Novel zinc chelators with dual activity in the inhibition of the kappa B site-binding proteins HIV-EP1 and NF-kappa B

J Med Chem. 1995 Aug 18;38(17):3264-70. doi: 10.1021/jm00017a011.

Abstract

Both HIV-EP1 (also called PRDII-BF1 or MBP-1), a zinc finger protein, and NF-kappa B, a Rel family protein, bind to kappa B site present in the enhancer of multiple cellular and viral genes involved in immune function and inflammatory response including HIV-1 LTR and human interferon beta gene. When cells are exposed to extracellular stimuli such as virus or phorbol ester, the activity of both HIV-EP1 and NF-kappa B is induced. Thus, kappa B site-directed transcription could be regulated by two distinct proteins in a cooperative way. Novel heterocyclic compounds comprising (dimethylamino)pyridine and histidine units, i.e., 1-4, have been designed and synthesized, aiming at inhibition of these kappa B site-binding proteins to discriminate their functions. These compounds exhibited remarkable zinc-binding capability as revealed by NMR study. Compounds 1 and 2 showed a marked inhibitory effect on the DNA binding activity of HIV-EP1 by removing zinc without interfering with the DNA binding activity of NF-kappa B. Since it has been demonstrated that zinc somehow influences the DNA binding of NF-kappa B, the effect of these heterocyclic compounds and their zinc complexes on NF-kappa B was examined. Zinc complexes of 3 and 4 exhibited the inhibitory effect on the DNA binding of NF-kappa B and/or homodimeric complexes of p50 and p65 subunits of NF-kappa B without affecting HIV-EP1. Thus, it became possible to inhibit either one of the two kappa B site-binding proteins without inhibiting the other.(ABSTRACT TRUNCATED AT 250 WORDS)

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Base Sequence
  • Binding Sites
  • Chelating Agents / chemistry*
  • DNA / metabolism
  • DNA-Binding Proteins / antagonists & inhibitors*
  • DNA-Binding Proteins / metabolism
  • Humans
  • Molecular Sequence Data
  • NF-kappa B / antagonists & inhibitors*
  • NF-kappa B / metabolism
  • Oligodeoxyribonucleotides
  • Transcription Factors
  • Zinc / chemistry*
  • Zinc Fingers

Substances

  • Chelating Agents
  • DNA-Binding Proteins
  • HIVEP1 protein, human
  • NF-kappa B
  • Oligodeoxyribonucleotides
  • Transcription Factors
  • DNA
  • Zinc