Synthesis and high-throughput evaluation of triskelion uracil libraries for inhibition of human dUTPase and UNG2

Yu Lin Jiang, Suhman Chung, Daniel J. Krosky, James T. Stivers

Research output: Contribution to journalArticlepeer-review

Abstract

Human nuclear uracil DNA glycosylase (UNG2) and deoxyuridine triphosphate nucleotidohydrolase (dUTPase) are the primary enzymes that prevent the incorporation and accumulation of deoxyuridine in genomic DNA. These enzymes are desirable targets for small molecule inhibitors given their roles in a wide range of biological processes ranging from chromosomal rearrangements that lead to cancer, viral DNA replication, and the formation of toxic DNA strand breaks during anticancer drug therapy. To accelerate the discovery of such inhibitors, we have developed a high-throughput approach for directed library synthesis and screening. In this efficient technology, a uracil-aldehyde ligand is covalently tethered to one position of a trivalent alkyloxyamine linker via an oxime linkage, and then the vacant linker positions are derivatized with a library of aldehydes. The resulting triskelion oximes were directly screened for inhibitory activity and the most potent of these showed micromolar binding affinities to UNG2 and dUTPase.

Original languageEnglish (US)
Pages (from-to)5666-5672
Number of pages7
JournalBioorganic and Medicinal Chemistry
Volume14
Issue number16
DOIs
StatePublished - Aug 15 2006

Keywords

  • Directed chemical libraries
  • Enzyme inhibition
  • High-throughput screening
  • Uracil DNA glycosylase
  • dUTPase

ASJC Scopus subject areas

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

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