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Robert J. Turesky - One of the best experts on this subject based on the ideXlab platform.
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Quantification of Hemoglobin and White Blood Cell DNA Adducts of the Tobacco Carcinogens 2‑Amino‑9H‑pyrido[2,3‑b]indole and 4‑Aminobiphenyl Formed in Humans by Nanoflow Liquid Chromatography/Ion Trap Multistage Mass Spectrometry
2017Co-Authors: Tingting Cai, Medjda Bellamri, Xun Ming, Woon-puay Koh, Robert J. TureskyAbstract:Aromatic amines covalently bound to hemoglobin (Hb) as Sulfinamide adducts at the cysteine 93 residue of the Hb β chain have served as biomarkers to assess exposure to this class of human carcinogens for the past 30 years. In this study, we report that 2-amino-9H-pyrido[2,3-b]indole (AαC), an abundant carcinogenic heterocyclic aromatic amine formed in tobacco smoke and charred cooked meats, also reacts with Hb to form a Sulfinamide adduct. A novel nanoflow liquid chromatography/ion trap multistage mass spectrometry (nanoLC-IT/MS3) method was established to assess exposure to AαC and the tobacco-associated bladder carcinogen 4-aminobiphenyl (4-ABP) through their Hb Sulfinamide adducts. Following mild acid hydrolysis of Hb in vitro, the liberated AαC and 4-ABP were derivatized with acetic anhydride to form the N-acetylated amines, which were measured by nanoLC-IT/MS3. The limits of quantification (LOQ) for AαC- and 4-ABP-Hb Sulfinamide adducts were ≤7.1 pg/g Hb. In a pilot study, the mean level of Hb Sulfinamide adducts of AαC and 4-ABP were, respectively, 3.4-fold and 4.8-fold higher in smokers (>20 cigarettes/day) than nonsmokers. In contrast, the major DNA adducts of 4-ABP, N-(2′-deoxyguanosin-8-yl)-4-aminobiphenyl, and AαC, N-(2′-deoxyguanosin-8-yl)-2-amino-9H-pyrido[2,3-b]indole, were below the LOQ (3 adducts per 109 bases) in white blood cell (WBC) DNA of smokers and nonsmokers. These findings reaffirm that tobacco smoke is a major source of exposure to AαC. Hb Sulfinamide adducts are suitable biomarkers to biomonitor 4-ABP and AαC; however, neither carcinogen binds to DNA in WBC, even in heavy smokers, at levels sufficient for biomonitoring
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Methemoglobin Formation and Characterization of Hemoglobin Adducts of Carcinogenic Aromatic Amines and Heterocyclic Aromatic Amines
2016Co-Authors: Khyatiben V. Pathak, Ting-lan Chiu, Elizabeth Ambrose Amin, Robert J. TureskyAbstract:Arylamines (AAs) and heterocyclic aromatic amines (HAAs) are structurally related carcinogens formed during the combustion of tobacco or cooking of meat. They undergo cytochrome P450 mediated N-hydroxylation to form metabolites which bind to DNA and lead to mutations. The N-hydroxylated metabolites of many AAs also can undergo a co-oxidation reaction with oxy-hemolgobin (HbO2) to form methemoglobin (met-Hb) and the arylnitroso intermediates, which react with the β-Cys93 chain of Hb to form Hb-arylSulfinamide adducts. The biochemistry of arylamine metabolism has been exploited to biomonitor certain AAs through their Hb arylSulfinamide adducts in humans. We examined the reactivity of HbO2 with the N-hydroxylated metabolites of 4-aminobiphenyl (ABP, HONH-ABP), aniline (ANL, HONH-ANL), and the HAAs 2-amino-9H-pyrido[2,3-b]indole (AαC, HONH-AαC), 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP, HONH-PhIP), and 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx, HONH-MeIQx). HONH-ABP, HO-ANL, and HONH-AαC induced methemoglobinemia and formed Hb Sulfinamide adducts. However, HONH-MeIQx and HONH-PhIP did not react with the oxy-heme complex, and met-Hb formation and chemical modification of the β-Cys93 residue were negligible. Molecular modeling studies showed that the distances between the H-ON-AA or H-ON-HAA substrates and the oxy-heme complex of HbO2 were too far away to induce methemoglobinemia. Different conformational changes in flexible helical and loop regions around the heme pocket induced by the H-ON-AA or H-ON-HAAs may explain the different proclivities of these chemicals to induce methemoglobinemia. Hb-Cys93β Sulfinamide and sulfonamide adducts of ABP, ANL, and AαC were identified, by Orbitrap MS, following the proteolysis of Hb with trypsin, Glu-C, or Lys-C. Hb Sulfinamide and sulfonamide adducts of ABP were identified in the blood of mice exposed to ABP, by Orbitrap MS. This is the first report of the identification of intact Hb Sulfinamide adducts of carcinogenic AAs in vivo. The high reactivity of HONH-AαC with HbO2 suggests that the Hb Sulfinamide adduct of AαC may be a promising biomarker of exposure to this HAA in humans
