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

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• 作者：Franchetti ; Palmarisa ; Cappellacci ; Loredana ; Pasqualini ; Michela ; Petrelli ; Riccardo ; Jayaprakasan ; Vetrichelvan ; et. al.
• 关键词：TAD analogues ; IMPDH inhibitors ; Cytotoxicity
• 刊名：Bioorganic and Medicinal Chemistry
• 出版年：2005
• 出版时间：March 15, 2005
• 年：2005
• 卷：13
• 期：6
• 页码：2045-2053
• 全文大小：264 K

文摘

Thiazole-4-carboxamide adenine dinucleotide (TAD) analogues T-2aaa-MeAD (1) and T-3aaa-MeAD (2) containing, respectively, a methyl group at the ribose 2aaa-C-, and 3aaa-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 2aaa-C-methyl- or 3aaa-C-methyl-adenosine 5aaa-monophosphate with 2aaa,3aaa-O-isopropylidene-tiazofurin 5aaa-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-2aaa-MeAD and T-3aaa-MeAD was noncompetitive with respect to NAD substrate. Binding of T-3aaa-MeAD was comparable to that of parent compound TAD, while T-2aaa-MeAD proved to be a weaker inhibitor. However, no significant difference was found in inhibition of the IMPDH isoenzymes. T-2aaa-MeAD and T-3aaa-MeAD were found to inhibit the growth of K562 cells (IC₅₀ 30.7 and 65.0aaM, respectively).