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PubMed2005

S-oxygenation of thiocarbamides I: Oxidation of phenylthiourea by chlorite in acidic media.

The oxidation of 1-phenyl-2-thiourea (PTU) by chlorite was studied in aqueous acidic media. The reaction is extremely complex with reaction dynamics strongly influenced by the pH of reaction medium. In excess chlorite concentrations the reaction stoichiometry involves the complete desulfurization of PTU to yield a urea residue and sulfate: 2ClO2- + PhN(H)CSNH2 + H2O --> SO4(2-) + PhN(H)CONH2 + 2Cl- + 2H+. In excess PTU, mixtures of sulfinic and sulfonic acids are formed. The reaction was followed spectrophotometrically by observing the formation of chlorine dioxide which is formed from the reaction of the reactive intermediate HOCl and chlorite: 2ClO2- + HOCl + H+ --> 2ClO2(aq) + Cl- + H2O. The complexity of the ClO2- - PTU reaction arises from the fact that the reaction of ClO2 with PTU is slow enough to allow the accumulation of ClO2 in the presence of PTU. Hence the formation of ClO2 was observed to be oligooscillatory with transient formation of ClO2 even in conditions of excess oxidant. The reaction showed complex acid dependence with acid catalysis in pH conditions higher than pKa of HClO2 and acid retardation in pH conditions of less than 2.0. The rate of oxidation of PTU was given by -d[PTU]/dt = k1[ClO2-][PTU] + k2[HClO2][PTU] with the rate law: -d[PTU]/dt = [Cl(III)](T)[PTU]0/K(a1) + [H+] [k1K(a1) + k2[H+]]; where [Cl(III)]T is the sum of chlorite and chlorous acid and K(a1) is the acid dissociation constant for chlorous acid. The following bimolecular rate constants were evaluated; k1 = 31.5+/-2.3 M(-1) s(-1) and k2 = 114+/-7 M(-1) s(-1). The direct reaction of ClO2 with PTU was autocatalytic in low acid concentrations with a stoichiometric ratio of 8:5; 8ClO2 + 5PhN(H)CSNH2 + 9H2O --> 5SO4(2-) + 5PhN(H)CONH2 + 8Cl- + 18H+. The proposed mechanism implicates HOCl as a major intermediate whose autocatalytic production determined the observed global dynamics of the reaction. A comprehensive 29-reaction scheme is evoked to describe the complex reaction dynamics.

Journal Article↗
PubMed1980

Unsymmetrical alkyl aryl thiourea compounds for use as cerebral blood flow tracers.

The synthesis and characterization of an homologous series of inert nonvolatile 14C-labeled unsymmetrical alkyl aryl thiourea compounds is described for their use as regional blood flow (rCBF) tracers employing autoradiographic procedures. In alert normocapnic rats the single-pass extraction values into brain for these thioureas were found to be dependent on their respective lipid solubilities ranging from 0.497 for 1-methyl-3-phenylthiourea to 0.730 for 1-butyl-3-phenylthiourea. The commonly used rCBF tracers [14C]antipyrine and [14C]iodoantipyrine had single-pass extraction values of 0.451 and 0.553, respectively. The single-pass extraction value for n-butanol was found to be the same as that for 1-butyl-3-phenylthiourea indicating that both n-butanol and 1-butyl-3-phenylthiourea are mildly diffusion limited at normal rates of flow in rat brain. Since 1-butyl-3-phenylthiourea diffused most readily into rat brain it was chosen as a potentially valuable rCBF tracer. Its brain-blood partition coefficient was found to be 1.09. The plasma distribution of this thiourea in blood varied inversely with the hematocrit, and the compound was freely exchangeable between plasma and erythrocytes. Employing 1-butyl-3-phenylthiourea to measure rCBF and its empirically derived brain extraction values the following flow rates in normocapnic rats were found: 3.2 ml . g-1 . min-1 for cochlear nucleus: 3.0 for inferior colliculus; 2.5 for medical geniculate; 1.9 for pontine gray and hypothalamus; 1.7 for caudate and cerebral cortex; and 1.2 for cerebellar gray and 0.41-0.50 for white matter structures. It was concluded from these studies that 1-butyl-3-phenylthiourea is more advantageous than iodoantipyrine for measuring rCBF, especially in those areas that possess very rapid rates of flow.

