Abstract:
A series of substituted dibenzo[l,4]dioxin-l-carboxamides has been synthesized and evaluated for in vitro and in vivo antitumor activity. The required substituted dibenzo[ 1,4]dioxin-l-carboxylic acids were prepared by a variety of methods. No regiospecific syntheaea were available for many of these, and separation of the mixtures of regioisomers obtained was sometimes difficult. The dibenzo[l,4]dioxin-l-carboxamides are active against wild-type P388 leukemia in vitro and in vivo, with structureactivity relationships resembling those for both the acridine-4-carboxamide and phenazine-1-carboxamide series of DNA-intercalating antitumor agents. In all three series, substituents placed peri to the carboxamide sidechain (the 5-position in the acridines, and the 9-position in the phenazines and dibenzo- [ 1,4]dioxins) enhance activity and potency. The 9-chlorodibenzodioxin-1-carboxamide was also curative against the remotely sited Lewis lung carcinoma. Several of the compounds showed much lower levels of cross-resistance to the P388/AMSA line than classical DNA-intercalating agents, which suggests that their primary mechanism of action may not be via interference with topoisomerase IIa. This is of interest with regard to the development of drugs to combat resistance mechanisms which arise by the expression of the top0 IIj3 isozyme.
