Abstract
The observation that expression of the IMPDH gene is tightly linked with cellular proliferation and transformation has led to an interest in developing inhibitors that deplete intracellular guanine nucleotide pools. IMPDH exists 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 determine the necessary components for selective type II IMPDH inhibition. The 6-benzoyl-3,3-disubstituted-1,5-diazabicyclo[3.1.0]hexane-2,4-diones were effective cytotoxic agents in human leukemias, lymphomas, breast, glioma and HeLa-S3 suspended uterine carcinoma screens with ED(50) values 0.3 to 12 microM. The agents acted as antimetabolites by inhibiting de novo purine biosynthesis at the key regulatory enzyme IMPDH, resulting in suppression of DNA synthesis and dGTP pool levels within 60 min. Furthermore, the derivatives were specific for the type II isoform as opposed to type I, acting in a competitive manner with K(i) values of 5.1 to 63 microM. Addition of the 6-benzoyl moiety 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 selectively inhibits type II IMPDH activity.
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Disclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.