Animals↗
PubMed2004

Development of N-benzamidothioureas as a new generation of thiourea-based receptors for anion recognition and sensing.

A series of neutral N-(substituted-benzamido)-N'-phenylthioureas (substituent = p-OC(2)H(5), p-CH(3), m-CH(3), H, p-Cl, p-Br, m-Cl, and p-NO(2)) were designed as anion receptors, in which the thiourea binding site was attached to the benzamido moiety via an N-N bond. The absorption spectra of these N-benzamidothioureas in acetonitrile peaked at ca. 270 nm were found to show unprecedented red shifts by 7 373 to 14 325 cm(-1) in the presence of anions such as AcO(-), F(-), and H(2)PO(4)(-). Under the same conditions, the classic neutral thiourea receptors, N-(substituted-phenyl)-N'-phenylthioureas, showed absorption spectral shifts in most cases of less than 800 cm(-1) with one exception of 6501 cm(-1). Control experiments, effects of protic solvent, and (1)H NMR titration confirmed the formation of hydrogen-bonding complexes between the new N-benzamidothiourea receptors and anions. The binding constants with AcO(-), for example, are at 10(5)-10(7) mol(-1) L order of magnitude, which are 13 to 590 times those of the corresponding classic N-phenylthioureas in the same solvent. It was found that, whereas the absorption of the N-benzamidothiourea receptors showed essentially no dependence on the substituent, the substantially red-shifted new absorption band of the N-benzamidothiourea-anion binding complex was sensitively subject to the substituent. A linear relationship was found between the absorption energies of the N-benzamidothiourea-acetate binding complexes and the Hammett constants of the substituents with a negative slope of -0.34 eV. This led to the assignment that the substantially red-shifted absorption band was the ground-state intramolecular charge-transfer absorption with the substituent locating in the electron acceptor moiety. It was concluded that anion binding to the thiourea moiety of the N-benzamidothiourea receptors switched on their ground-state charge transfer. An anion-binding induced structural change was suggested to occur around the N-N bond in N-benzamidothioureas, which resulted in a substantially increased electron donating ability of the electron donor in the receptor molecules. As a consequence, the ground-state charge transfer takes place in the N-benzamidothiourea-anion binding complexes, leading to unprecedented red shifts in the absorption spectra and substantially enhanced anion binding affinities than those of the corresponding N-phenylthiourea receptors. N-Benzamido-N'-phenylthioureas represent a new generation of neutral thiourea-based anion receptors that show substantially improved anion binding performance important for anion sensing and recognition.

Journal Article↗
PubMed1979

Effect of thiourea and substituted thioureas on dynein ATPase and on the turbidity response of Tetrahymena cilia.

The effects of thiourea and of several substituted thioureas -- phenylthiourea, alpha-naphtylthiourea, metiamide, and burimamide -- on dynein ATPase have been studied. The substituted thioureas are over 30 times more potent than thiourea in causing enhancement of 30S dynein ATPase activity and inhibition of 14S dynein ATPase activity. The effects of thiourea and phenylthiourea can be prevented by very low concentrations of beta-mercaptoethanol or dithiothreitol. Axonemal ATPase is also enhanced by the thioureas, but the reaction proceeds more slowly than for solubilized 30S dynein. Enhancement of 30S dynein ATPase by metiamide is prevented by low (approximately 1 microM) concentrations of ATP and, less effectively, by AMP-PNP, but not by AMP-PCP even though the latter is a stronger inhibitor of 30S dynein ATPase than is AMP-PNP. The thioureas inhibit the ATP-induced decrease in turbidity (measured as delta A350) of axonemal suspensions. Inhibition of the turbidity response is also prevented by low concentrations of beta-mercaptoethanol, but, in contrast to the irreversible enhancement of ATPase activity, inhibition of the turbidity response is largely reversible. The ability of 30S dynein to rebind onto twice-extracted axonemes is not changed by treatment with phenylthiourea or metiamide. These observations indicate that the thioureas react with at least two sets of SH or S--S groups on axonemes. Reaction with the group(s) on the 30S dynein causes an apparently irreversible enhancement of ATPase activity. Reaction with another group(s) causes a reversible inhibition of the turbidity response.

