The goal of this project is the development of new antineoplastic agents directed against tubulin, a protein critical for cell division. Work was initiated with combretastatin congeners, a series of newly isolated natural products, more active than combretastatin itself. The mechanism of action of 2,4-dichlorobenzyl thiocyanate was examined. The drug seems to specifically alkylate the tubulin molecule. Derivatives of 6-benzyl-1,3-benzodioxole continued to interest the laboratory because their facile synthesis permits a structure-function approach to the colchicine/podophyllotoxin binding site of tubulin. Derivatives of 5,6-diphenylpyridazin-3-one, which bind to a distinct site on tubulin, continued to be evaluated in a search for maximally active agents. Alkyl carbamates of aromatic amines were screened in a search for new antitubulin agents. Interactions of tubulin with N-(p-azidobenzoyl)-N'-Beta-aminoethylvindesine, a photoaffinity analog of vinblastine, were shown to be comparable to those of tubulin with vinblastine.
