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Biological Effects and Structure-Activity Relationships of 1,2-Dihydropyrido[3,4-b]pyrazines¹

Departments of Biochemistry [G. P. W., B. J. B., D. J. A., J. W.] and Organic Chemistry [C. T.], Southern Research Institute, Birmingham, Alabama 35255

The effects of a number of 1,2-dihydropyrido[3,4-b]pyrazines (1-deaza-7,8-dihydropteridines) upon the proliferation and the mitotic index of cultured L1210 cells and upon the survival of mice bearing P388 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 upon 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 upon the cultured cells were reversible, and the rate and degree of reversibility were influenced by the substituents at positions 2 and 3.

Tests performed with two 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.

¹ This work was supported by Grant 1-RO1-CA25311 from the National Cancer Institute, NIH.

² To whom requests for reprints should be addressed, at P. O. Box 55305, Birmingham, Ala 35255-5305.

Received 1/19/83. Accepted 4/29/83.