A series of derivatives of
5,6-diphenylpyridazin-3-one (DPP) was examined for interactions with calf brain
tubulin following the demonstration that many members of the class caused significant mitotic effects in intact animals, while others had activity against murine
P388 leukemia. In L1210 cells several DPP derivatives caused a rise in the mitotic index which correlated well with the cytotoxicity of the drugs. Active DPP derivatives markedly stimulated
tubulin-dependent
guanosine triphosphate hydrolysis and inhibited
tubulin polymerization or induced
tubulin oligomer formation, depending on specific reaction conditions. These new agents, however, did not interfere with the binding to
tubulin of radiolabeled
colchicine,
vinblastine,
maytansine, or
guanosine triphosphate. They thus appear to bind at a previously undescribed site on the
tubulin molecule. Some DPP derivatives have significant herbicidal activity, causing mitotic disruption and a rise in the mitotic index in seedling root tissues. Although the DPP derivatives most toxic to plant tissues differ from those most active in inhibiting calf brain
tubulin polymerization, virtually all active compounds bear a
nitrile substituent at position 4 of the pyridazinone ring. Most active derivatives also bear substituents of varying structure at position 2 of this ring, but no clear structure-function pattern is apparent at this position. The phenyl rings in the most active herbicidal DPP derivatives either are unsubstituted or bear
fluorine atoms. Derivatives with
chlorine substituents have no detectable herbicidal activity. In contrast, interactions with calf brain
tubulin are substantially enhanced if the phenyl rings bear
chlorine substituents.