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Synthesis, Mechanism of Action, and Antiviral Activity of a New Series of Covalent Mechanism-Based Inhibitors of S-Adenosyl-l-Homocysteine Hydrolase

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    Synthesis, Mechanism of Action, and Antiviral Activity of a New Series of Covalent Mechanism-Based Inhibitors of S-Adenosyl-l-Homocysteine Hydrolase
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    Université de Reims Champagne-Ardenne, UMR 6519, UFR Sciences, BP 1039, 51687 Reims Cedex, France, Université Louis Pasteur ECPM UMR 7507, 25, rue Becquerel F, 67087 Strasbourg Cedex 2, France, Rega Institute for Medical Research, Katholieke Universiteit of Leuven, Leuven, Belgium, and AstraZeneca - Reims, Centre de Recherches, BP 1050, Chemin de Vrilly, 51689 Reims Cedex 2, France
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    Journal of Medicinal Chemistry

    Cite this: J. Med. Chem. 2001, 44, 17, 2743–2752
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    https://doi.org/10.1021/jm0108350
    Published July 18, 2001
    Copyright © 2001 American Chemical Society
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    Abstract

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    A direct method for the preparation of 5‘-S-alkynyl-5‘-thioadenosine and 5‘-S-allenyl-5‘-thioadenosine has been developed. Treatment of a protected 5‘-acetylthio-5‘-deoxyadenosine with sodium methoxide and propargyl bromide followed by deprotection gave the 5‘-S-propargyl-5‘-thioadenosine 4. Under controlled base-catalysis with sodium tert-butoxide in tert-butyl alcohol 4 was quantitatively converted into 5‘-S-allenyl-5‘-thioadenosine 5 or 5‘-S-propynyl-5‘-thioadenosine 6. Incubation of recombinant human placental AdoHcy hydrolase with 4, 5, or 6 resulted in time- and concentration-dependent inactivation of the enzyme (Ki: 45 ± 0.5, 16 ± 1, and 15 ± 1 μM, respectively). Compound 4 caused complete conversion of the enzyme from its E-NAD+ to E-NADH form during the inactivation process. This indicates that 4 is a substrate for the 3‘-oxidative activity of AdoHcy hydrolase (type I inhibitor). In contrast, the NAD+/NADH content of the enzyme was not affected during the inactivation process with 5 and 6, and their mechanism of inactivation was further investigated. Addition of enzyme-sequestered water on the S-allenylthio group of 5 or S-propynylthio group of 6 within the active site should lead to the formation of the corresponding thioester 7. This acylating-intermediate agent could then undergo nucleophilic attack by a protein residue, leading to a type II mechanism-based inactivation. ElectroSpray mass spectra analysis of the inactivated protein by 5 supports this mechanistic proposal. Further studies (MALDI-TOF and ESI/MSn experiments) of the trypsin and endo-Lys-C proteolytic cleavage of the fragments of inactivated AdoHcy hydrolase by 5 were carried out for localization of the labeling. The antiviral activity of 4, 5, and 6 against a large variety of viruses was determined. Significant activity (EC50: 1.9 μM) was noted with 5 against vaccinia virus.

    Copyright © 2001 American Chemical Society

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     To whom correspondence should be addressed. Tel:  +33 3 26 91 33 08. Fax:  +33 3 26 91 31 66. E-mail:  [email protected].

    †

     Université de Reims Champagne-Ardenne.

    §

     Université Louis Pasteur − Strasbourg.

    ⊥

     Katholieke Universiteit of Leuven.

    ‖

     AstraZeneca − Reims.

    Cited By

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    This article is cited by 29 publications.

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    Journal of Medicinal Chemistry

    Cite this: J. Med. Chem. 2001, 44, 17, 2743–2752
    Click to copy citationCitation copied!
    https://doi.org/10.1021/jm0108350
    Published July 18, 2001
    Copyright © 2001 American Chemical Society
    Request reuse permissions

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