Rational synthesis and evaluation of IMP dehydrogenase and Hsp90 inhibitors

Owing to their diverse structures and unique mechanisms of action, natural products play a vital role in drug discovery. Geldanamycin, an antineoplastic antibiotic, is a potent inhibitor of the chaperone protein Hsp90 (heat-shock protein of 90 kDa), which is an attractive target for chemotherapy because of its role in the maturation and stability of a number of proteins involved in cancer. However, poor aqueous solubility and liver toxicity are the major disadvantages of geldanamycin. A number of alternative analogues were designed and synthesized using molecular modeling with the structure of geldanamycin-bound Hsp90 active site. These synthetic small molecules are based on quinolinedione, isoquinolinedione, benzoquinone or naphthoquinone moieties and possess some structural features common to geldanamycin. The inhibitory activity of these analogues was evaluated against the growth of six human cancer cell lines. These compounds showed varying levels of potency and differential cytotoxicity.;The DNA alkylator pyrrolo[1,2-a]benzimidazolequinone (PBI) was designed and synthesized previously in this laboratory. COMPARE analysis and molecular modeling studies showed that some PBI analogues are inhibitors of inosine monophosphate dehydrogenase (IMPDH). To study the structure-activity relationship and to improve the activity of this class of compounds, a library of amino/heterocyclic acids linked PBIs was created. Comparative testing of these compounds was done at National Cancer Institute against NCI 60 cell lines. Preliminary results showed these compounds to be potent and selective antitumor agents for melanoma and renal cancers. The dipeptide (L-Phe-D-Phe) linked PBI was selected and screened by the NO in the in vivo Hollow Fiber Assay. This derivative showed an intraperitoneal (IP) score of 40 and a subcutaneous (SC) score of 2, for a total of 42 along with a net cell kill, and was further advanced for xenograft testing.