Triazenes: Chemical, Biological, and Clinical Aspects

Triazenes: Chemical, Biological, and Clinical Aspects
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Log in to Wiley Online Library. Purchase Instant Access. View Preview. Learn more Check out. Citing Literature. Supporting Information As a service to our authors and readers, this journal provides supporting information supplied by the authors. Synthesis of 1- 2-fluorophenyl 4-amidophenyl triazene 3. To a solution of 2-fluoroaniline 0. A cold concentrated sodium carbonate solution was then added in small amounts until pH 7.

The microcrystalline product was recrystallized from a hexane:ethyl acetate mixture Yellow vitreous bar-shaped crystals of 3 suitable for X-ray diffraction analysis were obtained by slow evaporation of the solvent mixture within five days. Samples were submitted to agarose gel 0. The resulting gels were digitalized with a photodocumentation system. In order to verify the probable mechanism of DNA strand scission, the assays were repeated in the presence of free radical scavengers thiourea 40 mmol L -1 , glycerol 0.

Cleavage assays were also performed in argon atmosphere in order to verify the cleavage ability in absence of atmospheric oxygen according to the methodology described. In vitro antimicrobial activities of the triazene compounds were evaluated against 30 test organisms, including 14 Gram-positive and 16 Gram-negative bacterial strains. Determination of minimum inhibitory concentrations MICs. All compounds were tested at concentrations ranging from 0. TTC is colorless in the oxidized form and red when reduced.

Live microorganisms reduce TTC by enzymatic action, originating formazan kept inside granules in the cells, which become red. All tests were made three times. After isolation, the cells were washed three times in RPMI Sigma and the erythrocytes were lysed with hemolytic buffer. MTT was dissolved in phosphate buffered saline PBS at 5 mg mL -1 and filtered to sterilize and remove a small amount of insoluble residue.

The quantity of cells was estimated by hemocytometry and blue stained cells were scored as dead. The triazene doses varied from The DTIC solution was prepared in water. Control cultures received cells in absence of assayed compounds.

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Each assay was carried out three times. The cell survival fraction was calculated by the following equation:. The experimental data were transformed to sigmoid dose-response curves using nonlinear regression analysis GraphPad Prizm 5 , which enabled the calculation of the corresponding IC A single crystal on a glass fiber was used for the X-ray data collection. Crystal system and space group were unequivocally determined from the data sets and reciprocal space images.

Table 1 shows the crystallographic data and details of data collection and refinement, and Table 2 the selected bond lengths and angles. Infrared spectra.

Cartei, Giuseppe [WorldCat Identities]

The infrared spectra of 1 , 2 and 3 were analyzed in the spectral region cm The main absorptions and vibrational assignments were compared with literature data. In compound 3 these absorptions were assigned at and cm In compound 3 this absorption was absent. If the dimer unit is considered, two carbonyl stretching frequencies, symmetric and asymmetric, are observed.

The former is Raman active, and the asymmetric will be IR active only, assigned for most carboxyl dimers at cm This explains the well-defined absorption observed at cm -1 in the spectra of 3. All compounds showed the C-O stretching at cm The UV-Vis spectra of 1 , 2 and 3 dissolved in methanol were analyzed in the nm spectral region.

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Thank you. Thus, there is a huge potential demand to develop a facile and generally applicable 3-trifluoromethylpyrazole synthetic procedure for LSF and scaffolds diversification. Florian G. Liberti John R. Project Page Feedback Known Problems. My library Help Advanced Book Search.

The assignments made for the main absorptions are based on literature data. The electronic spectra of 1 , 2 and 3 were compared with those recorded in methanol for the compounds 1,3- bis 4-carboxyphenyl triazene 4 , 1,3- bis 4-fluorophenyl triazene 5 and 1,3- bis 4-acetamidophenyl triazene 6 respectively Figure 1.

Attempts to obtain single crystals suitable for structural analysis of 1 and 2 are in progress. Crystal data and experimental parameters of the structural analysis of 3 are presented in Table 1. Selected bond distances and angles are listed in Table 2. Compound 3 crystallizes in the monoclinic crystal system, the non-centrosymmetric polar space group Cc. Since the molecule of 3 is built only by light atoms that do not cause anomalous scattering, no significant intensity difference between the Friedel pairs hkl and -h-k-l could be observed in the collected reflection data.

