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PubMed2005

Characterization and purification of polyphenol oxidase from artichoke (Cynara scolymus L.).

In this study, the polyphenol oxidase (PPO) of artichoke (Cynara scolymus L.) was first purified by a combination of (NH(4))(2)SO(4) precipitation, dialysis, and a Sepharose 4B-L-tyrosine-p-aminobenzoic acid affinity column. At the end of purification, 43-fold purification was achieved. The purified enzyme migrated as a single band on sodium dodecyl sulfate-polyacrylamide gel electrophoresis. Polyacrylamide gel electrophoresis indicated that PPO had a 57 kDa molecular mass. Second, the contents of total phenolic and protein of artichoke head extracts were determined. The total phenolic content of artichoke head was determined spectrophotometrically according to the Folin-Ciocalteu procedure and was found to be 425 mg 100 g(-1) on a fresh weight basis. Protein content was determined according to Bradford method. Third, the effects of substrate specificity, pH, temperature, and heat inactivation were investigated on the activity of PPO purified from artichoke. The enzyme showed activity to 4-methylcatechol, pyrogallol, catechol, and L-dopa. No activity was detected toward L-tyrosine, resorsinol, and p-cresol. According to V(max)/K(m) values, 4-methylcatechol (1393 EU min(-1) mM(-1)) was the best substrate, followed by pyrogallol (1220 EU min(-1) mM(-1)), catechol (697 EU min(-1) mM(-1)), and L-dopa (102 EU min(-1) mM(-1)). The optimum pH values for PPO were 5.0, 8.0, and 7.0 using 4-methylcatechol, pyrogallol, and catechol as substrate, respectively. It was found that optimum temperatures were dependent on the substrates studied. The enzyme activity decreased due to heat denaturation of the enzyme with increasing temperature and inactivation time for 4-methylcatechol and pyrogallol substrates. However, all inactivation experiments for catechol showed that the activity of artichoke PPO increased with mild heating, reached a maximum, and then decreased with time. Finally, inhibition of artichoke PPO was investigated with inhibitors such as L-cysteine, EDTA, ascorbic acid, gallic acid, d,L-dithiothreitol, tropolone, glutathione, sodium azide, benzoic acid, salicylic acid, and 4-aminobenzoic acid using 4-methylcatechol, pyrogallol, and catechol as substrate. The presence of EDTA, 4-aminobenzoic acid, salicylic acid, gallic acid, and benzoic acid did not cause the inhibition of artichoke PPO. A competitive-type inhibition was obtained with sodium azide, L-cysteine, and d,L-dithiothreitol inhibitors using 4-methylcatechol as substrate; with L-cysteine, tropolone, d,L-dithiothreitol, ascorbic acid, and sodium azide inhibitors using pyrogallol as substrate; and with L-cysteine, tropolone, d,L-dithiotreitol, and ascorbic acid inhibitors using catechol as a substrate. A mixed-type inhibition was obtained with glutathione inhibitor using 4-methylcatechol as a substrate. A noncompetitive inhibition was obtained with tropolone and ascorbic acid inhibitors using 4-methylcatechol as substrate, with glutathione inhibitor using pyrogallol as substrate, and with glutathione and sodium azide inhibitors using catechol as substrate. From these results, it can be said that the most effective inhibitor for artichoke PPO is tropolone. Furthermore, it was found that the type of inhibition depended on the origin of the PPO studied and also on the substrate used.

Catechol Oxidase↗

PubMed2003

Isocyanates of N alpha-[(9-fluorenylmethyl)oxy]carbonyl amino acids: synthesis, isolation, characterization, and application to the efficient synthesis of urea peptidomimetics.

