Synthesis, conformational analysis, and biological activity of new analogues of thiazole-4-carboxamide adenine dinucleotide (TAD) as IMP dehydrogenase inhibitors

Abstract

Thiazole-4-carboxamide adenine dinucleotide (TAD) analogues T-2′-MeAD ( 1) and T-3′-MeAD ( 2) containing, respectively, a methyl group at the ribose 2′- C-, and 3′- C-position of the adenosine moiety, were prepared as potential selective human inosine monophosphate dehydrogenase (IMPDH) type II inhibitors. The synthesis of heterodinucleotides was carried out by CDI-catalyzed coupling reaction of unprotected 2′- C-methyl- or 3′- C-methyl-adenosine 5′-monophosphate with 2′,3′- O-isopropylidene-tiazofurin 5′-monophosphate, and then deisopropylidenation. Biological evaluation of dinucleotides 1 and 2 as inhibitors of recombinant human IMPDH type I and type II resulted in a good activity. Inhibition of both isoenzymes by T-2′-MeAD and T-3′-MeAD was noncompetitive with respect to NAD substrate. Binding of T-3′-MeAD was comparable to that of parent compound TAD, while T-2′-MeAD proved to be a weaker inhibitor. However, no significant difference was found in inhibition of the IMPDH isoenzymes. T-2′-MeAD and T-3′-MeAD were found to inhibit the growth of K562 cells (IC 50 30.7 and 65.0 μM, respectively).