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Mass Spectrometric Characterization of an Acid-Labile Adduct Formed with 2‑Amino-1-methyl-6-phenylimidazo[4,5‑b]pyridine and Albumin in Humans
2016Co-Authors: Yi Wang, Lijuan Peng, Peter W. Villalta, Karen Dingley, Michael A. Malfatti, K. W. Turteltaub, Robert J. TureskyAbstract:2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) is a carcinogenic heterocyclic aromatic amine formed during the high-temperature cooking of meats. The cytochrome P450-mediated N-hydroxylation of the exocyclic amine group of PhIP produces 2-hydroxyamino-1-methyl-6-phenylimidazo[4,5-b]pyridine, an electrophilic metabolite that forms adducts with DNA and proteins. Previous studies conducted by our laboratory showed that the reaction of N-oxidized PhIP metabolites with human albumin in vitro primarily occurs at the Cys34 residue, to produce an acid-labile linked Sulfinamide adduct. On the basis of these findings, we developed a sensitive ultraperformance liquid chromatography–mass spectrometry method to measure acid-labile albumin–PhIP adducts in human volunteers administered a dietary-relevant dose of 14C-labeled PhIP [Dingley, K. H., et al. (1999) Cancer Epidemiol., Biomarkers Prev. 8, 507–512]. Mild acid treatment of albumin (0.1 N HCl, 37 °C for 1 h) or proteolytic digestion with Pronase [50 mM ammonium bicarbonate buffer (pH 8.5) at 37 °C for 18 h] released similar amounts of covalently bound PhIP, which was characterized by multistage scanning and quantified by Orbitrap mass spectrometry. The amount of [14C]PhIP recovered by acid treatment of albumin 24 h following dosing accounted for 7.2–21.3% of the [14C]PhIP bound to albumin based on accelerator mass spectrometry measurements. 2-Amino-1-methyl-6-(5-hydroxy)phenylimidazo[4,5-b]pyridine, a hydrolysis product of the Cys34 S–N linked sulfenamide adduct of PhIP, was not detected in either acid-treated or protease-treated samples. These findings suggest that a portion of the PhIP bound to albumin in vivo probably occurs as an acid-labile Sulfinamide adduct formed at the Cys34 residue
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2-Amino-9H-pyrido[2,3-b]indole (AαC) Adducts and Thiol Oxidation of Serum Albumin as Potential Biomarkers of Tobacco Smoke
Journal of Biological Chemistry, 2015Co-Authors: Khyatiben V. Pathak, Medjda Bellamri, Yi Wang, Sophie Langouët, Robert J. TureskyAbstract:2-Amino-9H-pyrido[2,3-b]indole (AαC) is a carcinogenic heterocyclic aromatic amine formed during the combustion of tobacco. AαC undergoes bioactivation to form electrophilic N-oxidized metabolites that react with DNA to form adducts, which can lead to mutations. Many genotoxicants and toxic electrophiles react with human serum albumin (albumin); however, the chemistry of reactivity of AαC with proteins has not been studied. The genotoxic metabolites, 2-hydroxyamino-9H-pyrido[2,3-b]indole (HONH-AαC), 2-nitroso-9H-pyrido[2,3-b]indole (NO-AαC), N-acetyloxy-2-amino-9H-pyrido[2,3-b]indole (N-acetoxy-AαC), and their [(13)C6]AαC-labeled homologues were reacted with albumin. Sites of adduction of AαC to albumin were identified by data-dependent scanning and targeted bottom-up proteomics approaches employing ion trap and Orbitrap MS. AαC-albumin adducts were formed at Cys(34), Tyr(140), and Tyr(150) residues when albumin was reacted with HONH-AαC or NO-AαC. Sulfenamide, Sulfinamide, and sulfonamide adduct formation occurred at Cys(34) (AαC-Cys(34)). N-Acetoxy-AαC also formed an adduct at Tyr(332). Albumin-AαC adducts were characterized in human plasma treated with N-oxidized metabolites of AαC and human hepatocytes exposed to AαC. High levels of N-(deoxyguanosin-8-yl)-AαC (dG-C8-AαC) DNA adducts were formed in hepatocytes. The Cys(34) was the sole amino acid of albumin to form adducts with AαC. Albumin also served as an antioxidant and scavenged reactive oxygen species generated by metabolites of AαC in hepatocytes; there was a strong decrease in reduced Cys(34), whereas the levels of Cys(34) sulfinic acid (Cys-SO2H), Cys(34)-sulfonic acid (Cys-SO3H), and Met(329) sulfoxide were greatly increased. Cys(34) adduction products and Cys-SO2H, Cys-SO3H, and Met(329) sulfoxide may be potential biomarkers to assess exposure and oxidative stress associated with AαC and other arylamine toxicants present in tobacco smoke
