| Abstract
| - β-Methylene-BAD (8), a nonhydrolyzable analogue ofbenzamide adenine dinucleotide (BAD),was synthesized as potential inhibitor of human inosine monophosphatedehydrogenase(IMPDH). Treatment of 2‘,3‘-O-isopropylideneadenosine5‘-methylenebisphosphonate (15) withDCC affordedP1,P4-bis(2‘,3‘-O-isopropylideneadenosine)5‘-P1,P:P,P-dimethylenetetrakisphosphonate (17). This compound was further converted withDCC to an active intermediate 18which upon reaction with3-(2‘,3‘-O-isopropylidene-β-d-ribofuranosyl)benzamide(19) gave, afterhydrolysis and deisopropylidenation, the desired β-methylene-BAD(8) in 95% yield. In a similarmanner, treatment of 18 with2‘,3‘-O-isopropylidenetiazofurin (21) followed byhydrolysis anddeprotection afforded β-methylene-TAD (5) in 91% yield.Compound 8 (IC50 = 0.665 μM)wasfound to be a 6−8 times less potent inhibitor of IMPDH than5 (IC50 = 0.107 μM) and wasalmost equally potent against IMPDH type I and type II. AlthoughTAD and β-methylene-TAD were bound by LADH with the same affinity, the binding affinity of8 toward LADH (Ki= 333 μM) was found to be 50-fold lower than that of the parentpyrophosphate 7 (Ki =6.3μM).
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