Chapter 2.7 Organic Compounds: Synthesis and Hydrolysis BIO201

In other words, no conclusions could be drawn about the orientation of the molecules relative to the polar axes in the unit cell of 3. Two symmetrically independent molecules of 3 were observed in the asymmetric unit of the unit cell Figure 2. The observed intermolecular hydrogen bonding involving the amide group made the independent molecules deviate from planarity, becoming chiral. This property is supported by the deviations observed from normal N-N and C aryl -N bond lengths.

Table 3 lists the geometric parameters of the intermolecular hydrogen-bonding in 3. Atom O2' deviates 0.

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From Book News, Inc. A class of antitumor agents is discussed in 16 papers, which include explorations of the synthesis, chemical properties, biotransformation. Triazenes. Chemical, Biological, and Clinical Aspects. Editors: Giraldi, Tullio, Connors, Thomas, Cartei, Mechanisms of the Biological Actions of Triazenes.

Due to the symmetry independence of each molecule of 3, which originates the 1-D arrangement, both chains running in opposite directions to each other along the crystallographic b axis are also symmetrically independent, as indicated in Figure 3. Compounds 1 and 2 are able to cleave plasmid DNA by transforming the supercoiled form FI into the circular relaxed form II by single strand scission, while compound 3 was not able to show cleavage activity in the same conditions employed for 1 and 2.

However, compound 3 has demonstrated more cleavage efficiency in pH 6. The shape of the linear form can be attributed to an increase in the number of random cleavage events indicating low selectivity. In order to verify the plasmid DNA cleavage mechanism for 1 , 2 and 3 , assays were carried out in the presence of 0. The experiments showed that these conditions did not affect the cleavage activity of 1 , 2 and 3 , suggesting that free hydroxyl radicals do not participate in the cleavage reaction. In conclusion, the plasmid DNA cleavage activity of 1 , 2 and 3 is probably based on a hydrolytic mechanism.

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It is important to point out that all natural nucleases act through a hydrolytic mechanism. Two susceptibility endpoints were recorded for each isolate. The MIC is the lowest concentration of the compound in which the microorganism does not demonstrate visible growth. Minimum bactericidal concentration MBC , in its turn, is defined as the lowest concentration yielding negative subculture or only one colony. The observed MICs of 1 , 2 and 3 against the tested organisms are comparable to those of the similar compounds 1- 2-fluorophenyl 4-acetylphenyl triazene, 1- 4-ethoxyphenyl 4-carboxyphenyl triazene, 1- 4-nitrophenyl 4-carboxyphenyl triazene and 1- 4-acetylaminophenyl 4-carboxyphenyl triazene.

Also, the periplasmic space contains large concentrations of enzymes which are able to decompose exogenous molecules. However, the mode of action of the reported compounds is still undetailed. Most anticancer agents act on DNA or its precursors, inhibiting their synthesis or causing irreparable damage to their molecules. Examples are alkylating agents, cisplatin and antibiotics with antitumor activity, which are able to act at various cell cycle phases and are called non phase-specific.

In this context, the bleomycins A 2 and B 2 form an important group of antibiotics able to cleave DNA through an oxidative mechanism. Other examples of antibiotics used in anticancer therapy are dactinomycin, daunorubicin, doxorubicin, epirubicin, mitoxantrone, idarubicin and doxorubicin or adriamycin. The ability of the triazenes 1 , 2 and 3 to kill human cancer cells was investigated using marrow bone cultures of leukemia patients and peripheral blood of control patient with a standard bioassay, MTT.

Cells were exposed to 1 , 2 and 3 during 24 h in order to evaluate the effects of the investigated triazenes as described in the experimental section. For comparison purposes, DTIC cytotoxicity was evaluated under the same conditions. Based on the concentration-response curve, the cell survival did not depend on the triazene concentration for compounds 1 , 2 and 3 Figure 5. Table 4 shows the results of the antiproliferative effect of 1 , 2 and 3 on acute myeloid leukemia cells and control patient cells. IC 50 values in the range of 1.

Triazenes: Chemical, Biological, and Clinical Aspects

The compounds 1 , 2 and 3 demonstrated cytotoxicity very similar against AML3, while compound 1 appeared to be more cytotoxic than 2 and 3 against AML1. These results suggest that the replacement of fluorine by chlorine in compound 1 increased the antileukemic activity of the triazenes in all leukemic cells tested. The correct dose is one of the most important aspects to achieve the best antitumor effect without increasing toxicity too much, considering that the therapeutic window of most antineoplastic agents is narrow.