resistant cells, and an amplified production of dihydrofolate reductase in the resistant cells.

Animals↗

PubMed2005

Design, synthesis, and evaluation of orally active 4-(2,4-difluoro-5-(methoxycarbamoyl)phenylamino)pyrrolo[2,1-f][1,2,4]triazines as dual vascular endothelial growth factor receptor-2 and fibroblast growth factor receptor-1 inhibitors.

A series of substituted 4-(2,4-difluoro-5-(methoxycarbamoyl)phenylamino)pyrrolo[2,1-f][1,2,4]triazines was identified as potent and selective inhibitors of the tyrosine kinase activity of the growth factor receptors VEGFR-2 (Flk-1, KDR) and FGFR-1. The enzyme kinetics associated with the VEGFR-2 inhibition of compound 50 (K(i) = 52 +/- 3 nM) confirmed that the pyrrolo[2,1-f][1,2,4]triazine analogues are competitive with ATP. Several analogues demonstrated low-nanomolar inhibition of VEGF- and FGF-dependent human umbilical vein endothelial cell (HUVEC) proliferation. Replacement of the C6-ester substituent of the pyrrolo[2,1-f][1,2,4]triazine core with heterocyclic bioisosteres, such as substituted 1,3,5-oxadiazoles, afforded compounds with excellent oral bioavailability in mice (i.e., 50 F(po) = 79%). Significant antitumor efficacy was observed with compounds 44, 49, and 50 against established L2987 human lung carcinoma xenografts implanted in athymic mice. A full account of the synthesis, structure-activity relationships, pharmacology, and pharmacokinetic properties of analogues within the series is presented.

Administration, Oral↗

PubMed1998

Synthesis and pharmacological activity of triazolo[1,5-a]triazine derivatives inhibiting eosinophilia.

In continuation of our previous work on eosinophilia inhibitors, we synthesized an additional series of inhibitors, which consisted of 5-amino-1-[(methylamino)thiocarbonyl]-1H-1,2,4-triazole derivatives and a newly developed series of 1,2,4-triazolo[1,5-a]-1,3,5-triazine derivatives. We evaluated their inhibitory activity on the airway eosinophilia model, which was induced by the intravenous (iv) injection of Sephadex particles. In the 1,2,4-triazole series with various substituents at the 3 position of the triazole ring such as 2-furyl, pyridyl, and phenoxy, none of derivatives had comparable activity to the previously reported compound GCC-AP0341, 5-amino-3-(4-chlorophenyl)-1-[(methylamino)thiocarbonyl]-1H-1,2, 4-triazole. In the triazolo[1,5-a]triazine series, 2-(4-chlorophenyl)-6-methyl-1,2,4-triazolo[1,5-a]-1,3, 5-triazine-7(6H)-thione (3h) was highly potent, and when given orally it had an ID50 value of 0.3 mg/kg, which is comparable to that of GCC-AP0341. The fact that the structure-activity relationship of these two series was quite similar suggests that a common substructure, such as the 1,2,4-triazole ring with a substituted phenyl ring at the 3 position and a thiocarbonyl moiety at the 1 position, could contribute to the activity. Our selected compound 3h was less active than GCC-AP0341 in the antigen-induced hyper-responsiveness model in guinea pigs; however, we plan to carry out further studies on eosinophil functions, especially on their activation, using our two compounds, 3h and GCC-AP0341.

Animals↗