Synthesis, cytotoxicity, DNA interaction and topoisomerase II inhibition properties of tetrahydropyrrolo[3,4-a]carbazole-1,3-dione and tetrahydropyrido-[3,2-b]pyrrolo[3,4-g]indole-1,3-dione derivatives

Bioorg Med Chem. 2001 Jun;9(6):1533-41. doi: 10.1016/s0968-0896(01)00026-8.

Abstract

Three tetrahydropyrrolo[3,4-a]carbazole-1,3-diones (6--8) and two tetrahydropyrido[3,2-b]pyrrolo[3,4-g]indole-1,3-diones (11--12) have been synthesized. Their interaction with DNA was probed by absorption and thermal melting studies. Compounds 8 and 12 both equipped with a hydroxyethyl-aminoethyl side-chain demonstrated higher affinities for poly(dA-dT)(2) than compounds 6, 7 and 11 bearing a dimethylaminoethyl side-chain. Circular and electric linear dichroism measurements showed that all five drugs behave as typical DNA intercalating agents. A plasmid cleavage assay was used to evaluate the capacity of the drugs to inhibit human topoisomerase II. Compounds 8 and 12 which bind strongly to DNA were found to stabilize DNA-topoisomerase II covalent complexes but their topoisomerase II inhibitory properties do not correlate with their cytotoxic potential. Compounds 6 and 7 are essentially inactive whereas compounds 8, 11 and 12 exhibit a high toxicity to P388 murine leukemia cells and provoke a marked accumulation in the G2/M phase of the cell cycle. These compounds form a new class of DNA-targeted antitumor agents.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Biochemistry / methods
  • Cell Cycle / drug effects
  • Circular Dichroism
  • DNA / metabolism*
  • Drug Screening Assays, Antitumor
  • Enzyme Inhibitors / chemistry*
  • Enzyme Inhibitors / metabolism
  • Enzyme Inhibitors / pharmacology*
  • Humans
  • Indoles / chemistry*
  • Indoles / metabolism
  • Indoles / pharmacology*
  • Leukemia / drug therapy
  • Mice
  • Molecular Structure
  • Pyrroles / chemistry*
  • Pyrroles / metabolism
  • Pyrroles / pharmacology*
  • Topoisomerase II Inhibitors*
  • Toxicity Tests
  • Tumor Cells, Cultured

Substances

  • 2-((2-(-hyroxyethyl)amino)ethyl)-10-methyl-1,2,3,10-(2,3-b)pyrrolo(3,4-e)indole-1,3-dione
  • Enzyme Inhibitors
  • Indoles
  • Pyrroles
  • Topoisomerase II Inhibitors
  • DNA