Discovery of Small-Molecule Inhibitors of the ATPase Activity of Human Papillomavirus E1 Helicase

Journal of Medicinal Chemistry

Volumn 47, Issue 1, 2004, Pages 18-21

  Faucher, Anne Marie ^a   White, Peter W ^a   Brochu, Christian ^a   Grand Maître, Chantal ^a   Rancourt, Jean ^a   Fazal, Gulrez ^a  

^a BOEHRINGER INGELHEIM CANADA LTD   (Canada)

Author keywords

[No Author keywords available]

Indexed keywords

(BIPHENYL 4 SULFONYL)ACETIC ACID; ADENOSINE TRIPHOSPHATASE; ADENOSINE TRIPHOSPHATASE INHIBITOR; HELICASE; UNCLASSIFIED DRUG;

ARTICLE; CONCENTRATION RESPONSE; DNA REPLICATION; ENZYME ACTIVITY; IC 50; INHIBITION KINETICS; VIRUS INHIBITION; VIRUS REPLICATION; WART VIRUS;

ACETIC ACIDS; ADENOSINE TRIPHOSPHATASES; ANTIVIRAL AGENTS; BIPHENYL COMPOUNDS; HUMANS; ONCOGENE PROTEINS, VIRAL; PAPILLOMAVIRIDAE; STRUCTURE-ACTIVITY RELATIONSHIP; SULFONES;

EID: 0346731236     PISSN: 00222623     EISSN: None     Source Type: Journal    
DOI: 10.1021/jm034206x     Document Type: Article

References (19)

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7. 4b to maximize its sensitivity to inhibitors.
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10. (a) A detailed account of the experiments performed to clarify the mechanism of inhibition of the compounds in this series will be published separately. White, P. W.; et al. Manuscript in preparation.
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12. 50 values are approximately 10-fold higher at 50 μM ATP.
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14. Recently, an X-ray structure of the helicase domain of SV40 large T antigen (a helicase belonging to the same superfamily as HPV E1 but with very low homology) has been published: Li, D.; Zhao, R.; Lilyestrom, W.; Gai, D.; Zhang, R.; DeCaprio, J. A.; Fanning, E.; Jochimiak, A.; Szakonyi, G.; Chen, X. Structure of the Replicative Helicase of the Oncoprotein SV40 Large Tumor Antigen. Nature 2003, 423, 512-518.
15. Presumably due to a fragmentation reaction analogous to that of the Julia coupling of alkylsulfonylbenzothiazolyl to aldehydes. Baudin, J. B.; Hareau, G.; Julia, S. A. A Direct Synthesis of Olefins by Reaction of Carbonyl Compounds with Lithio Derivatives of 2-[Alkyl- or (2′-Alkenyl)- or Benzyl-sulfonyl]-benzothiazoles. Tetrahedron Lett. 1991, 32 (9), 1175-1178.
16. Diverse amines were selected using the "Molecular Operating Environment" MOE software available from Chemical Computing Group Inc., Montréal, Canada: httpwww.chemcorp.com. See Supporting Information for a sample of the amine building blocks used in this library.
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18. The sulfonylacetic acid methyl ester prodrugs were inactive in the cell-based assay, but their low aqueous solubility limited the concentration at which they could be tested to 1-10 μM.
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