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Computer-assisted structure-activity correlations.

M Nasr, K D Paull, V L Narayanan

    Advances in Pharmacology and Chemotherapy
    |January 1, 1984
    PubMed
    Summary
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    Michael acceptors, including unsaturated ketones, lactones, and lactams, show potential as anticancer agents. Structure-activity analysis of over 14,000 compounds reveals key features enhancing antitumor activity against specific leukemias.

    Area of Science:

    • Medicinal Chemistry
    • Computational Chemistry
    • Pharmacology

    Background:

    • Michael acceptors, such as alpha,beta-unsaturated ketones, lactones, and lactams, are investigated for anticancer properties.
    • Understanding structure-activity relationships is crucial for developing effective antitumor agents.

    Purpose of the Study:

    • To evaluate the antitumor activity of diverse Michael acceptors against P388 and L1210 leukemias.
    • To identify structural features that correlate with enhanced anticancer efficacy.

    Main Methods:

    • Computer-assisted structure-activity relationship (SAR) analysis of over 14,000 compounds from the NCI database.
    • Utilized substructure searching and Boolean logic for data manipulation.
    • Investigated various classes of Michael acceptors, including olefinic and lactone/lactam derivatives.

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    Main Results:

    • Olefinic conjugated Michael-type acceptors (styrenes, cinnamic acid derivatives, nitro, cyano, sulfone, sulfoxide, acetylenic compounds) demonstrated activity against P388 lymphocytic leukemia.
    • Specific activating groups (e.g., --OH, --OR, epoxide) adjacent to the unsaturated center, particularly with an alpha-methylene-gamma-lactone, significantly boosted P388 activity.
    • Most compounds showed limited efficacy against the more resistant L1210 lymphoid leukemia.

    Conclusions:

    • Computer-assisted SAR analysis is effective for evaluating large compound libraries.
    • Structural modifications, especially the incorporation of activating groups and the alpha-methylene-gamma-lactone moiety, can optimize antitumor activity.
    • The P388 leukemia model appears more sensitive to these Michael acceptors than the L1210 model.