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    Synthesis and Biological Evaluation of Analogues of AKT (Protein Kinase B) Inhibitor-IV

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    Sun_2011.pdf (1.336Mb)
    Issue Date
    2011-03-10
    Author
    Sun, Qi
    Wu, Runzhi
    Cai, Sutang
    Lin, Yuan
    Sellers, Llewlyn
    Sakamoto, Kaori
    He, Biao
    Peterson, Blake R.
    Publisher
    American Chemical Society
    Type
    Article
    Article Version
    Scholarly/refereed, author accepted manuscript
    Rights
    This document is the Accepted Manuscript version of a Published Work that appeared in final form in the Journal of Medicinal Chemistry, copyright © American Chemical Society after peer review and technical editing by the publisher. To access the final edited and published work see http://dx.doi.org/10.1021/jm100912b.
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    Abstract
    Inhibitors of the PI3-kinase/AKT (protein kinase B) pathway are under investigation as anticancer and antiviral agents. The benzimidazole derivative AKT inhibitor-IV (ChemBridge 5233705) affects this pathway and exhibits potent anticancer and antiviral activity. To probe its biological activity, we synthesized AKT inhibitor-IV and 21 analogues using a novel six-step route based on ZrCl4-catalyzed cyclization of 1,2-arylenediamines with α,β-unsaturated aldehydes. We examined effects on viability of HeLa carcinoma cells, viability of normal human cells (NHBE), replication of recombinant parainfluenza virus 5 (PIV5) in HeLa cells, and replication of the intracellular bacterium Mycobacterium fortuitum in HeLa cells. Replacement of the benzimidazole N-ethyl substitutent of AKT inhibitor-IV with N-hexyl and N-dodecyl groups enhanced antiviral activity and cytotoxicity against the cancer cell line, but these compounds showed substantially lower toxicity (from 6-fold to >20-fold) against NHBE cells, and no effect on M. fortuitum, suggesting inhibition of one or more host protein(s) required for proliferation of cancer cells and PIV5. The key structural elements identified here may facilitate identification of targets of this highly biologically active scaffold.
    URI
    http://hdl.handle.net/1808/23629
    DOI
    https://doi.org/10.1021/jm100912b
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    • Medicinal Chemistry Scholarly Works [248]
    Citation
    Sun, Q., Wu, R., Cai, S., Lin, Y., Sellers, L., Sakamoto, K., … Peterson, B. R. (2011). Synthesis and Biological Evaluation of Analogues of AKT (Protein Kinase B) Inhibitor-IV. Journal of Medicinal Chemistry, 54(5), 1126–1139. http://doi.org/10.1021/jm100912b

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    Contact KU ScholarWorks
    785-864-8983
    KU Libraries
    1425 Jayhawk Blvd
    Lawrence, KS 66045
    785-864-8983

    KU Libraries
    1425 Jayhawk Blvd
    Lawrence, KS 66045
    Image Credits
     

     

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