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Michael Novak

Publications and source records attributed to Michael Novak.

9 recordsLinked to original sources
PubMed2006

4'-substituted-4-biphenylyloxenium ions: reactivity and selectivity in aqueous solution.

Azide trapping shows that the 4'-substituted-4-biphenylyloxenium ions 1b-d are generated during hydrolysis of 4-aryl-4-acetoxy-2,5-cyclohexadienones, 2c and 2d, and O-(4-aryl)phenyl-N-methanesulfonylhydroxylamines, 3b and 3c. In addition, the 4'-bromo-substituted ester, 2d, undergoes a kinetically second-order reaction with N3- that accounts for a fraction of the azide adduct, 5d. Since both first-order and second-order azide trapping occurs simultaneously in 2d, the second-order reaction is not enforced by the short lifetime of 1d, which has similar azide/solvent selectivity to the unsubstituted ion, 1a. In contrast the 4'-CN and 4'-NO2 ions 1e and 1f cannot be detected by azide trapping during the hydrolysis of the dichloroacetic acid esters 2e' and 2f' even though 18O labeling experiments show that a fraction of the hydrolysis of both esters occurs through C(alkyl)-O bond cleavage. These esters exhibit only second-order trapping by azide. Correlations of the azide/solvent selectivities of 1a-d with the calculated relative driving force for hydration of the ions (DeltaE of eq 4) determined at the pBP/DN//HF/6-31G and BP/6-31G//HF/6-31G levels of theory suggest that 1e and 1f have lifetimes in the 1-100 ps range. Ions with these short lifetimes are not in diffusional equilibrium with nonsolvent nucleophiles, and must be trapped by such nucleophiles via a preassociation mechanism. The second-order trapping that is observed in these two cases is enforced by the short lifetime of the cations, and may occur by a concerted S(N)2' mechanism or by internal azide trapping of an ion sandwich produced by azide-assisted ionization. Comparison of azide/solvent selectivities of the oxenium ions 1a-c with the corresponding biphenylylnitrenium ions 8a-c shows that 4'-substituent effects on reactivity in both sets of ions are similar in magnitude, although the nitrenium ions are ca. 30-fold more stable in an aqueous environment than the corresponding oxenium ions. The magnitude of the 4'-substituent effects for electron-donating substituents suggest that both sets of ions are more accurately described as 4-aryl-1-imino-2,5-cyclohexadienyl or 4-aryl-1-oxo-2,5-cyclohexadienyl carbocations. Calculated structures of the oxenium ions are also consistent with this interpretation.

Journal Article↗
PubMed2006

Silver-coated dressing acticoat caused raised liver enzymes and argyria-like symptoms in burn patient.

BACKGROUND: Treatment of acute burn wounds with silver sulfadiazine (SSD) has raised concern about potential silver toxicity. Numerous adverse reactions and side effects have been reported and an increasing resistance to SSD, especially in Pseudomonas strains, have motivated researchers to search for an alternative wound dressing. METHODS: Recently, a silver-coated wound dressing Acticoat (Smith & Nephew, Inc.) has become available for use in burn patients. It is a three-ply dressing, consisting of an inner rayon/polyester absorptive core between two layers of silver-coated, high-density polyethylene mesh. In a moist environment, the nanocrystals of silver are released and improve the microbial control in the wound. RESULTS: After 1 week of local treatment with Acticoat in a young, previously healthy 17-year-old boy with 30% mixed depth burns, hepatotoxicity and argyria-like symptoms, a grayish discoloration of the patient's face, appeared. The silver levels in plasma (107 microg/kg) and urine (28 microg/kg) were clearly elevated, as well as the liver enzymes. As soon as the local application of Acticoat was aborted, the clinical symptoms and liver enzymes returned to the normal values. CONCLUSIONS: This is the first report on silver toxicity in a patient with 30% burns who received Acticoat for local treatment. Due to substantial experiences with adverse SSD reactions and side effects, it is appropriate to keep the possibility of a toxic silver effect in burn patients treated with Acticoat silver-coated wound dressing in mind. The silver levels in plasma and/or urine should be monitored.

Adolescent↗
PubMed2005

The hydrolysis of 4-acyloxy-4-substituted-2,5-cyclohexadienones: limitations of aryloxenium ion chemistry.

