Synthesis and biological activity of analogues of diazaquinomycin A, a new thymidylate synthase inhibitor.

Diazaquinomycin A (1), a new thymidylate (TMP) synthase inhibitor, is poorly soluble in various solvents and exhibits no antitumor activity, while a series of the analogues prepared from 1 are more soluble in water and chloroform than 1, and some of them exhibit antitumor activity in mice. Some analogues in which the lactam rings are replaced by pyridine rings did not inhibit TMP synthase. The diethoxy analogue 25 is a 10-fold more potent inhibitor of TMP synthase than 1. The diacetoxy analogue 23 exhibits significant antitumor activity (T/C: 175%) against Meth-A fibrosarcoma in mice.