Design, synthesis, and biological evaluation of cytotoxic 11-aminoalkenylindenoisoquinoline and 11-diaminoalkenylindenoisoquinoline topoisomerase I inhibitors

Xiangshu Xiao, Smitha Antony, Glenda Kohlhagen, Yves Pommier, Mark Cushman

Research output: Contribution to journalArticle

44 Citations (Scopus)

Abstract

The cytotoxic indenoisoquinolines are a novel class of noncamptothecin topoisomerase I inhibitors having certain features that compare favorably with the camptothecins. A new strategy was adopted to attach aminoalkenyl substituents at C-11 of the indenoisoquinoline ring system, which, according to molecular modeling, would orient the side chains toward the DNA minor groove. All of the newly synthesized compounds were more cytotoxic than the parent indenoisoquinoline NSC 314622. Despite an imperfect correlation between cytotoxicities and topoisomerase I inhibition results, the hypothetical structural model of the cleavage complex presented here provides a conceptual framework to explain the structure-activity relationships.

Original languageEnglish (US)
Pages (from-to)5147-5160
Number of pages14
JournalBioorganic and Medicinal Chemistry
Volume12
Issue number19
DOIs
StatePublished - Oct 1 2004
Externally publishedYes

Fingerprint

NSC 314622
Topoisomerase I Inhibitors
Camptothecin
Type I DNA Topoisomerase
Molecular modeling
Structural Models
Structure-Activity Relationship
Cytotoxicity
DNA

Keywords

  • Anticancer
  • Indenoisoquinoline
  • McMurry coupling
  • Topoisomerase I

ASJC Scopus subject areas

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

Cite this

Design, synthesis, and biological evaluation of cytotoxic 11-aminoalkenylindenoisoquinoline and 11-diaminoalkenylindenoisoquinoline topoisomerase I inhibitors. / Xiao, Xiangshu; Antony, Smitha; Kohlhagen, Glenda; Pommier, Yves; Cushman, Mark.

In: Bioorganic and Medicinal Chemistry, Vol. 12, No. 19, 01.10.2004, p. 5147-5160.

Research output: Contribution to journalArticle

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