Mechanism-based design of inosine 5-monophosphate dehydrogenase inhibitors: synthesis and biological activities of 5-ethynyl-1-beta-D-ribofuranosylimidazole-4-carboxamide (EICAR) and its derivatives.
Inosine 5 -monophosphate dehydrogenase (IMPDH) catalyzes the nicotinamide adenine dinucleotide (NAD)-dependent oxidation of inosine 5 -monophosphate (IMP) to xanthosine 5 -monophosphate (XMP), and is one of the key rate-determining enzymes of de novo guanine nucleotide biosynthesis in mammalian systems. Based on the proposed catalytic mechanism of IMPDH, we designed and synthesized 5-ethynyl-1-beta-D-ribofuranosylimidazole-4-carboxamide (5b, EICAR) from 5-amino-1-beta-D-ribofuranosylimida-zole-4-carboxamide (AICAR) via palladium chemistry. EICAR is a potent cytostatic agent that inhibits various tumor cells in culture including human solid tumor cells in vitro and in vivo. EICAR also showed broad-spectrum antiviral activities, about 10- to 100-fold greater than those of ribavirin. An examination of the structure-activity relationships revealed that an alkynyl group, especially an ethynyl group at the 5-position, is important for its activity due to the inhibition of IMPDH. The mode of action of EICAR is also discussed.
Minakawa
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Graduate School of Pharmaceutical Sciences, Hokkaido University, Kita-12, Nishi-6, Kita-ku, Sapporo, 060-0812, Japan.
Matsuda
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A
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology*; D002384:Catalysis; D015195:Drug Design; D005472:Fluorouracil / Q000494:pharmacology; D006801:Humans; D007168:IMP Dehydrogenase / Q000037:antagonists & inhibitors*; D020128:Inhibitory Concentration 50; D007939:Leukemia L1210 / Q000188:drug therapy; D008956:Models, Chemical; D012254:Ribavirin / Q000494:pharmacology; D012263:Ribonucleosides / Q000138:chemical synthesis* / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D012263:Ribonucleosides; C059077:5-ethynyl-1-ribofuranosylimidazole-4-carboxamide; D012254:Ribavirin; D007168:IMP Dehydrogenase; D005472:Fluorouracil