Adenosine Triphosphatases↗
PubMedDate not supplied

Phenoloxidase and cytotoxicity in the compound ascidian Botryllus schlosseri.

The vacuoles of morula cells (MC) of the colonial ascidian Botryllus schlosseri contain phenoloxidase (PO). As the release of their vacuolar content at the border of incompatible contacting colonies is associated with the formation of necrotic masses which characterize the rejection reaction, the role of PO in Botryllus cytotoxicity was investigated. When hemocytes are incubated with blood plasma from incompatible (heterologous) colonies, MC degranulate and, after 60 min, the cytotoxicity index becomes significantly greater than that observed in controls incubated with autologous plasma. The rise in cell mortality is completely inhibited by the addition of PO inhibitors sodium benzoate, tropolone and phenylthiourea, and serine protease inhibitors phenylmethylsulfonyl fluoride, benzamidine, N-tosyl-L-phenylalanine chloromethyl ketone and N-tosyl-L-lysine chloromethyl ketone. The addition of either reducing agents L-cysteine and ascorbic acid or reactive oxygen species scavenger enzymes superoxide dismutase and catalase has a similar effect. Significant inhibition of cytotoxicity is also observed with the quinone scavenger, 3-methyl-2-benzothiazolinone hydrazone. In the presence of sodium benzoate and phenylthiourea, there is a significant reduction in the number, size and color intensity of necrotic masses along the contact border of incompatible colonies. A significant increase in superoxide anion production, completely inhibited by sodium benzoate, is observed when hemocytes are incubated with heterologous blood plasma. These results indicate that: (i) PO is the enzyme responsible for the cytotoxicity observed in both hemocyte cultures and rejection reactions; (ii) PO is present inside MC vacuoles as a proenzyme which is activated, upon release, by humoral proteases; (iii) cytotoxicity appears to be mainly due to oxidative stress generated by PO during oxidation of polyphenols to quinones without the involvement of other oxidases such as NADPH oxidase and peroxidase.

Animals↗
PubMed1998

2-Nitrophenylcarbamoyl-(S)-prolyl-(S)-3-(2-naphthyl)alanyl-N-benzyl-N - methylamide (SDZ NKT 343), a potent human NK1 tachykinin receptor antagonist with good oral analgesic activity in chronic pain models.

A lead compound which had sub-micromolar affinity for the rabbit NK1 receptor but negligible affinity for rat NK1 receptors, 3a, was discovered by directed screening. 2-Substitution in the ring of the benzylthiourea substituent in the initial lead was found to be important, and halogens (Cl, Br) in this position were found to improve affinity for the human receptor. The activity of a series of 2-halo-substituted benzylthioureas was then optimized by modification of the proline diphenylmethyl amide, guided by a simple conceptual model based on structural overlay between these early antagonists and NK1 selective peptides. In this way, aromatic amino acid amides were identified which had improved affinity with respect to the starting diphenylmethyl (DPM) amides. The first sub-nanomolar ligand for the human NK1 receptor which arose from this series, 4af, combined a 2-chlorobenzylthiourea unit with a 2-naphthylalanine amide. Contemporaneously it was discovered that the benzylthiourea unit could be simplified to a phenylthiourea providing that an appropriate 2-substituent was also incorporated. Combination of these two series gave 2-NO2 phenylthiourea analogues which led directly to the analogous urea, 5f (2-nitrophenylcarbamoyl-(S)-prolyl-(S)-3-(2-naphthyl)alanyl-N-benz yl- N-methylamide, SDZ NKT 343), a highly potent ligand for the human NK1 receptor (Ki = 0.16 nM). In addition to its high in vitro potency, 5f proved to be a potent orally active analgesic in guinea pig models of chronic inflammatory and neuropathic pain. The nature of the 2-aryl substituent was found to be critical for oral activity in this series. Clinical evaluation of 5f as a novel analgesic agent is currently underway.

