Journal of Pharmaceutical Sciences

1966

DOI: 10.1002/jps.2600550307

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Analogs of Tetrahydrofolic Acid XXXII

¹

,

Thomas J. Schwan

²

,

Jaroslav Novotný

³

et al.

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Cited by 32 publications

(4 citation statements)

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“…The preparation of this compound was achieved by the reaction of N-Boc-protected GSH 7 (20) with the mono-Boc-protected MDI derivative 6. The Bocprotected MDI derivative 6 was prepared starting with the literature known amino acid 4 (21). Reaction with excess Boc 2 O under standard conditions resulted in good yields of compound 5, which was converted in a straightforward manner to the isocyanate 6 under Curtius conditions (22).…”

Section: Resultsmentioning

confidence: 99%

Synthesis, Characterization, and Solvolysis of Mono- and Bis-S-(glutathionyl) Adducts of Methylene-bis-(phenylisocyanate) (MDI)

¹

,

²

,

³

2002

Chem. Res. Toxicol.

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Bifunctional isocyanates are highly reactive compounds that undergo nucleophilic attack by a variety of functional groups available in the biological system. While the etiology of the respiratory disease caused by diisocyanates is not fully understood, a great deal of research has been performed to elucidate the chemical mechanisms involved in the direct and indirect effects of these compounds. Since adducts of isocyanates are found not only to proteins along the entire respiratory tree but also to proteins in the circulatory system, it is likely that a transport mechanism for the isocyanate from the respiratory to the circulatory system exists. The initial reaction of isocyanates with cellular thiols to form thiocarbamates, which are known to release the isocyanate under physiological conditions, is believed to provide a possible carrier mechanism for the isocyanate functional group. Previous work with aliphatic mono-isocyanates and the aromatic diisocyanate toluene diisocyanate has demonstrated the feasibility of this mechanism. Adding to this database, the products of the reaction of the highly water-insoluble, low vapor pressure, methylene-bis-(phenylisocyanate) (MDI) with glutathione were synthesized, and their chemical stability under various pH and buffer conditions was tested. Novel synthetic routes were developed for both the mono- and bis-S-(glutathionyl) adducts with MDI that yielded each compound in analytically pure form. Both compounds were found to be unstable under mild basic conditions (phosphate-buffered saline, pH 7.4, and NaHCO(3), pH 8.2), however to a different degree. Furthermore, a significant influence of the pH value (the rate of degradation increases with pH) and the concentration of free glutathione (increasing thiol stabilizes the adduct) on the stability was observed, indicating a base-catalyzed mechanism of the degradation/formation of the thiocarbamate bond. Unlike the monoadduct, which forms almost exclusively the polyurea upon degradation, a variety of products were formed upon degradation of the bis adduct. Though the disappearance of the bis adduct was complete as measured by HPLC, (1)H NMR spectra showed the existence of residual thiocarbamate bonds in the final mixture. In both cases, no evidence of the free methylene-bis-phenylamine (MDA) could be detected under the applicable conditions.

“…The preparation of this compound was achieved by the reaction of N-Boc-protected GSH 7 (20) with the mono-Boc-protected MDI derivative 6. The Bocprotected MDI derivative 6 was prepared starting with the literature known amino acid 4 (21). Reaction with excess Boc 2 O under standard conditions resulted in good yields of compound 5, which was converted in a straightforward manner to the isocyanate 6 under Curtius conditions (22).…”

Section: Resultsmentioning

confidence: 99%

Synthesis, Characterization, and Solvolysis of Mono- and Bis-S-(glutathionyl) Adducts of Methylene-bis-(phenylisocyanate) (MDI)

¹

,

²

,

³

2002

Chem. Res. Toxicol.

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Bifunctional isocyanates are highly reactive compounds that undergo nucleophilic attack by a variety of functional groups available in the biological system. While the etiology of the respiratory disease caused by diisocyanates is not fully understood, a great deal of research has been performed to elucidate the chemical mechanisms involved in the direct and indirect effects of these compounds. Since adducts of isocyanates are found not only to proteins along the entire respiratory tree but also to proteins in the circulatory system, it is likely that a transport mechanism for the isocyanate from the respiratory to the circulatory system exists. The initial reaction of isocyanates with cellular thiols to form thiocarbamates, which are known to release the isocyanate under physiological conditions, is believed to provide a possible carrier mechanism for the isocyanate functional group. Previous work with aliphatic mono-isocyanates and the aromatic diisocyanate toluene diisocyanate has demonstrated the feasibility of this mechanism. Adding to this database, the products of the reaction of the highly water-insoluble, low vapor pressure, methylene-bis-(phenylisocyanate) (MDI) with glutathione were synthesized, and their chemical stability under various pH and buffer conditions was tested. Novel synthetic routes were developed for both the mono- and bis-S-(glutathionyl) adducts with MDI that yielded each compound in analytically pure form. Both compounds were found to be unstable under mild basic conditions (phosphate-buffered saline, pH 7.4, and NaHCO(3), pH 8.2), however to a different degree. Furthermore, a significant influence of the pH value (the rate of degradation increases with pH) and the concentration of free glutathione (increasing thiol stabilizes the adduct) on the stability was observed, indicating a base-catalyzed mechanism of the degradation/formation of the thiocarbamate bond. Unlike the monoadduct, which forms almost exclusively the polyurea upon degradation, a variety of products were formed upon degradation of the bis adduct. Though the disappearance of the bis adduct was complete as measured by HPLC, (1)H NMR spectra showed the existence of residual thiocarbamate bonds in the final mixture. In both cases, no evidence of the free methylene-bis-phenylamine (MDA) could be detected under the applicable conditions.

