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Robert J. Turesky - One of the best experts on this subject based on the ideXlab platform.
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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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optimizing proteolytic digestion conditions for the analysis of serum albumin adducts of 2 amino 1 methyl 6 phenylimidazo 4 5 b pyridine a potential human carcinogen formed in cooked meat
Journal of Proteomics, 2014Co-Authors: Lijuan Peng, Robert J. TureskyAbstract:Abstract Heterocyclic aromatic amines (HAAs) are carcinogens formed during the cooking of meats or arise in tobacco smoke. The genotoxic N-oxidized metabolites of HAAs bind to Cys residues of proteins to form arylsulfinamide adducts. However, these adducts are unstable and undergo hydrolysis during enzymatic digestion, and thus have been precluded as biomarkers of exposure to HAAs. Arylsulfinamide adducts of HAAs can undergo oxidation to form stable arylsulfonamide linkages, which are chemically stable and amenable for analysis. 2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) is a carcinogen present in cooked meat. We established a quantitative MS-based method to measure the sulfinamide adduct of PhIP formed at the cysteine34 (Cys34) residue of human serum albumin (SA), following chemical oxidation of PhIP-modified SA with m-chloroperoxybenzoic acid. Different enzyme systems (trypsin; chymotrypsin; trypsin/chymotrypsin; proteinase K; pronase E; and pronase E/leucine aminopeptidase/prolidase) were evaluated for their proficiency of digestion of SA modified with PhIP. The strongest signal was observed for the L31QQC*PFEDHVK41 peptide, by ultraperformance liquid chromatography and ion trap MS. A limit of quantification value was 0.3 fmol of LQQC*PFEDHVK per μg SA, or 2.5 adducts per 105 SA molecules, when assaying 0.75 μg of SA. Biological significance This article describes a mass spectrometric based method to characterize and measure human serum albumin (SA) adducts of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), a carcinogenic heterocyclic aromatic amine formed in cooked meats and tobacco smoke. PhIP undergoes metabolic activation to form reactive N-oxidized intermediates that bind to DNA and proteins. N-oxidized PhIP metabolites bind to the Cys34 residue of SA to form a sulfinamide linkage. However, the linkage undergoes hydrolysis during proteolysis, precluding the employment of this adduct as a biomarker in human studies. We have shown that the sulfinamide linkage undergoes oxidation to form the [cysteine-S-yl-PhIP]-S-dioxide, a sulfonamide linked adduct which is stable toward proteolysis. The specificity and efficiency of several different proteases toward the digestion of the SA-Cys34-PhIP adduct were examined. The combination of trypsin and chymotrypsin produced the single-missed cleaved peptide LQQC * PFEDHVK in high yield. Moreover, denaturation and chemical reduction of the internal Cys disulfide bonds of SA were not required for the recovery of LQQC * PFEDHVK. The novel chemistry and proteomic approaches developed in this study may be applied to monitor biologically reactive N-oxidized intermediates of arylamines through their adduction products formed at nucleophilic Cys residues of proteins.
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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...
Lijuan Peng - One of the best experts on this subject based on the ideXlab platform.