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capturing labile sulfenamide and Sulfinamide serum albumin adducts of carcinogenic arylamines by chemical oxidation
Analytical Chemistry, 2013Co-Authors: Lijuan Peng, Robert J. TureskyAbstract:Aromatic amines and heterocyclic aromatic amines (HAAs) are a class of structurally related carcinogens that are formed during the combustion of tobacco or during the high temperature cooking of meats. These procarcinogens undergo metabolic activation by N-oxidation of the exocyclic amine group to produce N-hydroxylated metabolites, which are critical intermediates implicated in toxicity and DNA damage. The arylhydroxylamines and their oxidized arylnitroso derivatives can also react with cysteine (Cys) residues of glutathione or proteins to form, respectively, sulfenamide and Sulfinamide adducts. However, sulfur–nitrogen linked adducted proteins are often difficult to detect because they are unstable and undergo hydrolysis during proteolytic digestion. Synthetic N-oxidized intermediates of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), a carcinogenic HAA produced in cooked meats, and 4-aminobiphenyl, a carcinogenic aromatic amine present in tobacco smoke, were reacted with human serum albumin (SA...
Rob M. J. Liskamp - One of the best experts on this subject based on the ideXlab platform.
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Molecular construction of sulfonamide antisense oligonucleotides
The Journal of organic chemistry, 2019Co-Authors: Valerijs Korotkovs, Linus F. Reichenbach, Clémentine Pescheteau, Glenn A. Burley, Rob M. J. LiskampAbstract:An efficient and scalable synthesis of new oligonucleotide monomers was developed for replacement of the phosphodiester backbone of RNA by a sulfonamide-containing backbone to enable construction of sulfonamide antisense oligonucleotides (SaASOs). It was shown that by employing these sulfonamide RNA (SaRNA) monomers, it was possible to synthesize oligomers in solution. The properties of a sulfonamide moiety replacement were evaluated by incorporation of a SaRNA-monomer into a DNA strand and performing thermal stability tests of the resulting DNA and RNA-double-strand hybrids. Although sulfonamide modification caused a decrease in melting temperature (Tm) of both hybrids, it was lower for the sulfonamide-containing DNA-RNA hybrid than that for the sulfonamide-containing DNA-DNA hybrid.
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Synthesis of peptides containing a Sulfinamide or a sulfonamide transition-state isostere
Tetrahedron, 1993Co-Authors: Wilna J. Moree, Gijs A. Van Der Marel, Liesbeth C. Van Gent, Rob M. J. LiskampAbstract:A versatile synthesis of peptides incorporating the Sulfinamide or sulfonamide transition-state analogue is described. Apart from the easily accessible Gly-Xxx isosteres used as haptens to elicit catalytic antibodies, other amino acids than Gly can be prepared by α-alkylation of the sulfonamide containing peptides. This is illustrated with the synthesis of a potential HIV-protease inhibitor 27.
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Synthesis of peptides containing the β-substituted aminoethane Sulfinamide or sulfonamide transition-state isostere derived from amino acids
Tetrahedron Letters, 1992Co-Authors: Wilna J. Moree, Gijs A. Van Der Marel, Rob M. J. LiskampAbstract:α-amino acids can be converted to homochiral β-substituted aminoethane Sulfinamide or sulfonamide transition-state isosteres, which can be incorporated into peptides. These transition-state analogues e.g. the sulfonamide isostere of Phe-Phe will be used for the generation of catalytic antibodies as well as for the development of protease inhibitors.