The title compounds serve as potential precursors to aryloxenium ions, often proposed, but primarily uncharacterized intermediates in phenol oxidations. The uncatalyzed and acid-catalyzed decomposition of 4-acetoxy-4-phenyl-2,5-cyclohexadienone, 2a, generates the quinol, 3a. (18)O-Labeling studies performed in (18)O-H(2)O, and monitored by LC/MS and (13)C NMR spectroscopy that can detect (18)O-induced chemical shifts on (13)C resonances, show that 3a was generated in both the uncatalyzed and acid-catalyzed reactions by C(alkyl)-O bond cleavage consistent with formation of an aryloxenium ion. Trapping with N(3)(-) and Br(-) confirms that both uncatalyzed and acid-catalyzed decompositions occur by rate-limiting ionization to form the 4-biphenylyloxenium ion, 1a. This ion has a shorter lifetime in H(2)O than the corresponding nitrenium ion, 7a (12 ns for 1a, 300 ns for 7a at 30 degrees C). Similar analyses of the product, 3b, of acid- and base-catalyzed decomposition of 4-acetoxy-4-methyl-2,5-cyclohexadienone, 2b, in (18)O-H(2)O show that these reactions are ester hydrolyses that proceed by C(acyl)-O bond cleavage processes not involving the p-tolyloxenium ion, 1b. Uncatalyzed decomposition of the more reactive 4-dichloroacetoxy-4-methyl-2,5-cyclohexadienone, 2b', is also an ester hydrolysis, but 2b' undergoes a kinetically second-order reaction with N(3)(-) that generates an oxenium ion-like substitution product by an apparent S(N)2'mechanism. Estimates based on the lifetimes of 1a, 7a, and the p-tolylnitrenium ion, 7b, and the calculated relative stabilities of these ions toward hydration indicate that the aqueous solution lifetime of 1b is ca. 3-5 ps. Simple 4-alkyl substituted aryloxenium ions are apparently not stable enough in aqueous solution to be competitively trapped by nonsolvent nucleophiles.

Journal Article↗
PubMed2004

Generation and trapping of the 4-biphenylyloxenium ion by water and azide: comparisons with the 4-biphenylylnitrenium ion.

Generation of the 4-biphenylyloxenium ion, 1a, from hydrolysis of 4-acetoxy-4-phenyl-2,5-cyclohexadienone, 2a, is demonstrated by common ion rate depression and azide trapping. The ion is less selective with a shorter lifetime (12 ns at 30 degrees C) in aqueous solution than the corresponding nitrenium ion, 6a (ca 0.3 mus at 30 degrees C). Its lifetime is considerably longer than those of structurally related carbenium ions. Unlike 6a, 1a reacts with N3-, in part, at the distal ring to generate 4'-azido-4-hydroxybiphenyl, 5. These results are rationalized by calculations at the HF/6-31G* and pBP/DN*//HF/6-31G* levels that show that 1a is planar but is less stable than 6a relative to their hydration products by ca. 12 kcal/mol. The p-tolyloxenium ion, 1b, has not been unequivocally demonstrated to be formed in H2O, but kinetic data show that it must be at least 104-fold less stable than 1a relative to their respective 4-acetoxy derivatives. It is also calculated to be ca. 19 kcal/mol less stable than the corresponding nitrenium ion, 6b, relative to their hydration products.

Journal Article↗
PubMed2003

Unusual reactions of the model carcinogen N-acetoxy-N-acetyl-2-amino-alpha-carboline.

The aqueous solution reactions of the title compound, 1, were examined for comparison to those previously reported for another model carcinogen N-pivaloyloxy-2-amino-alpha-carboline, 2. Both of these are models for the ultimate carcinogenic metabolites of 2-amino-alpha-carboline (AalphaC), a food-derived heterocyclic amine mutagen and carcinogen. The present study was undertaken to determine the effect of the N-acetyl group on the chemistry of such compounds. The N-acetyl group slows down N-O bond cleavage by a factor of (5.5 x 10(3))-fold. This allows other reactions not observed in 2, or in other model carcinogens, to be observed. Among these are acyl-transfer reactions to the aqueous solvent, both uncatalyzed and catalyzed by N3-. In addition, the conjugate acid of 1, 1H+, is subject to a spontaneous decomposition not previously observed in other esters of heterocyclic hydroxylamines or hydroxamic acids. This reaction yields the hydroxylamine, 5, and does so without the intermediacy of the hydroxamic acid, 3, and with 18O exchange from the solvent into the hydroxylamine O. This unique reaction may be caused by an intramolecular proton donation by the pyridyl N-H to the amide carboxyl that catalyzes an intramolecular nucleophilic attack by the carboxyl O of 1H+. A nitrenium ion pathway can still be detected for 1, but, unlike 2 and related esters, this reaction is in competition with other processes throughout the pH range of the study.

Amides↗
PubMed2002

Reactivity and selectivity of the N-acetyl-Glu-P-1, N-acetyl-Glu-P-2, N-acetyl-MeIQx, and N-acetyl-IQx nitrenium ions: comparison to carbocyclic N-arylnitrenium ions.

