Isosteric analogues of nicotinamide adenine dinucleotide derived from furanfurin, thiophenfurin, and selenophenfurin as mammalian inosine monophosphate dehydrogenase (type I and II) inhibitors

J Med Chem. 1998 May 7;41(10):1702-7. doi: 10.1021/jm970772e.

Abstract

Dinucleotides TFAD (6), FFAD (7), and SFAD (8), isosteric NAD analogues derived, respectively, from C-nucleosides 5-beta-d-ribofuranosylthiophene-3-carboxamide (thiophenfurin, 1), 5-beta-d-ribofuranosylfuran-3-carboxamide (furanfurin, 2), and 5-beta-d-ribofuranosylselenophene-3-carboxamide (selenophenfurin, 5), were synthesized as human inosine monophosphate dehydrogenase (IMPDH) type I and II inhibitors. The synthesis was carried out by imidazole-catalyzed coupling of the 5'-monophosphate of 1, 2, and 5 with AMP. These dinucleotides, which are also analogues of thiazole-4-carboxamide adenine dinucleotide (TAD) and selenazole-4-carboxamide adenine dinucleotide (SAD), the active metabolites of the oncolytic C-nucleosides 2-beta-D-ribofuranosylthiazole-4-carboxamide (tiazofurin) and 2-beta-D-ribofuranosylselenazole-4-carboxamide (selenazofurin), were evaluated for their inhibitory potency against recombinant human IMPDH type I and II. The order of inhibitory potency found was SAD > SFAD = TFAD = TAD >> FFAD for both enzyme isoforms. No significant difference was found in inhibition of IMPDH type I and II.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Enzyme Inhibitors* / chemical synthesis
  • Enzyme Inhibitors* / pharmacology
  • Humans
  • IMP Dehydrogenase / antagonists & inhibitors*
  • Kinetics
  • NAD* / analogs & derivatives
  • NAD* / chemical synthesis
  • NAD* / chemistry
  • NAD* / pharmacology
  • Organoselenium Compounds / chemistry*
  • Recombinant Proteins / antagonists & inhibitors
  • Ribonucleosides / chemistry*

Substances

  • Enzyme Inhibitors
  • Organoselenium Compounds
  • Recombinant Proteins
  • Ribonucleosides
  • furanfurin
  • selenophenfurin
  • NAD
  • thiophenfurin
  • IMP Dehydrogenase