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Peptides containing a Sulfinamide or a sulfonamide moiety: New transition-state analogues
Tetrahedron Letters, 1991Co-Authors: Wilna J. Moree, Gijs A. Van Der Marel, Rob M. J. LiskampAbstract:A versatile synthesis of two new types of transition-state analogues of the amide bond hydrolysis is described: the Sulfinamide and the sulfonamide moiety. These transition-state analogues are part of peptides which will be used for the generation of catalytic antibodies as well as for development of protease inhibitors.
Zhuo Tang - One of the best experts on this subject based on the ideXlab platform.
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Chiral Brønsted-Acid-Catalyzed Asymmetric Oxidation of Sulfenamide by Using H2O2: A Versatile Access to Sulfinamide and Sulfoxide with High Enantioselectivity
ACS Catalysis, 2019Co-Authors: Shu-sen Chen, Jin Zhu, Qi-wei Wang, Zhuo TangAbstract:Herein, we describe an example of catalytic asymmetric synthesis of Sulfinamides. Aromatic sulfenamides were chosen as useful substrates, because of the indispensable N–H bond, which could form an efficient hydrogen bond with chiral phosphoric acid. H2O2 (35%) was used as the terminal oxidant for preparation of Sulfinamides in high yields and enantioselectivities, which could be easily derivatized to sulfoxides and other Sulfinamides without loss of the enantioselectivity.
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Using Sulfinamides as high oxidation state sulfur reagent for preparation of sulfenamides
Tetrahedron Letters, 2018Co-Authors: Long-jun Ma, Guangxun Li, Jin Huang, Jin Zhu, Zhuo TangAbstract:Abstract Traditional preparation of sulfenamides require the use of low oxidation state of sulfur reagent such as RSCl, (RS) 2 or RSH, which are toxic, odorous and difficult to deal with due to the harsh reaction conditions. Here high oxidation state of sulfur reagent—aliphatic Sulfinamide, were used for preparation of sulfenamide in one step efficiently. Different aromatic amines with all sorts of functional groups, especially amino groups and hydroxyl groups, were transformed to the corresponding sulfenamides in moderate yields, which was difficult to obtain with previous methods.
Wilna J. Moree - One of the best experts on this subject based on the ideXlab platform.
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Synthesis of peptides containing a Sulfinamide or a sulfonamide transition-state isostere
Tetrahedron, 1993Co-Authors: Wilna J. Moree, Gijs A. Van Der Marel, Liesbeth C. Van Gent, Rob M. J. LiskampAbstract:A versatile synthesis of peptides incorporating the Sulfinamide or sulfonamide transition-state analogue is described. Apart from the easily accessible Gly-Xxx isosteres used as haptens to elicit catalytic antibodies, other amino acids than Gly can be prepared by α-alkylation of the sulfonamide containing peptides. This is illustrated with the synthesis of a potential HIV-protease inhibitor 27.
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Synthesis of peptides containing the β-substituted aminoethane Sulfinamide or sulfonamide transition-state isostere derived from amino acids
Tetrahedron Letters, 1992Co-Authors: Wilna J. Moree, Gijs A. Van Der Marel, Rob M. J. LiskampAbstract:α-amino acids can be converted to homochiral β-substituted aminoethane Sulfinamide or sulfonamide transition-state isosteres, which can be incorporated into peptides. These transition-state analogues e.g. the sulfonamide isostere of Phe-Phe will be used for the generation of catalytic antibodies as well as for the development of protease inhibitors.
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Peptides containing a Sulfinamide or a sulfonamide moiety: New transition-state analogues
Tetrahedron Letters, 1991Co-Authors: Wilna J. Moree, Gijs A. Van Der Marel, Rob M. J. LiskampAbstract:A versatile synthesis of two new types of transition-state analogues of the amide bond hydrolysis is described: the Sulfinamide and the sulfonamide moiety. These transition-state analogues are part of peptides which will be used for the generation of catalytic antibodies as well as for development of protease inhibitors.
Carolyn C. Brackett - One of the best experts on this subject based on the ideXlab platform.
