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Steroidomimetic Tetrahydroisoquinolines for the Design of New Microtubule Disruptors

  1. Author:
    Leese, M. P.
    Jourdan, F.
    Dohle, W.
    Kimberley, M. R.
    Thomas, M. P.
    Bai, R. L.
    Hamel, E.
    Ferrandis, E.
    Potter, B. V. L.

  2. Author Address

    [Leese, Mathew P.; Jourdan, Fabrice; Dohle, Wolfgang; Kimberley, Meriel R.; Thomas, Mark P.; Potter, Barry V. L.] Univ Bath, Dept Pharm & Pharmacol, Bath BA2 7AY, Avon, England. [Bai, Ruoli; Hamel, Ernest] NCI, Screening Technol Branch, Dev Therapeut Program, Div Canc Treatment & Diag,NIH, Frederick, MD 21702 USA. [Ferrandis, Eric] Inst Rech Henri Beaufour, IPSEN, F-91966 Les Ulis, France.;Potter, BVL (reprint author), Univ Bath, Dept Pharm & Pharmacol, Bath BA2 7AY, Avon, England;B.V.L.Potter@bath.ac.uk
    1. Year: 2012
    2. Date: Jan
  2. Journal: Acs Medicinal Chemistry Letters
    1. 3
    2. 1
    3. Pages: 5-9
  4. Type of Article: Article
  5. ISSN: 1948-5875
  1. Abstract:

    Structure-activity relationship translation offers an expeditious means for discovery of new active series. This approach was applied to discover tetrahydroisoquinoline (THIQ)-based steroidomimetic microtubule disruptors. The two A-ring elements of a three-point steroidal pharmacophore were incorporated into a THIQ-based A,B-ring mimic to which an H-bond acceptor was attached as the third motif Optimization of the representative 6c through conformational biasing delivered a 10-fold gain in activity and a new series of microtubule disruptors (e.g., 9c) with antiproliferative activity in the nanomolar range. The THIQ derivatives match, or surpass, the activities of the steroidal series and exhibit improved physicochemical properties.

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External Sources

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  2. DOI: 10.1021/ml200232c
  3. View record in Web of Science®
  4. WOS: 000299587100002

Library Notes

  1. Fiscal Year: FY2011-2012
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