Studies with benzamide riboside, a recent inhibitor of inosine 5 '-monophosphate dehydrogenase
INOSINE MONOPHOSPHATE DEHYDROGENASE: A MAJOR THERAPEUTIC TARGET(2003)
Abstract
Benzamide riboside was synthesized as a potential inhibitor of poly(ADP-ribose)polymerase (PARP). However, it was a weak inhibitor of PARP, but instead an extremely potent inhibitor of cell proliferation. We demonstrated that it was a selective inhibitor of inosine 5'-monophosphate dehydrogenase (IMPDH). Benzamide riboside is converted intracellularly to an analogue of NAD, BAD (benzamide adenine dinucleotide) that is a potent inhibitor of IMPDH. We characterized the formation of BAD in cells, and it was followed by the chemical synthesis of BAD and its non-hydrolyzable methylene bis(phosphonate) analogues. On a molar basis, benzamide riboside exhibits more potent antitumor activity than tiazofurin, the first inhibitor of IMPDH that we had previously demonstrated to be acting through its NAD analogue, TAD (thiazole-4-carboxamide adenine dinucleotide). In the National Cancer Institute's panel of 60 tumors, benzamide riboside showed selective antitumor activity against human central nervous system tumors. In addition, benzamide riboside induces apoptosis in human ovarian carcinoma N.1 cells, a property not shared by tiazofurin. Induction of apoptosis by benzamide riboside is associated with a down-regulation of Cdc25A, a cell cycle specific phosphatase. New and potent analogues of benzamaide riboside and its active metabolites are being synthesized to find specific inhibitors for IMPDH Type II, expression of which is up-regulated in tumor cells. IMPDH inhibitors are not only valuable as chemotherapeutic agents but also as probes for investigating biochemical functions of guanylates in intact cells. (C) 2003 American Chemical Society.
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