Synthesis of 2-thiobarbituric acid derivatives as potential anticancer agents

Barbiturates as a class have rarely shown anticancer activity. Narayanan et al. at the National Cancer Institute evaluated the anticancer activity of approximately 1800 barbituric acid and thiobarbituric acid derivatives. Only one compound was active; this is Merbarone (5-[N-phenylcarboxamido]2-thiobarbituric acid, I). It showed remarkable activity against four murine tumor models. The enolic function and the tricarbonylmethane group have been suggested to be of importance in the activity of Merbarone (I). To test if these factors affect the anticancer activity of Merbarone (I), a series of N-aryl and N-heterocyclic analogs of (I) was synthesized. The reverse amides of (I) were also synthesized. All of these derivatives were sent for anticancer screening at NCI. The most active compound was found to be 1,3-dimethyl-5-[N-(4-nitrophenyl)carboxamido]-2-thiobarbituric acid. To assess the possibility that the nitro group is optimal for anticancer activity, in this research we intended to synthesize a series of nitroaryl derivatives of (I) and test their anticancer activities. A modified Curtius reaction was used to prepare the 5-nitroarylcarboxamido-2-thiobarbituric acid derivatives. Only two new carboxamido-2-thiobarbituric acid derivatives were prepared. When anticancer activities of these two compounds were investigated at the NCI, both compounds were inactive.; Evidence has been presented in support of a charge transfer mechanism for various conjugated compounds possessing antineoplastic activities. The mechanism involves the transfer of electron from cellular materials by an electron transfer agent to oxygen. The oxy radicals formed then attack the cancer cells. This research involves the synthesis of a series of conjugated thiobarbiturates, a total of twenty derivatives were prepared and twelve are new. The synthesis of these derivatives was carried out by the acid catalyzed condensation of one molecule of the aromatic aldehyde and one molecule of 2-thiobarbituric acid. In vitro antineoplastic activities for 5-arylidene-2-thiobarbituric acid derivatives were obtained from the NCI. Two of the compounds showed significant specificities for specific human tumor cell lines. Seven compounds from the 5-arylidene-2-thiobarbituric acid derivatives were screened for their antiproliferative effect on MCF-7 breast cancer cells, three compounds demonstrated exceptional activity.