The Curtius rearrangement of Fmoc-amino acid azides 1 was carried out in toluene by refluxing the solution for 30 min. The resulting isocyanates 2 have been isolated as crystalline solids and are fully characterized by IR, (1)H NMR, (13)C NMR, and mass spectra. They are found to be stable for several months when stored at 4 degrees C. The acyl azides of Asp, Glu, Ser, Tyr, and Lys with side-chain protection having tert-butyl, benzyl, and Boc groups were also converted to the corresponding isocyanates 2h-m. The rearrangement of Fmoc-amino acid azides in toluene to isocyanates 2 under microwave irradiation was also accomplished. The direct exposure of solid azides to microwaves for 60 s led to the completion of the rearrangement. The resulting isocyanates, after recrystallization, were found to be analytically pure. The scale-up of the rearrangement, under microwave irradiation as tested up to 0.75 mol, posed no problems and led to the isolation of the isocyanates in 91-96% yield. The utility of isocyanates as building blocks in the synthesis of urea peptides 4 is demonstrated. Further, the coupling of isocyantes 2 directly with N,O-bis(trimethylsilyl) derivatives of amino acids 6 resulted in urea peptide acids 7 with good yield in high purity. Thus, the synthesis of urea peptide acids 7d-g containing Asp, Glu, Ser, and Tyr with a free side-chain functional group have been carried out.

Amino Acids↗

PubMed2004

Glycosylthiomethyl chloride: a new species for S-neoglycoconjugate synthesis. Synthesis of 1-N-glycosylthiomethyl-1,2,3-triazoles.

Reaction of O-acyl-protected glycosylthiols with dichloromethane afforded readily glycosylthiomethyl chlorides, which gave with sodium azide the corresponding glycosylthiomethyl azides 17-22. Reaction of these azides with dicyclopentadiene as dipolarophile led to tandem 1,3-dipolar cycloaddition/retro-Diels-Alder reaction furnishing the parent 1-glycosylthiomethyl-1,2,3-triazoles 23-25. Reaction of azides with acetylene derivatives gave directly 1-glycosylthiomethyl-1,2,3-triazoles which are ring-substituted.

Glycosides↗

PubMed2004

A comparison of acetyl- and methoxycarbonylnitrenes by computational methods and a laser flash photolysis study of benzoylnitrene.

Density functional theory (DFT), CCSD(T), and CBS-QB3 calculations were performed to understand the chemical and reactivity differences between acetylnitrene (CH(3)C(=O)N) and methoxycarbonylnitrene (CH(3)OC(=O)N) and related compounds. CBS-QB3 theory alone correctly predicts that acetylnitrene has a singlet ground state. We agree with previous studies that there is a substantial N-O interaction in singlet acetylnitrene and find a corresponding but weaker interaction in methoxycarbonylnitrene. Methoxycarbonylnitrene has a triplet ground state because the oxygen atom stabilizes the triplet state of the carbonyl nitrene more than the corresponding singlet state. The oxygen atom also stabilizes the transition state of the Curtius rearrangement and accelerates the isomerization of methoxycarbonylnitrene relative to acetylnitrene. Acetyl azide is calculated to decompose by concerted migration of the methyl group along with nitrogen extrusion; the free energy of activation for this concerted process is only 27 kcal/mol, and a free nitrene is not produced upon pyrolysis of acetyl azide. Methoxycarbonyl azide, on the other hand, does have a preference for stepwise Curtius rearrangement via the free nitrene. The bimolecular reactions of acetylnitrene and methoxycarbonylnitrene with propane, ethylene, and methanol were calculated and found to have enthalpic barriers that are near zero and free energy barriers that are controlled by entropy. These predictions were tested by laser flash photolysis studies of benzoyl azide. The absolute bimolecular reaction rate constants of benzoylnitrene were measured with the following substrates: acetonitrile (k = 3.4 x 10(5) M(-1) (s-1)), methanol (6.5 x 10(6) M(-1) s(-1)), water (4.0 x 10(6) M(-1) s(-1)), cyclohexane (1.8 x 10(5) M(-1) s(-1)), and several representative alkenes. The activation energy for the reaction of benzoylnitrene with 1-hexene is -0.06 +/- 0.001 kcal/mol. The activation energy for the decay of benzoylnitrene in pentane is -3.20 +/- 0.02 kcal/mol. The latter results indicate that the rates of reactions of benzoylnitrene are controlled by entropic factors in a manner reminiscent of singlet carbene processes.