The model ultimate carcinogens 1a-d, related to the metabolites of the food-derived carcinogenic heterocyclic amines Glu-P-1, Glu-P-2, MeIQx, and IQx, spontaneously decompose in neutral aqueous solution to generate the heterocyclic nitrenium ions, 2a-d. The less reactive esters 1a and 1b also undergo acid-catalyzed ester hydrolysis to generate the corresponding hydroxamic acids at pH <2, while the more reactive 2c and 2d are prone to rearrangement in nonaqueous solvents. The reactions of the nitrenium ions with AcO(-), HPO(4)(2-), N(3)(-), and 2'-deoxyguanosine (d-G) were characterized in aqueous solution by using a combination of competitive trapping methods and product isolation and identification. The reactions with N(3)(-) and d-G generally follow patterns previously established for carbocyclic nitrenium ions, but the reactions with AcO(-) and HPO(4)(2-) are unusual. Similar reactions have previously only been reported for heterocyclic 1-alkyl-2-imidazolium ions. The N(3)(-)/solvent selectivities of these ions (5.1 x 10(6) M(-1) for 2a, 2.3 x 10(6) M(-1) for 2b, 1.2 x 10(5) M(-1) for 2c, and 5.2 x 10(4) M(-1) for 2d) are comparable to those of highly selective carbocyclic nitrenium ions. If k(az) for these ions is diffusion limited at ca. 5 x 10(9) M(-1) s(-1) the aqueous solution lifetimes of these ions range from 10 micros (2d) to 1 ms (2a). These ions are also highly selective for trapping by d-G, but comparisons to other nitrenium ions show that they are 10- to 50-fold less selective for trapping by d-G than they would be if both the N(3)(-) and d-G reactions were diffusion limited. This is not a consequence of their heterocyclic structures. Several carbocyclic ions show similar behavior. The relatively inefficient trapping of 2c and 2d by d-G may account for the observation of the unusual minor N-2 d-G adduct that is isolated for both of these nitrenium ions, but has not previously been observed for the reactions of other nitrenium ions with monomeric d-G.

Acetylation↗
PubMed2002

Kinetics of hydrolysis of 8-(arylamino)-2'-deoxyguanosines.

The 8-(arylamino)-2'-deoxyguanosines, or C-8 adducts, are the major adducts formed by reaction of N-arylnitrenium ions derived from carcinogenic and mutagenic amines with 2'-deoxyguanosine (d-G) and guanosine residues of DNA. The hydrolysis kinetics of three C-8 adducts 1a-c were determined by UV and HPLC methods at 20 degrees C under acidic, neutral, and mildly alkaline conditions. At pH < 2 the dominant hydrolysis process is spontaneous cleavage of the C-N bond of the doubly protonated substrate, 1H(2)(+2) (Scheme 2). The C-8 adducts are 2- to 5-fold more reactive than d-G under these conditions. At 3 < pH < 6 the hydrolysis kinetics are dominated by cleavage of the C-N bond of the monoprotonated nucleoside 1H(+). Under these conditions the hydrolysis kinetics are accelerated by 40- to 1300-fold over that of d-G. The rate increase appears to be caused by a combination of steric acceleration of C-N bond cleavage and a decrease in the ionization constant of 1H(+), K(a1), due to the electron-donating properties of the arylamino C-8 substituent. Under neutral pH conditions a slow (k(obs) approximately 10(-8) s(-1) to 5 x 10(-7) s(-1)) spontaneous cleavage of the C-N bond of the neutral nucleoside, 1, occurs that has not been previously reported for simple purine nucleosides. Finally, under mildly alkaline conditions a process consistent with spontaneous decomposition of the anion 1(-) or OH(-)-induced decomposition of 1 is observed. The latter process has been observed for other purine nucleosides, including the closely related 1d, and involves nucleophilic attack of OH(-) on C-8 to cleave the imidazole ring of the purine.

Algorithms↗
PubMed2002

Correlations of nitrenium ion selectivities with quantitative mutagenicity and carcinogenicity of the corresponding amines.

There is a correlation (r(adj)(2) = 0.5491-0.6338) of quantitative mutagenicity, log m, for a series of heterocyclic (HCAs) and carbocyclic (AAs) aromatic amines in Salmonella typhimurium TA 98 (18 amines) and TA 100 (15 amines) vs log S, the log of the azide/solvent selectivity of the corresponding nitrenium ion. Monocyclic aromatic amines, MAAs, are less mutagenic than other amines of similar log S. Multiple variable linear regression analysis led to a two parameter regression model, significant at the 95% confidence level for both variables, that includes log S and a ring index variable, I(rings), that is 0 for MAAs and 1 for all other amines. These models have r(adj)(2) = 0.8448 for TA 98, and 0.8927 for TA 100. Inclusion of a third variable, Clog P, increases r(adj)(2) to 0.8913 for TA 98 and 0.9011 for TA 100. This model is significant at the 95% confidence level for all variables for TA 98, but only for two of the three variables for TA 100. The confidence level is 80% for Clog P in TA 100. Quantitative carcinogenicity data in mice and rats are more weakly correlated with log S (r(adj)(2) = 0.5357 for 12 amines in mice, r(adj)(2) = 0.4216 for 10 amines in rats). Several two parameter regression models, all containing Clog P and one containing log S, adequately correlate the mouse data.

Amines↗