BIOLOGICAL EFFECTS AND STRUCTURE-ACTIVITY-RELATIONSHIPS OF 1,2-DIHYDROPYRIDO[3,4-B]PYRAZINES

  • 1 January 1983
    • journal article
    • research article
    • Vol. 43  (8) , 3567-3575
Abstract
The effects of a number [35] of 1,2-dihydropyrido[3,4-b]pyrazines (1-deaza-7,8-dihydropteridines) on the proliferation and the mitotic index of cultured L1210 [mouse leukemia]cells and on the survival of mice bearing P3888 leukemia were determined. The 1,2-dihydro structure and amino groups or masked amino groups at positions 5 and 7 were necessary for activity, and various substituents at positions 2 and 3 had considerable influence on the activity. A number of these pyrazines had significant activity against i.p. P388 leukemia in mice, and several pyrazines were more active than the corresponding oxazines or thiazines in both the in vitro and the in vivo systems. The effects of the pyrazines on the cultured cells were reversible, and the rate and degree of reversibility were influenced by the substituents at positions 2 and 3. Test performed with 2 of the pyrazines yielded results that indicate that these compounds, like the known agent nocodazole, might compete with colchicine for binding to tubulin. Synergistic killing of cultured L1210 cells was obtained with combinations of one of the pyrazines and vincristine.

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