Journal Article↗

PubMed2001

Effect of the respiratory activity on photoinhibition of the cyanobacterium Synechocystis sp.

The influence of respiratory activity on photosynthesis in Synechocystis cells that had been exposed to high light intensity was studied using distinct conditions of nitrogen supply. The photoinhibitory rate of N-sufficient cells was not influenced by the presence of different nitrogen sources. In contrast, when N-starved cells were resupplied with ammonium, they were protected from photoinhibition. Although N-starved cells presented a higher rate of dark O(2) uptake than N-sufficient ones, the photoinhibitory rate increased in both cases after addition of sodium azide or sodium azide plus salicylhydroxamic acid in the photoinhibitory treatment. In the absence of the D(1) protein repair mechanism, photodamage to Photosystem II was faster in N-sufficient cells than in N-starved ones. Mitigation of photodamage disappeared when the respiratory activity of N-starved cells was partially suppressed by the addition of sodium azide or sodium azide and salicylhydroxamic acid. Our results suggest that electron flow through cyanobacterial terminal oxidases can assist Photosystem I in removing electrons from the reduced plastoquinone pool, thus contributing to both reopening of Photosystem II reaction centers and avoiding photogeneration of reactive oxygen species under photoinhibitory conditions.

Journal Article↗

PubMed2003

Tetrazole synthesis via the palladium-catalyzed three component coupling reaction.

The synthesis of tetrazoles was achieved via the palladium-catalyzed three component coupling (TCC) reaction; The TCC reaction of malononitrile derivatives, allyl acetate and trimethylsilyl azide proceeds very smoothly under a catalytic amount of Pd(PPh3)4 to give 2-allyltetrazoles, and further the TCC reaction of various activated cyano compounds, allyl methyl carbonate and trimethylsilyl azide proceeds readily under a catalytic amount of Pd2(dba)3 x CHCl3 and (2-furyl)3P to give 2-allyltetrazoles. pi-Allylpalladium azide complex is proposed as a key intermediate in the catalytic cycle and the [3 + 2] cycloaddition between the pi-allylpalladium azide complex and cyano compounds most probably gives the tetrazole frameworks. The deallylation of the derived allyltetrazoles was attained via the two-step procedure; the ruthenium-catalyzed isomerization and ozonolysis.

Allyl Compounds↗

PubMed2003

Asymmetric synthesis of anti-(2S,3S)- and syn-(2R,3S)-diaminobutanoic acid.

Conjugate addition of homochiral lithium N-benzyl-N-alpha-methylbenzylamide to tert-butyl (E)-cinnamate or tert-butyl (E)-crotonate and in situ amination with trisyl azide results in the exclusive formation of the corresponding 2-diazo-3-amino esters in > 95% de. Amination of the lithium (E)-enolates of tert-butyl (3S,alphaR)-3-N-benzyl-N-alpha-methylbenzylamino-3-phenylpropanoate or tert-butyl (3S,alphaS)-3-N-benzyl-N-alpha-methylbenzylaminobutanoate with trisyl azide gives the (2R,3R,alphaR)- and (2S,3S,alphaS )-anti-2-azido-3-amino esters in good yields and in 85% de and > 95% de respectively. Alternatively, tert-butyl anti-(2S,3S,alphaS)-2-hydroxy-3-N-benzyl-N-alpha-methylbenzylaminobutanoate may be converted selectively to tert-butyl anti-(2S,3S,alphaS)-2-azido-3-N-benzyl-N-alpha-methylbenzylaminobutanoate by aziridinium ion formation and regioselective opening with azide. Deprotection of tert-butyl (2S,3S,alphaS)-2-azido-3-aminobutanoate via Staudinger reduction, hydrogenolysis and ester hydrolysis furnishes anti-(2S,3S)-diaminobutanoic acid in 98%, de and 98% ee. The asymmetric synthesis of the diastereomeric syn-(2R,3S)-diaminobutanoic acid (98% de and 98% ee) was accomplished via functional group manipulation of tert-butyl anti-(2S,3S,alphaS)-2-hydroxy-3-N-benzyl-N-alpha-methylbenzylaminobutanoate in a protocol involving azide inversion of tert-butyl (2S,3S)-2-mesyloxy-3-N-Boc-butanoate and subsequent deprotection.