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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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optimizing proteolytic digestion conditions for the analysis of serum albumin adducts of 2 amino 1 methyl 6 phenylimidazo 4 5 b pyridine a potential human carcinogen formed in cooked meat
Journal of Proteomics, 2014Co-Authors: Lijuan Peng, Robert J. TureskyAbstract:Abstract Heterocyclic aromatic amines (HAAs) are carcinogens formed during the cooking of meats or arise in tobacco smoke. The genotoxic N-oxidized metabolites of HAAs bind to Cys residues of proteins to form arylsulfinamide adducts. However, these adducts are unstable and undergo hydrolysis during enzymatic digestion, and thus have been precluded as biomarkers of exposure to HAAs. Arylsulfinamide adducts of HAAs can undergo oxidation to form stable arylsulfonamide linkages, which are chemically stable and amenable for analysis. 2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) is a carcinogen present in cooked meat. We established a quantitative MS-based method to measure the sulfinamide adduct of PhIP formed at the cysteine34 (Cys34) residue of human serum albumin (SA), following chemical oxidation of PhIP-modified SA with m-chloroperoxybenzoic acid. Different enzyme systems (trypsin; chymotrypsin; trypsin/chymotrypsin; proteinase K; pronase E; and pronase E/leucine aminopeptidase/prolidase) were evaluated for their proficiency of digestion of SA modified with PhIP. The strongest signal was observed for the L31QQC*PFEDHVK41 peptide, by ultraperformance liquid chromatography and ion trap MS. A limit of quantification value was 0.3 fmol of LQQC*PFEDHVK per μg SA, or 2.5 adducts per 105 SA molecules, when assaying 0.75 μg of SA. Biological significance This article describes a mass spectrometric based method to characterize and measure human serum albumin (SA) adducts of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), a carcinogenic heterocyclic aromatic amine formed in cooked meats and tobacco smoke. PhIP undergoes metabolic activation to form reactive N-oxidized intermediates that bind to DNA and proteins. N-oxidized PhIP metabolites bind to the Cys34 residue of SA to form a sulfinamide linkage. However, the linkage undergoes hydrolysis during proteolysis, precluding the employment of this adduct as a biomarker in human studies. We have shown that the sulfinamide linkage undergoes oxidation to form the [cysteine-S-yl-PhIP]-S-dioxide, a sulfonamide linked adduct which is stable toward proteolysis. The specificity and efficiency of several different proteases toward the digestion of the SA-Cys34-PhIP adduct were examined. The combination of trypsin and chymotrypsin produced the single-missed cleaved peptide LQQC * PFEDHVK in high yield. Moreover, denaturation and chemical reduction of the internal Cys disulfide bonds of SA were not required for the recovery of LQQC * PFEDHVK. The novel chemistry and proteomic approaches developed in this study may be applied to monitor biologically reactive N-oxidized intermediates of arylamines through their adduction products formed at nucleophilic Cys residues of proteins.
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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...
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Capturing Labile Sulfenamide and Sulfinamide Serum Albumin Adducts of Carcinogenic Arylamines by Chemical Oxidation
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) and formed labile Sulfenamide or sulfinamide adducts at the Cys34 residue. Oxidation of the carcinogen-modified SA with m-chloroperoxybenzoic acid (m-CPBA) produced the arylsulfonamide adducts, which were stable to heat and the chemical reduction conditions employed to denature SA. The sulfonamide adducts of PhIP and 4-ABP were identified, by liquid chromatography/mass spectrometry, in proteolytic digests of denatured SA. Thus, selective oxidation of arylamine-modified SA produces stable arylsulfonamide-SA adducts, which may serve as biomarkers of these tobacco and dietary carcinogens
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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Chiral Brønsted-Acid-Catalyzed Asymmetric Oxidation of Sulfenamide by Using H2O2: A Versatile Access to Sulfinamide and Sulfoxide with High Enantioselectivity
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.
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.
Valentino J. Stella - One of the best experts on this subject based on the ideXlab platform.
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Reprint of "MDCK cell permeability characteristics of a Sulfenamide produg: strategic implications in considering Sulfenamide prodrugs for oral delivery of NH acids" [Bioorg. Med. Chem. Lett. 21 (2011) 172-175].
Bioorganic & medicinal chemistry letters, 2011Co-Authors: Victor R. Guarino, Kwame W. Nti-addae, Valentino J. StellaAbstract:The objective of this Letter is both to report the permeability results of a linezolid-based Sulfenamide prodrug in an MDCK cell model (enterocyte surrogate system) and to discuss the strategic implications of these results for considering Sulfenamide prodrugs to enhance the oral delivery of weakly acidic NH-acids (e.g., amides, ureas, etc.). The two main findings from this study are that the Sulfenamide prodrug does not appear to survive intracellular transport due to conversion to linezolid and that there appears to be an apically-oriented surface conversion pathway that can additionally serve to convert the Sulfenamide prodrug to linezolid upon approach of the apical membrane. It is hoped that these findings, along with the discussion of the strategic implications, will facilitate a greater awareness of the potential strengths and weaknesses inherent in the Sulfenamide prodrug approach for enhancing the oral delivery of weakly acidic NH-acid drugs.
