CI-898 (hydrochloride) (Synonyms: CI-898 trihydrochloride)

CI-898 is a lipophilic antifolate inhibitor of dihydrofolate reductase (DHFR; Kds = 4.5, 1.4, and 0.1 nM for the bovine, murine, and E. coli enzyme, respectively). It has enhanced binding to DHFR in the presence of the cofactor NADPH (Kds = 0.03, 0.43, and 0.03 nM, respectively, for the bovine, murine, and E. coli enzyme). Cl-898 (30 nM) inhibits growth (IC50 = 20 nM after two days) and halts the cell cycle at the G1/S phase in L1210 mouse lymphocytic leukemia cells and is active against methotrexate-resistant cancer cell lines. It also inhibits the growth of S. faecalis and S. aureus when used at concentrations less than 0.25 μg/ml. In vivo, Cl-898 (0.44 mg/kg per day, p.o.) suppresses malarial effects in a mouse model of P. berghei infection and increases median survival time in a mouse model of T. gondii infection when administered at a dose of 180 mg/kg. It also enhances the activity of doxorubicin , cyclophosphamide , and 6-thioguanine in mice with advanced stage P338 leukemia.