Journal Article↗

PubMed1995

Dissection of stress-activated glucose transport from insulin-induced glucose transport in mammalian cells using wortmannin and ML-9.

The signaling pathways responsible for the activation of glucose transport by insulin and by metabolic stress in mammalian cells were studied in Clone 9 cells and 3T3-L1 adipocytes. Exposure of both cell types to azide or insulin markedly increased their glucose uptake capacity (Vmax.) without affecting their apparent affinity for glucose (Km). The effects of azide and insulin were not additive. Wortmannin, a selective inhibitor of phosphatidylinositol (PI) 3-kinase, did not affect stimulation of transport by azide but inhibited insulin-induced glucose transport with a Ki of < 10 nM. ML-9, a putative mitogen-activated protein kinase inhibitor, was equipotent in its inhibition of azide- and insulin-stimulated glucose transport. These findings suggest that multiple signalling cascades are involved in the stimulation of glucose transport in mammalian cells and that PI 3-kinase, an essential link in the pathway by which insulin stimulates glucose transport, is not necessary for the activation of glucose uptake by metabolic stress.

3T3 Cells↗

PubMed1979

Identification of the polypeptide chains in Torpedo californica electroplax membranes that interact with a local anesthetic analog.

Procaine amide azide, a derivative of the local anesthetic procaine amide, was prepared and its interactions with acetylcholine receptor-rich membrane fragments from Torpedo californica electroplax were studied. Procaine amide azide was radiolabeled by a method that may be of general use for the preparation of other radioactive tertiary amines. When low concentrations of 3H-labeled procaine amide azide were photolyzed in the presence of receptor-rich membrane preparations, a simple pattern of incorporated radioactivity was seen after electrophoresis on sodium dodecyl sulfate/polyacrylamide gels. Only two major labeled bands were seen, corresponding to apparent Mr of about 43,000 and 90,000. When the length of the gels was increased, the labeled band of lower Mr was resolved into two labeled proteins, one major and one minor, with apparent Mr of 43,000 and 40,000, respectively. The radioactivity incorporated into the protein of Mr 40,000 could be attributed to interaction of [3H]procaine amide azide with cholinergic ligand-binding sites, whereas labeling of the polypeptide of Mr 43,000 appears to represent interaction of the photolabile derivative with another class of sites. The labeling component of 90,000 Mr could be removed by preparation of membrane fragments in iodoacetamide-containing buffer and therefore appeared unrelated to the acetylcholine receptor.

Affinity Labels↗

PubMed1989

Aspartic acid-96 is the internal proton donor in the reprotonation of the Schiff base of bacteriorhodopsin.

