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Synthesis, Activity, and Structural Analysis of Novel alpha-Hydroxytropolone Inhibitors of Human Immunodeficiency Virus Reverse Transcriptase-Associated Ribonuclease H

  1. Author:
    Chung, S. M.
    Himmel, D. M.
    Jiang, J. K.
    Wojtak, K.
    Bauman, J. D.
    Rausch, J. W.
    Wilson, J. A.
    Beutler, J. A.
    Thomas, C. J.
    Arnold, E.
    Le Grice, S. F. J.

  2. Author Address

    [Chung, SM; Rausch, JW; Le Grice, SFJ] NCI, RT Biochem Sect, HIV Drug Resistance Program, Frederick, MD 21702 USA [Himmel, DM; Wojtak, K; Bauman, JD; Arnold, E] Rutgers State Univ, Ctr Adv Biotechnol & Med, Piscataway, NJ 08854 USA [Himmel, DM; Wojtak, K; Bauman, JD; Arnold, E] Rutgers State Univ, Dept Chem & Chem Biol, Piscataway, NJ 08854 USA [Jiang, JK; Thomas, CJ] NIH Chem Genom Ctr, Rockville, MD 20850 USA [Wilson, JA; Beutler, JA] NCI, Mol Discovery Program, Frederick, MD 21702 USA;Le Grice, SFJ (reprint author), NCI, RT Biochem Sect, HIV Drug Resistance Program, Frederick, MD 21702 USA;legrices@mail.nih.gov
    1. Year: 2011
    2. Date: Jul
  2. Journal: Journal of Medicinal Chemistry
    1. 54
    2. 13
    3. Pages: 4462-4473
  4. Type of Article: Article
  5. ISSN: 0022-2623
  1. Abstract:

    The alpha-hydroxytroplone, manicol (5,7-dihydroxy-2-isopropenyl-9-methyl-1,2,3,4-tetrahydro-benzocyclohepte n-6-one), potently and specifically inhibits ribonuclease H (RNase H) activity of human immunodeficiency virus reverse transcriptase (HIV RT) in vitro. However, manicol was ineffective in reducing virus replication in culture. Ongoing efforts to improve the potency and specificity over the lead compound led us to synthesize 14 manicol derivatives that retain the divalent metal-chelating alpha-hydroxytropolone pharmacophore. These efforts were augmented by a high resolution structure of p66/p51. HIV-1 RT containing the nonnucleoside reverse transcriptase inhibitor (NNRTI), TMC278 and manicol in the DNA polymerase and RNase H active sites, respectively. We demonstrate here that several modified alpha-hydroxytropolones exhibit antiviral activity at noncytotoxic concentrations. Inclusion of RNase H active site mutants indicated that manicol analogues can occupy an additional site in or around the DNA polymerase catalytic center. Collectively, our studies will promote future structure-based design of improved alpha-hydroxytropolones to complement the NRTI and NNRTI currently in clinical use.

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External Sources

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  2. DOI: 10.1021/jm2000757
  3. View record in Web of Science®
  4. WOS: 000292479600012

Library Notes

  1. Fiscal Year: FY2010-2011
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