“…A large number of studies of the specificity of the dihydrofolate binding site (particularly for inhibitors) have been reported (see Blakley, 1969;Baker, 1967). The majority of these studies have been concerned with the pteridine moiety of the substrate or inhibitor, though the binding of NHjBzGlu has been recognized for a number of years (Baker et al, 1966). While it is true that the major part of the very considerable binding energy of methotrexate and related compounds (IF0 = -12 to -15 kcal/mol) is attributable to the pteridine ring, significant variations in affinity are seen with changes in the NHiBzGlu moiety (Baker et al, 1964;Blakley, 1969;Johns et al, 1973).…”

Section: Discussionmentioning

confidence: 99%

Nuclear magnetic resonance studies of the binding of substrate analogs and coenzyme to dihydrofolate reductase from Lactobacillus casei

et al. 1974

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The interactions of the coenzyme, NADPH, and of /7-aminobenzoyl-L-glutamate, a fragment of the substrate, with Lactobacillus casei dihydrofolate reductase have been studied by nuclear magnetic resonance spectroscopy. The aromatic proton resonances of p-aminobenzoyl-L-glutamate shift upfield in the presence of the enzyme by 0.41 and 0.58 ppm (protons ortho and meta to the glutamate moiety, respectively); the binding constant is 1.05 X 103 M~'. Similar chemical-shift changes on binding are observed with p-nitrobenzoyl-L-glutamate, but with p-aminobenzoyl-D-glutamate, no changes in chemical shift of the aromatic protons are observed, although it binds to the same site with a binding constant of 0.34 X 103 M~'. In the presence of NADPH, all three compounds bind approximately 3.5-fold more tightly, and the shifts of the aromatic protons of p-aminobenzoyl-and p-nitrobenzoyl-L-gluta-Dihydrofolate reductase(5,6,7,8-tetrahydrofolate:NADP oxidoreductase, EC 1.5.1.3) catalyzes the reduction of dihydrofolate to tetrahydrofolate. This reaction is of considerable importance in one-carbon metabolism, notably in thymidylate biosynthesis. Dihydrofolate reductases are also the target of a potent and important group of inhibitors of considerable chemotherapeutic interest (Blakley, 1969; Hitchings and Burchall, 1965). In order to improve our understanding of the mode of action of these folate antagonists at the molecular level, we are undertaking a detailed study of ligand binding to dihydrofolate reductase from a methotrexate-resistant strain of Lactobacillus casei.We have begun by studying the binding of p-aminobenzoyl-L-glutamate (NHaBzGlu),* 1 a fragment of the substrate molecule, by high-resolution nmr spectroscopy. Both dihydrofolate and inhibitors such as methotrexate bind very tightly to dihydrofolate reductase (Kd ce. 10s-1010 M_l) and are thus in slow exchange on the nmr time scale. Fragments such as L-NH2BzG1u, however, bind much more weakly, are in rapid exchange, and can thus be studied much more conveniently. The low molecular weight of L. casei dihydrofolate reductase (17,500;Dann et al., 1974) has made it possible to study the nmr spectrum of the protein as well as the ligand in some detail.

“…The irreversible inhibition of phosphorylase b was a very specific reaction (Table III). Sulfonyl fluoride derivatives were chosen as irreversible inhibitors because a specific reversible complex of the moiety bearing the SG2F group with the enzyme must be formed before the SG2F group will react and form a covalent linkage (Baker et al, 1966). Two sulfonyl fluoride derivatives, XXXVI and XXXVIII, significantly irreversibly modify phosphorylase b, but showed no activity in the absence of AMP.…”

Section: Discussionmentioning

confidence: 99%

Chemistry of the adenosine monophosphate site of rabbit muscle glycogen phosphorylase. I. Hydrophobic nature and affinity labeling of the allosteric site

1973

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To obtain a better understanding of the function and site of interaction of AMP, several adenine and hypoxanthine derivatives were tested as inhibitors of rabbit skeletal muscle phosphorylase b. Adenine derivatives substituted in the 8 position with hydrophobic groups were the most effective inhibitors tested. Substituent constants, it, were used to evaluate the hydrophobic nature of the adenine derivatives. Derivatives with increasing

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