Above pH 8 the decay of the photocycle intermediate M of bacteriorhodopsin splits into two components: the usual millisecond pH-independent component and an additional slower component with a rate constant proportional to the molar concentration of H+, [H+]. In parallel, the charge translocation signal associated with the reprotonation of the Schiff base develops a similar slow component. These observations are explained by a two-step reprotonation mechanism. An internal donor first reprotonates the Schiff base in the decay of M to N and is then reprotonated from the cytoplasm in the N----O transition. The decay rate of N is proportional to [H+]. By postulating a back reaction from N to M, the M decay splits up into two components, with the slower one having the same pH dependence as the decay of N. Photocycle, photovoltage, and pH-indicator experiments with mutants in which aspartic acid-96 is replaced by asparagine or alanine, which we call D96N and D96A, suggest that Asp-96 is the internal proton donor involved in the re-uptake pathway. In both mutants the stoichiometry of proton pumping is the same as in wild type. However, the M decay is monophasic, with the logarithm of the decay time [log (tau)] linearly dependent on pH, suggesting that the internal donor is absent and that the Schiff base is directly reprotonated from the cytoplasm. Like H+, azide increases the M decay rate in D96N. The rate constant is proportional to the azide concentration and can become greater than 100 times greater than in wild type. Thus, azide functions as a mobile proton donor directly reprotonating the Schiff base in a bimolecular reaction. Both the proton and azide effects, which are absent in wild type, indicate that the internal donor is removed and that the reprotonation pathway is different from wild type in these mutants.

Aspartic Acid↗

PubMed1972

Endogenous metabolism of fungus spores: stimulation by physical and chemical means.

Endogenous respiration of spores of the fungus Myrothecium verrucaria can be stimulated up to over-10 fold by diverse chemicals or by physical treatments. Greatest effects were caused by azide (12-fold at 250 mum) and by 2,4-dinitrophenol (7-fold at 300 mum). Marked stimulation was also caused by 10 mum silver (5-fold), 30 mum pentachlorophenol (6-fold), 10 mum carbonyl cyanide m-chlorophenyl hydrazone (4.5-fold) and 10 mum merthiolate (4-fold). Physical treatments such as heat (50 C), freezing, and sonication at sublethal levels were also stimulatory. Stimulation by azide or dinitrophenol was much greater in young than in old spores, whereas response to other chemicals and to freezing was relatively unaffected by spore age. In older spores the effect of azide was no greater than some other inhibitors. During incubation with azide, the endogenous trehalose reserves decreased and changes in free amino acids occurred, both increases and decreases. Thus anabolic as well as catabolic changes occur as evidenced also by the germination of a few (up to 5%) spores. The mechanisms of stimulation must be varied and complex. Permeability changes in the membrane confining endogenous reserves are proposed as a common initial cause. Additional changes in characteristics of membranes of other subcellular particles, as well as enzymic phenomena such as uncoupling of oxidative phosphorylation, are presumably involved in instances where greater stimulation occurs. The data are consistent with the hypothesis that dormancy in these spores results from separation of substrates from metabolic enzymes and more specifically that metabolites are sequestered rather than enzymes.

Journal Article↗

PubMed2002

(-)-alpha-Isosparteine copper(II) diazide.

In the title complex, [Cu(N(3))(2)(C(15)H(26)N(2))], the Cu atom is surrounded by the two N atoms of the chelating (-)-alpha-isosparteine ligand and another two N atoms from the two azide anions, forming a distorted CuN(4) tetrahedron. The two azide anions are terminally bound to the Cu(II) atom, and the dihedral angle between the N(sparteine)[bond]Cu[bond]N(sparteine) and N(azide)[bond]Cu[bond]N(azide) planes is 50.0 (2) degrees.

Journal Article↗

PubMed2005

catena-Poly[[{4-bromo-2-[2-(dimethylamino)ethyliminomethyl]phenolato}copper(II)]-mu-azido].

The title complex, [Cu(C11H14BrN2O)(N3)]n, is an interesting azide-bridged polynuclear copper(II) compound. The Cu(II) atom is five-coordinated in a square-pyramidal configuration, with one O and two N atoms of one Schiff base and one terminal N atom of a bridging azide ligand defining the basal plane, and another terminal N atom of another bridging azide ligand occupying the axial position. The {4-bromo-2-[2-(dimethylamino)ethyliminomethyl]phenolato}copper(II) moieties are linked by the bridging azide ligands, forming polymeric chains running along the b axis. Adjacent chains are further linked by weak Br...Br interactions into a sheet.

