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Spiromustine analogues. Relationships between structure, plasma stability, and antitumor activity.

A Haces, J S Driscoll, J S Roth

    Journal of Pharmaceutical Sciences
    |March 1, 1986
    PubMed
    Summary
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    Spiromustine analogues were synthesized to improve stability and antitumor activity. Closer proximity of the hydantoin ring to the nitrogen mustard moiety enhanced stability and maintained efficacy against leukemia.

    Area of Science:

    • Medicinal Chemistry
    • Pharmacology
    • Organic Synthesis

    Background:

    • Spiromustine, a hydantoin-containing nitrogen mustard, is undergoing Phase I clinical trials.
    • Its in vitro plasma half-life is influenced by the hydantoin ring structure.

    Purpose of the Study:

    • To synthesize and evaluate spiromustine analogues with varying spacer lengths between the hydantoin ring and nitrogen mustard.
    • To assess the impact of structural modifications on hydrolytic stability and antitumor activity.

    Main Methods:

    • Synthesis of analogues with 2-5 methylene spacer groups.
    • Evaluation of hydrolytic stability and pKa values.
    • Assessment of antitumor activity against murine P-388 leukemia.
    • Mass spectral analysis to identify structure-related ions.

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    Main Results:

    • Hydrolytic stability correlated with analogue structure and pKa values.
    • A shorter spacer (closer proximity) between the hydantoin ring and nitrogen mustard conferred greater stability.
    • Antitumor activity against P-388 leukemia decreased with increased hydrolytic instability.
    • A relationship was found between analogue structure and a specific mass spectral rearrangement ion.

    Conclusions:

    • The proximity of the hydantoin ring to the nitrogen mustard moiety is a key factor in stabilizing spiromustine analogues.
    • Optimizing hydrolytic stability is crucial for maintaining antitumor efficacy.
    • Structure-activity relationships were elucidated, aiding in the design of improved nitrogen mustard compounds.