2,3-Dimethoxybenzo[i]phenanthridines: Topoisomerase I-targeting anticancer agents

Dajie Li, Baoping Zhao, Sai Peng Sim, Tsai Kun Li, Angela Liu, Leroy-Fong Liu, Edmond J. LaVoie

Research output: Contribution to journalArticle

47 Citations (Scopus)

Abstract

Appropriately substituted benzo[i]phenanthridines structurally related to nitidine, a benzo[c]phenanthridine alkaloid with antitumor activity, are active as topoisomerase I-targeting agents. Studies on benzo[i]phenanthridines have indicated analogues that possess a 2,3-methylenedioxy moiety and at least one and preferably two methoxyl groups at the 8- and 9-positions, such as 8,9-dimethoxy-2,3-methylenedioxybenzo[i]phenanthridine, 2, are active as topoisomerase I-targeting agents. Tetramethoxylated benzo[i]phenanthridines, wherein the 2,3-methylenedioxy moiety is replaced with methoxyl groups at the 2- and 3-position, are inactive as a topoisomerase I-targeting agent. These results initially suggested that the 2,3-methylenedioxy moiety was critical to the retention of potent activity. Further studies revealed that 2,3-dimethoxy-8,9-methylenedioxybenzo[i]phenanthridine, 7a, is more potent than 2 as a topoisomerase I-targeting agent. The observation that 2,3-dimethoxylated benzo[i]phenanthridines can actually exhibit enhanced activity prompted the present study in which several 8-substituted 2,3-dimethoxybenzo[i]phenanthridines were prepared and their pharmacological activities evaluated. The influence of NH 2, CN, CH 2OH, OBn, OCH 3, OH, and NHCOCH 3substituents at the 8-position on the relative activity of these 2,3-dimethoxybenzo[i]phenanthridines was examined. Relative to these derivatives, 7a was the most potent topoisomerase I-targeting agent, possessing similar cytotoxicity to that of nitidine in the human lymphoblast tumor cell line, RPMI8402.

Original languageEnglish
Pages (from-to)521-528
Number of pages8
JournalBioorganic and Medicinal Chemistry
Volume11
Issue number4
DOIs
Publication statusPublished - Feb 2002
Externally publishedYes

Fingerprint

Phenanthridines
Type I DNA Topoisomerase
Antineoplastic Agents
Cytotoxicity
Tumor Cell Line
Alkaloids
Tumors
Cells
Pharmacology

ASJC Scopus subject areas

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

Cite this

2,3-Dimethoxybenzo[i]phenanthridines : Topoisomerase I-targeting anticancer agents. / Li, Dajie; Zhao, Baoping; Sim, Sai Peng; Li, Tsai Kun; Liu, Angela; Liu, Leroy-Fong; LaVoie, Edmond J.

In: Bioorganic and Medicinal Chemistry, Vol. 11, No. 4, 02.2002, p. 521-528.

Research output: Contribution to journalArticle

Li, Dajie ; Zhao, Baoping ; Sim, Sai Peng ; Li, Tsai Kun ; Liu, Angela ; Liu, Leroy-Fong ; LaVoie, Edmond J. / 2,3-Dimethoxybenzo[i]phenanthridines : Topoisomerase I-targeting anticancer agents. In: Bioorganic and Medicinal Chemistry. 2002 ; Vol. 11, No. 4. pp. 521-528.
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