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

Research output: Contribution to journalArticle

25 Scopus citations

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 (IC50 30.7 and 65.0 μM, respectively).

Original languageEnglish (US)
Pages (from-to)2045-2053
Number of pages9
JournalBioorganic and Medicinal Chemistry
Volume13
Issue number6
DOIs
StatePublished - Mar 15 2005

Keywords

  • Cytotoxicity
  • IMPDH inhibitors
  • TAD analogues

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Organic Chemistry
  • Drug Discovery
  • Pharmaceutical Science

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    Franchetti, P., Cappellacci, L., Pasqualini, M., Petrelli, R., Jayaprakasan, V., Jayaram, H. N., Boyd, D. B., Jain, M. D., & Grifantini, M. (2005). Synthesis, conformational analysis, and biological activity of new analogues of thiazole-4-carboxamide adenine dinucleotide (TAD) as IMP dehydrogenase inhibitors. Bioorganic and Medicinal Chemistry, 13(6), 2045-2053. https://doi.org/10.1016/j.bmc.2005.01.007