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Reversion of Sulfenamide prodrugs in the presence of free thiol-containing proteins
Journal of pharmaceutical sciences, 2011Co-Authors: Kwame W. Nti-addae, Jennifer S. Laurence, Andria L. Skinner, Valentino J. StellaAbstract:The purpose of this work was to study the reaction kinetics between two model Sulfenamide prodrugs of linezolid, N-(phenylthio)linezolid and N-[(2-ethoxycarbonyl)ethylthio]linezolid, with free thiol-containing proteins; commercial human serum albumin (HSA); a constitutively active mutant of the protein tyrosine phosphatase PRL-1 (PRL-1-C170S-C171S), a model protein; and diluted fresh human plasma. The reaction was followed by high-performance liquid chromatography, both for the loss of prodrug and appearance of linezolid, and at different pH values with molar excess of the proteins relative to the prodrugs. Pseudo first-order kinetics was observed. Consistent with earlier findings for the reaction between similar Sulfenamides and small-molecule thiols, the reaction kinetics appeared to be consistent with thiolate attack at the Sulfenamide bond to release the parent drug. The proteins reacted significantly slower on a molar basis than their small-molecule counterparts. It appears that proteins such as HSA may play a role in the in vivo conversion of Sulfenamide prodrugs to their parent drug.
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MDCK cell permeability characteristics of a Sulfenamide prodrug: strategic implications in considering Sulfenamide prodrugs for oral delivery of NH-acids.
Bioorganic & medicinal chemistry letters, 2010Co-Authors: Victor R. Guarino, Kwame W. Nti-addae, Valentino J. StellaAbstract:The objective of this Letter is both to report the permeability results of a linezolid-based Sulfenamide prodrug in an MDCK cell model (enterocyte surrogate system) and to discuss the strategic implications of these results for considering Sulfenamide prodrugs to enhance the oral delivery of weakly acidic NH-acids (e.g., amides, ureas, etc.). The two main findings from this study are that the Sulfenamide prodrug does not appear to survive intracellular transport due to conversion to linezolid and that there appears to be an apically-oriented surface conversion pathway that can additionally serve to convert the Sulfenamide prodrug to linezolid upon approach of the apical membrane. It is hoped that these findings, along with the discussion of the strategic implications, will facilitate a greater awareness of the potential strengths and weaknesses inherent in the Sulfenamide prodrug approach for enhancing the oral delivery of weakly acidic NH-acid drugs.
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In vitro conversion of model Sulfenamide prodrugs in the presence of small molecule thiols.
Journal of pharmaceutical sciences, 2010Co-Authors: Kwame W. Nti-addae, Valentino J. StellaAbstract:ABSTRACT: Sulfenamide prodrugs of amide and urea functional group containing drugs have recently been proposed as a means of altering the physical and bioproperties of problematic drug molecules containing these two functionalities. Sulfenamides have been shown to revert to the parent drug via reaction with thiols. Explored here is the mechanism for this reaction. The stoichiometry and pH dependency of the in vitro reversion of two model prodrugs of the oxazolidinone, linezolid, and a Sulfenamide of phthalimide were studied at 25°C in the presence of thiols, including cysteine and glutathione, of varying basicity. High-performance/pressure liquid chromatography and liquid chromatography–mass spectrometry results showed the near quantitative reversion of the Sulfenamides to the parent drug with simultaneous formation of a mixed disulfide. The pH and the dependency of the reaction on the basicity of the thiol strongly supported the role of the thiolate specie in the conversion. The reaction is consistent with an S N 2 type mechanism seen in the reaction of some thiols with disulfides.
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Preparation, characterization and in vivo conversion of new water-soluble Sulfenamide prodrugs of carbamazepine.
Bioorganic & medicinal chemistry letters, 2007Co-Authors: Jeffrey N. Hemenway, Kwame W. Nti-addae, Victor R. Guarino, Valentino J. StellaAbstract:Improved synthetic methods are reported for the preparation of Sulfenamide derivatives of carbamazepine (CBZ) for evaluation as prodrugs. These Sulfenamide prodrugs were designed to rapidly release CBZ in vivo by cleavage of the Sulfenamide bond by chemical reaction with glutathione and other sulfhydryl compounds. Physicochemical characterization and in vivo conversion of a new prodrug of CBZ was evaluated to further establish the proof of concept of the Sulfenamide prodrug approach.
