Pyrazole-related nucleosides. Design, synthesis and antiproliferative activity of methyl 4-iodo-1--D -ribofuranosyl-pyrazole-3-carboxylate (IPCAR) and derivatives, against human leukemia, lymphoma and solid tumor cell lines in vitro

Abstract

A structure-activity relationship (SAR) study on some new 1-beta-D-ribofuranosyl-3,4-substituted pyrazole derivatives led us to obtain 4-iodo-1-beta-D-ribofuranosyl-pyrazole-3-carboxylate (3, IPCAR) and its 3-methyl-1,2,4-oxadiazole analog (11) at position C3. These compounds showed good potency, wide spectrum of antiproliferative activity and low cytotoxicity against resting peripheral blood lymphocytes (PBL). Although none of the test compounds displayed antiviral activity, IPCAR was able to potentiate the anti-HIV-1 activity of dideoxyinosine (ddI), thus behaving like the known inosine monophosphate dehydrogenase (IMPDH) inhibitors ribavirin and tiazofurin. The corresponding methyl esters of the latter two drugs (15 and 16) were also prepared, but they proved inactive. Overall, these results suggest that the target of IPCAR may be an enzyme other than IMPDH involved in the purine de novo biosynthesis