Journal Article↗

PubMed1995

The oxidation of hemocyanin. Kinetics, reaction mechanism and characterization of met-hemocyanin product.

The reaction that gives met-hemocyanin from Octopus vulgaris oxy-hemocyanin has been reinvestigated under several experimental conditions. Various anions including azide, fluoride and acetate have been found to promote this reaction. Kinetic data indicate that the reaction mechanism is different from that currently accepted involving a peroxide displacement of bound dioxygen through an associative chemistry on an open axial position of the copper ions [Hepp, A. F., Himmelwright, R. S., Eickman, N. C. & Solomon, E. I. (1979) Biochem. Biophys. Res. Commun. 89, 1050-1057; Solomon, E. I. in Copper proteins (Spiro, T. G., ed.) pp. 43-108, J. Wiley, New York]. Our study suggests that the protonated form of the anion is likely to be the species reacting with the oxygenated form of the protein. Furthermore, it is also proposed that protonation of bound dioxygen generates an intermediate hydroperoxo-dicopper(II) complex to which the exogenous anion is also bound. This intermediate in not accumulated and preceds the release of hydrogen peroxide by reaction with water. Upon dialysis it leads to the met-hemocyanin form. The structure of this dinuclear copper(II) derivative contains a di-mu-hydroxo bridge but there is evidence from optical and circular dichroism spectra for partial protonation of these bridges at low pH. As a consequence, while one azide molecule binds in the bridging mode to met-hemocyanin with low affinity (K = 30 M-1) at pH 7.0, it binds with much higher affinity at pH 5.5 (K = 1500 M-1), where a second azide ligand also binds in the terminal mode (K = 20 M-1). The coordination mode of the azide ligands is deduced from the optical and circular dichroism spectra of the protein complexes.

Animals↗

PubMed1969

Occurrence of false-positive most probable number tests for fecal streptococci in marine waters.

By the use of the most probable number technique with azide dextrose and ethyl violet azide broths for enterococci, the common occurrence of false-positive tests was noted when marine and estuarine waters were sampled. Organisms isolated included a marine bacterium, gram-positive and gram-negative nonmarine bacteria, and yeasts. All cultures were capable of growth in azide-dextrose, ethyl violet-azide, and KF broths. Representative isolates grew in media containing 0.08% NaN(3). The tentatively accepted most probable number method for fecal streptococci is thus of dubious value in assessment of sewage pollution levels in estuarine waters. All positive tubes must be examined microscopically for the presence of nonstreptococcal forms.

Bacteriological Techniques↗

PubMed1979

[Existence of several non-specific recognition systems in macrophages].

Rat peritoneal cells were made to bind five particle species: immunoglobulin-coated Sheep red cells, glutaraldehyde-treated Sheep red cells, latex beads, leishmania and tumor cells. The dependence of binding on various physico-chemical parameters was studied. The binding of latex beads or Leishmania was not inhibited by cold (4 degrees C), sodium azide, cytochalasin B and ethyleneglycol or dimethylsulphoxide. The binding of immunoglobulin-coated Sheep red cells was unaffected by cold and azide, but it was inhibited by cytochalasin B, ethyleneglycol and dimethylsulphoxide. The binding of glutaraldehyde-treated Sheep red cells was inhibited by cold, azide and ethyleneglycol, but it resisted cytochalasin B and dimethylsulphoxide. The binding of tumor cells was inhibited by azide, cytochalasin B, ethyleneglycol and dimethylsulphoxide. It is concluded that: (a) macrophages are endowed several sets of non-specific binding structures that are differently affected by physico-chemical parameters, which provides a simple way of characterizing them; (b) the expression of a given binding structure on the macrophage membrane is modulated by metabolic inhibitors; (c) some lymphocytes were able to bind tumor cells or Leishmania. Thus, lymphocytes and macrophages might share some non-specific adhesive structures.