Analgesics↗
PubMed2004

Human flavin-containing monooxygenase form 2 S-oxygenation: sulfenic acid formation from thioureas and oxidation of glutathione.

Thioureas are oxygenated by flavin-containing monooxygenases (FMOs), forming reactive sulfenic and/or sulfinic acids. Sulfenic acids can reversibly react with GSH and drive oxidative stress through a redox cycle. For this reason, thiourea S-oxygenation is an example of FMO-dependent bioactivation of a xenobiotic. Functional FMO2 is expressed in the lung of 26% of individuals of African descent and 5% of Hispanics but not in Caucasians or Asians. We have previously demonstrated that human FMO2.1 protein expressed in Sf9 microsomes has high activity toward a series of thioureas that are known or suspected lung toxicants including thiourea, 1-phenylthiourea, and ethylenethiourea. We now show by HPLC and LC-MS that 1-phenylthiourea and alpha-naphthylthiourea are converted to their sulfenic acids. GSH in the incubations at concentrations of 0.5-1.0 mM completely eliminated the sulfenic acid with resultant production of GSSG. These results indicate that individuals with the FMO21 allele may be at enhanced risk of pulmonary damage upon exposure to thioureas.

Chromatography, High Pressure Liquid↗
PubMed1988

Blood groups as genetic markers in glaucoma.

A series of 474 mixed cases of glaucoma was assessed to determine whether there were any genetic differences between different types of glaucoma. A careful distinction was made between chronic open angle glaucoma (COAG), acute and chronic angle closure glaucoma, ocular hypertension, low tension glaucoma, patients with large cup disc ratios, and various types of secondary glaucoma including pseudoexfoliation of the lens capsule, uveitic and traumatic glaucoma. Using ABO blood groups, Rhesus groups, ABH secretion or non-secretion, and phenylthiourea tasting we identified certain differences. The differences from normal were significant decrease in Rh-negative patients in chronic closed angle glaucoma (p less than 0.05), a decrease in ABH secretors in ocular hypertension (p less than 0.01), and fewer HB secretors in patients with COAG (p less than 0.02). There was a significant decrease in AH secretors and increase in HB secretors in both pseudoexfoliation with raised intraocular pressure compared with COAG (p less than 0.01) and in secondary glaucomas as a group compared with COAG (p less than 0.01). Tasters of phenylthiourea were more common in traumatic and uveitic glaucoma than in normal controls (p less than 0.05). These results suggest that secondary glaucoma develops in different subjects from COAG, while patients who develop a rise in intraocular pressure proceed to cupping and field loss if they have a certain genetic constitution. The groups of patients are too small for the differences to be of great prognostic value.

Blood Group Antigens↗
PubMed2001

Application of the nitroblue tetrazolium-reduction method for studies on the production of reactive oxygen species in insect haemocytes.

The in vitro generation of reactive oxygen species (ROS) in haemocytes of Galleria mellonella, Aporia crataegi, Dendrolimus sibiricus, Aglais urticae (Lepidoptera) and Gryllus bimaculatus (Orthoptera), was studied by the method of nitroblue tetrazolium (NBT) reduction. Formazan formation (product of NBT reduction) was observed in haemocytes of all the insects examined, except A. urticae. Lypopolysaccharide and zymosan reduced the number of NBT-positive cells after 1 h incubation and an increase was registered after 4 h incubation. The inhibitors of the respiratory chain enzyme (sodium azide) and melanogenesis (phenylthiourea) reduced formazan formation in nonactivated insect blood cells. No influence of sodium azide and phenylthiourea was found on the activated haemocytes. The results suggest that the generation of ROS in insect haemocytes occured as a result of processes such as respiration and melanization during phagocytosis and encapsulation.

