Tetramisole analogues as inhibitors of alkaline phosphatase, an enzyme involved in the resistance of neoplastic cells to 6-thiopurines.

A series of tetramisole derivatives was synthesized and tested for inhibitory activity against alkaline phosphatase which was partially purified from a murine ascitic neoplasm resistant to 6-thiopurines (Sarcoma 180/TG). These agents included derivatives substituted with halogens, CH3, or NO2 groups at either the meta or para position of the phenyl ring of tetramisole and 2,3-dehydrotetramisole. The phenyl ring of tetramisole and 2,3-dehydrotetramisole was also replaced by a naphthyl ring, and the phenyl ring of 2,3-dehydrotetramisole was substituted by a thienyl ring system. The presence of both the thiazolidine and dihydroimidazole rings of tetramisole was found to be essential for enzyme inhibitory activity. Substitution of a naphthyl for the phenyl group and dehydrogenation at the 2,3 position of the thiazolidine ring were found to significantly enhance inhibitory activity for alkaline phosphatase. Tests employing (S)-(-)-6-(4-bromophenyl)-2,3,5,6-tetrahydroimidazo[2,1-b]thiazole oxalate in combination with 6-thioguanine demonstrated that the inhibitor of alkaline phosphatase was capable of increasing the toxicity of 6-thioguanine to Sarcoma 180/TG cells in tissue culture.