Mechanism of action of the antitumor agents 6-benzoyl-3,3-disubstituted-1,5-diazabicyclo[3.1.0]hexane-2,4-diones: Potent inhibitors of human type II inosine 5 '-monophosphate dehydrogenase

The observation that expression of the IMPDH gene is tightly linked with ce llular proliferation and transformation has led to an interest in developin g inhibitors that deplete intracellular guanine nucleotide pools. IMPDH exi sts as 2 isoforms, one of which is induced in tumor cells, type II and thus has led to new interest in this target for the design of isoform-selective anticancer chemotherapeutic agents. Several classes of IMPDH inhibitor are now in use or under development; however, only the 1,5-diazabicyclo[3.1.0] hexane-2,4-diones show selectivity for the type II isoform. In the current study, we further evaluated chemical modification of this class to determin e the necessary components for selective type II IMPDH inhibition. The 6-be nzoyl-3,3-disubstituted-1,5-diazabicyclo[3.1.0]hexane-2,4-diones were effec tive cytotoxic agents in human leukemias, lymphomas, breast, glioma and HeL a-S-3 suspended uterine carcinoma screens with ED., values 0.3 to 12 muM. T he agents acted as antimetabolites by inhibiting de novo purine biosynthesi s at the key regulatory enzyme IMPDH, resulting in suppression of DNA synth esis and dGTP pool levels within 60 min. Furthermore, the derivatives were specific for the type II isoform as opposed to type 1, acting in a competit ive manner with K-i values of 5.1 to 63 muM. Addition of the 6-benzoyl moie ty to the bicyclic parent ring structure afforded the most potent agent in the novel class of 1,5-diazabicyclo[3.1.0]hexane-2,4-diones that selectivel y inhibits type II IMPDH activity. (C) 2001 Wiley-Liss, Inc.