Development of novel inhibitor probes of DNA polymerase III based on dGTP analogs of the HPUra type: base, nucleoside and nucleotide derivatives of N2-(3,4-dichlorobenzyl)guanine

Nucleic Acids Res. 1990 Dec 25;18(24):7381-7. doi: 10.1093/nar/18.24.7381.


6-(p-Hydroxyphenylhydrazino)uracil (H2-HPUra) is a selective and potent inhibitor of the replication-specific class III DNA polymerase (pol III) of Gr+ bacteria. Although formally a pyrimidine, H2-HPUra derives its inhibitory activity from its specific capacity to mimic the purine nucleotide, dGTP. We describe the successful conversion of the H2-HPUra inhibitor prototype to a bona fide purine, using N2-(benzyl)guanine (BG) as the basis. Structure-activity relationships of BGs carrying a variety of substituents on the aryl ring identified N2-(3,4-dichlorobenzyl)guanine (DCBG) as a nucleus equivalent to H2-HPUra with respect to potency and inhibitor mechanism. DCBdGTP, the 2'-deoxyribonucleoside 5'-triphosphate form of DCBG, was synthesized and characterized with respect to its action on wild-type and mutant forms of B. subtilis DNA pol III. DCBdGTP acted on pol III by the characteristic inhibitor mechanism and formally occupied the dNTP binding site with a fit which permitted its polymerization.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Base Sequence
  • Binding Sites
  • DNA Polymerase III / antagonists & inhibitors*
  • DNA Polymerase III / metabolism
  • Deoxyguanine Nucleotides / metabolism
  • Deoxyguanine Nucleotides / pharmacology*
  • Guanine / analogs & derivatives*
  • Guanine / metabolism
  • Guanine / pharmacology
  • Molecular Sequence Data
  • Uracil / analogs & derivatives*
  • Uracil / pharmacology


  • Deoxyguanine Nucleotides
  • N(2)-(3,4-dichlorobenzyl)-2'-deoxyguanosine 5'triphosphate
  • N(2)-(3,4-dichlorobenzyl)guanine
  • 6-(4-hydroxyphenylhydrazino)uracil
  • Uracil
  • Guanine
  • deoxyguanosine triphosphate
  • DNA Polymerase III