Animals↗
PubMed1991

Quinone and quinone methide as transient intermediates involved in the side chain hydroxylation of N-acyldopamine derivatives by soluble enzymes from Manduca sexta cuticle.

Proteins solubilized from the pharate cuticle of Manduca sexta were fractionated by ammonium sulfate precipitation and activated by the endogenous enzymes. The activated fraction readily converted exogenously supplied N-acetyldopamine (NADA) to N-acetylnorepinephrine (NANE). Either heat treatment (70 degrees C for 10 min) or addition of phenylthiourea (2.5 microM) caused total inhibition of the side chain hydroxylation. If chemically prepared NADA quinone was supplied instead of NADA to the enzyme solution containing phenylthiourea, it was converted to NANE. Presence of a quinone trap such as N-acetylcysteine in the NADA-cuticular enzyme reaction not only prevented the accumulation of NADA quinone, but also abolished NANE production. In such reaction mixtures, the formation of a new compound characterized as NADA-quinone-N-acetylcysteine adduct could be readily witnessed. These studies indicate that NADA quinone is an intermediate during the side chain hydroxylation of NADA by Manduca cuticular enzyme(s). Since such a conversion calls for the isomerization of NADA quinone to NADA quinone methide and subsequent hydration of NADA quinone methide, attempts were also made to trap the latter compound by performing the enzymatic reaction in methanol. These attempts resulted in the isolation of beta-methoxy NADA (NADA quinone methide methanol adduct) as an additional product. Similarly, when the N-beta-alanyldopamine (NBAD)-Manduca enzyme reaction was carried out in the presence of L-kynurenine, two diastereoisomers of NBAD quinone methide-kynurenine adduct (= papiliochrome IIa and IIb) could be isolated.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1986

Tyrosinase isozyme heterogeneity in differentiating B16/C3 melanoma.

The B16/C3 murine melanoma is a pigmented tumor that is rich in the copper-containing enzyme, tyrosinase. This enzyme, which converts tyrosine to melanin precursors, is largely associated with membrane fractions of cells and exists in a number of discrete isozymic forms ranging in molecular mass from 58,000 to 150,000 daltons and pI from 3.4 to 5.2. One of these isozymes (Mr = 58,000, pI 3.4) has been purified to homogeneity. The purified enzyme catalyzes the hydroxylation of L-tyrosine to L-dihydroxyphenylalanine (L-DOPA) and the conversion of L-DOPA to dopaquinone. Ascorbic acid, tetrahydrofolate, and dopamine can serve as cofactors in the hydroxylase reaction. The Michaelis constants for the purified enzyme were 7 X 10(-4) M for L-tyrosine and 6 X 10(-4) M for L-DOPA. The Vmax for L-DOPA was much greater than the Vmax for L-tyrosine indicating that tyrosine hydroxylation is rate-limiting in melanin precursor biosynthesis. Two putative copper chelators, phenylthiourea and diethyldithiocarbamide inhibited both the tyrosine hydroxylase and L-DOPA oxidase activities of the enzyme. Phenylthiourea was a noncompetitive inhibitor while diethyldithiocarbamide was a competitive inhibitor indicating that these agents act by different mechanisms. When digested with proteases and glycosidases, higher molecular weight forms of tyrosinase co-migrated with the purified enzyme in isoelectric focusing and sodium dodecyl sulfate-polyacrylamide gel electrophoresis suggesting that the isozyme was derived from larger precursors. Thus, post-translational processing of tyrosinase may underlie isozyme diversity and this may be important in the control of melanogenesis in this tumor model.

Amino Acids↗