Synthesis and in vitro anticancer evaluation of some 4,6-diamino-1,3,5-triazine-2-carbohydrazides as Rad6 ubiquitin conjugating enzyme inhibitors

Series of 4-amino-6-(arylamino)-1,3,5-triazine-2-carbohydrazides (3a-e) and N′-phenyl-4,6-bis(arylamino)-1,3,5-triazine-2-carbohydrazides (6a-e) have been synthesized. New triazines showed better IC50 values in survival assays of various tumor cell lines. Particularly, new triazines 6a-c, exhibited much lower IC50 (3.3-22 μM) values compared to TZ9 (the previously reported Rad6B-inhibitory diamino-triazinylmethyl benzoate anticancer agent). Moreover, when compared to TZ9 in in vitro ubiquitin conjugation assays, compounds 6a, b, c, e exhibited superior Rad6B inhibitory properties, both in its conjugation to ubiquitin and to the substrate H2A.