Novel autoxidative cleavage reaction of 9-fluoredenes discovered during synthesis of a potential DNA-threading indenoisoquinoline

J Org Chem. 2004 Oct 29;69(22):7495-501. doi: 10.1021/jo048808f.


The indenoisoquinolines are a novel class of cytotoxic non-camptothecin topoisomerase I inhibitors. A potential DNA-threading agent was designed by attaching different amine side chains on the lactam nitrogen as well as on the C11 position of the indenoisoquinoline ring system. It was hypothesized that substituents on the lactam nitrogen could protrude out toward the DNA major groove while those on the C11 project out toward the DNA minor groove in the ternary "cleavage complex." Compound 4 was synthesized in order to test this DNA-threading scenario. It was found unexpectedly that an alkenyl substituent on the C11 position was autoxidatively cleaved under basic conditions to afford a ketone. A possible mechanism for this unusual oxidative cleavage was proposed on the basis of the studies of a 9-fluoredene model compound. The proposed mechanism was further supported by computational studies. Although the designed compound 4 showed potent cytotoxicities in various cancer cell lines, it was less potent than its nonthreading counterparts and was not a topoisomerase I inhibitor.

Publication types

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

MeSH terms

  • Antineoplastic Agents / chemical synthesis*
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology
  • Camptothecin
  • Cell Line, Tumor
  • DNA / drug effects
  • Drug Design
  • Drug Screening Assays, Antitumor
  • Enzyme Inhibitors / chemical synthesis*
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology
  • Fluorenes / chemical synthesis*
  • Fluorenes / chemistry
  • Fluorenes / pharmacology
  • Humans
  • Isoquinolines / chemical synthesis*
  • Isoquinolines / chemistry
  • Isoquinolines / pharmacology
  • Models, Molecular
  • Oxidation-Reduction
  • Structure-Activity Relationship
  • Topoisomerase I Inhibitors*


  • 11-(3'-aminopropylidene)-6-(3'-aminopropyl)-5,6-dihydro-2,3-dimethoxy-8,9-methylenedioxy-5-oxo-11H-indeno-(1,2-c)isoquinoline dihydrochloride
  • Antineoplastic Agents
  • Enzyme Inhibitors
  • Fluorenes
  • Isoquinolines
  • Topoisomerase I Inhibitors
  • DNA
  • Camptothecin