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Sulfonamide allergy and cross-reactivity
Current Allergy and Asthma Reports, 2007Co-Authors: Carolyn C. BrackettAbstract:Concerns about cross-allergenicity between sulfonamide antibiotics and nonantibiotic sulfonamide-containing drugs continue to complicate pharmacotherapy. Several elegant investigations have demonstrated unequivocal lack of interaction between the sulfonamide group and either cellular or humoral immunity. The immunologic determinant of type I immunologic responses to sulfonamide antibiotics is the N1 heterocyclic ring, and nonantibiotic sulfonamides lack this structural feature. Many non-type I hypersensitivity responses to sulfonamide antibiotics are attributable to reactive metabolites that cause either direct cytotoxicity or humoral or cellular responses. Metabolite formation is stereospecific to the N4 amino nitrogen of the sulfonamide antibiotics, a structure not found on any nonantibiotic sulfonamide drugs. Cellular immune responses to sulfonamide antibiotics are responsible for many non-immunoglobulin E-mediated dermatologic reactions; however, the stereospecificity of T-cell response renders cross-reactivity between sulfonamide antibiotics and nonantibiotics highly unlikely. Apparent cross-reactivity responses to sulfonamide-containing drugs likely represent multiple concurrent, rather than linked, drug hypersensitivities.
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Likelihood and Mechanisms of Cross‐Allergenicity Between Sulfonamide Antibiotics and Other Drugs Containing a Sulfonamide Functional Group
Pharmacotherapy, 2004Co-Authors: Carolyn C. Brackett, Harleen Singh, John H. BlockAbstract:Concerns about cross-allergenicity between sulfonamide antibiotics and nonantibiotic, sulfonamide-containing drugs persist and can complicate patients' drug therapy unnecessarily. No interaction between the human immune system and the sulfonamide functional group has been demonstrated. The immunologic determinant of type I, immediate hypersensitivity responses to sulfonamide antibiotics is the N1 heterocyclic ring. Nonantibiotic sulfonamides do not contain this structural feature. Non-type I hypersensitivity responses to sulfonamide antibiotics are largely attributable to reactive metabolites that may cause either direct cytotoxicity or immunologic response. Formation of these metabolites is a stereospecific process that occurs at the N4 amino nitrogen of the sulfonamide antibiotics, a structure also not found on any nonantibiotic sulfonamide drugs. The stereospecificity of these reactions implies that cross-reactivity with nonantibiotic sulfonamide-containing drugs is highly unlikely; this assertion is supported by recent literature. However, T-cell recognition of unmetabolized, nonhaptenated parent sulfonamide antibiotic appears to occur in a small subset of hypersensitive patients. Several of the severe cutaneous reactions associated with sulfonamide antibiotics are mediated by T cells. It is not known whether T-cell recognition of antibiotic is related to the sulfonamide functional group. Until the mechanism of this recognition is elucidated, cross-reactivity with nonantibiotic sulfonamides appears to remain at least theoretically possible.
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likelihood and mechanisms of cross allergenicity between sulfonamide antibiotics and other drugs containing a sulfonamide functional group
Pharmacotherapy, 2004Co-Authors: Carolyn C. Brackett, Harleen Singh, John H. BlockAbstract:Concerns about cross-allergenicity between sulfonamide antibiotics and nonantibiotic, sulfonamide-containing drugs persist and can complicate patients' drug therapy unnecessarily. No interaction between the human immune system and the sulfonamide functional group has been demonstrated. The immunologic determinant of type I, immediate hypersensitivity responses to sulfonamide antibiotics is the N1 heterocyclic ring. Nonantibiotic sulfonamides do not contain this structural feature. Non-type I hypersensitivity responses to sulfonamide antibiotics are largely attributable to reactive metabolites that may cause either direct cytotoxicity or immunologic response. Formation of these metabolites is a stereospecific process that occurs at the N4 amino nitrogen of the sulfonamide antibiotics, a structure also not found on any nonantibiotic sulfonamide drugs. The stereospecificity of these reactions implies that cross-reactivity with nonantibiotic sulfonamide-containing drugs is highly unlikely; this assertion is supported by recent literature. However, T-cell recognition of unmetabolized, nonhaptenated parent sulfonamide antibiotic appears to occur in a small subset of hypersensitive patients. Several of the severe cutaneous reactions associated with sulfonamide antibiotics are mediated by T cells. It is not known whether T-cell recognition of antibiotic is related to the sulfonamide functional group. Until the mechanism of this recognition is elucidated, cross-reactivity with nonantibiotic sulfonamides appears to remain at least theoretically possible.
