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

Palmarisa Franchetti, Loredana Cappellacci, Michela Pasqualini, Riccardo Petrelli, Vetrichelvan Jayaprakasan, Hiremagalur N Jayaram, Donald B Boyd, Manojkumar D Jain, Mario Grifantini

Dipartimento di Scienze Chimiche, Università di Camerino, 62032 Camerino, Italy.

Bioorganic & medicinal chemistry 2005 Mar 15

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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 65.0muM, respectively).

Citation

Palmarisa Franchetti, Loredana Cappellacci, Michela Pasqualini, Riccardo Petrelli, Vetrichelvan Jayaprakasan, Hiremagalur N Jayaram, Donald B Boyd, Manojkumar D Jain, Mario Grifantini. Synthesis, conformational analysis, and biological activity of new analogues of thiazole-4-carboxamide adenine dinucleotide (TAD) as IMP dehydrogenase inhibitors. Bioorganic & medicinal chemistry. 2005 Mar 15;13(6):2045-53