Agglutination Tests↗

PubMed1977

Activation of guanylate cyclase in cerebral cortex of rat by hydroxylamine.

Hydroxylamine actived guanylate cyclase in particulate fraction of cerebral cortex of rat. Activation was most remarkable in crude mitochondrial fraction. When the crude mitochondrial fraction was subjected to osmotic shock and fractionated, guanylate cyclase activity recovered in the subfractions as assayed with hydroxylamine was only one-third of the starting material. Recombination of the soluble and the particulate fractions, however, restored guanylate cyclase activity to the same level as that of the starting material. When varying quantities of the particulate and soluble fractions were combined, enzyme activity was proportional to the quantity of the soluble fraction. Heating of the soluble or particulate fraction at 55 degrees for 5 min inactivated guanylate cyclase. The heated particulate fraction markedly activated guanylate cyclase activity in the native soluble fraction, while the heated soluble fraction did not stimulate enzyme activity in the particulate. The particulate fraction preincubated with hydroxylamine at 37 degrees for 5 min followed by washing activated guanylate cyclase activity in the soluble fraction in the absence of hydroxylamine. Further fractionation of the crude mitochondrial fraction revealed that the factor(s) needed for the activation by hydroxylamine is associated with the mitochondria. The mitochondrial fraction of cerebral cortex activated guanylate cyclase in supernatant of brain, liver, or kidney in the presence of hydroxylamine. The mitochondrial fraction prepared from liver or kidney, in turn, activated soluble guanylate cyclase in brain. Activation of guanylate cyclase by hydroxylamine was compared with that of sodium azide. Azide activated guanylate cyclase in the synaptosomal soluble fraction, while hydroxylamine inhibited it. The particulate fraction preincubated with azide followed by washing did not stimulate guanylate cyclase activity in the absence of azide. The activation of guanylate cyclase by hydroxylamine is not due to a change in the concentration of the substrate GTP, Addition of hydroxylamine did not alter the apparent Km value of guanylate cyclase for GTP. Guanylate cyclase became less dependent on manganese in the presence of hydroxylamine. Thus the activation of guanylate cyclase by hydroxylamine is due to the change in the Vmax of the reaction.

Animals↗

PubMed1987

Triazene metabolism. VI. 3-Azidomethyl-3-alkyl-1-aryltriazenes, a new class of anti-tumour triazene with potential pro-drug applications.

The synthesis of a new series of 3-azidomethyl-3-methyl-1-aryltriazenes is described. 3-Acetoxymethyl-3-methyl-1-aryltriazenes react with a large molar excess of sodium azide in aqueous acetone to afford the 3-azidomethyltriazenes in high yield. The rate of formation of the azidomethyltriazene increasing azide concentration, suggesting either an SN2 mechanism or a significant ionic strength effect on an SN1 reaction. In the absence of azide ion, the acetoxymethyltriazene undergoes a slow hydrolysis to give a bis-anilinomethane, which presumably arises via hydrolysis of the triazene to the aniline followed by condensation with formaldehyde released during the hydrolysis. The azidomethyltriazenes undergo facile hydrolysis in aqueous buffer solution with identical kinetic parameters to those of the hydrolysis of hydroxymethyltriazenes, suggesting that the azides may be good pro-drugs for the cytotoxic monomethyltriazene, the hydrolysis product derived from the hydroxymethyltriazene. Indeed, the azidomethyltriazenes have comparable anti-tumour activity against the P388 and PC6 tumours to other triazenes in this series. Furthermore, the azidomethyltriazenes display selective toxicity towards a human tumour cell line (the BE cell line) which is deficient in the repair of O6-methylguanine lesions, suggesting that these triazenes are capable of generating the monomethyltriazene without the need for metabolic activation.

Antineoplastic Agents↗