Substituted dibenzo[c,h]cinnolines: Topoisomerase I-targeting anticancer agents

Younong Yu, Sudhir K. Singh, Angela Liu, Tsai Kun Li, Leroy-Fong Liu, Edmond J. LaVoie

Research output: Contribution to journalArticle

71 Citations (Scopus)

Abstract

Several substituted dibenzo[c,h]cinnolines were synthesized and evaluated for their potential to target topoisomerase I and for their relative cytotoxic activity. Select benzo[i]phenanthridines are capable of stabilizing the cleavable complex formed with topoisomerase I and DNA. This study was initiated to examine whether dibenzo[c,h]cinnolines, which are in essence aza analogues of benzo[i]phenanthridines, possess similar pharmacological properties. 2,3-Dimethoxy-8,9-methylenedioxybenzo[i]phenanthridine is one of the more potent benzo[i]phenanthridine derivatives in regard to topoisomerase I-targeting activity and cytotoxicity. The structure-activity relationship observed with these substituted dibenzo[c,h]cinnolines parallels that observed for benzo[i]phenanthridine derivatives. Compared to similarly substituted benzo[i]phenanthridines, the dibenzo[c,h]cinnoline analogues exhibit more potent topoisomerase I-targeting activity and cytotoxicity. The relative IC50 values obtained in assessing the cytotoxicity of 2,3-dimethoxy-8,9-methylenedioxydibenzo[c,h]cinnoline and 2,3-dimethoxy-8,9-methylenedioxybenzo[i]phenanthridine in the human lymphoblastma cell line, RPMI8402, are 70 and 400 nM, respectively. In tumor cell lines selected for resistance to camptothecin and known to express mutant topoisomerase I, benzo[i]phenanthridine derivatives were not cross-resistant. In contrast, similarly substituted dibenzo[c,h]cinnolines with significant topoisomerase I-targeting activity did exhibit cross-resistance in these camptothecin-resistant cell lines. The cytotoxicity of these dibenzo[c,h]cinnolines was not diminished in cells overexpressing the efflux transporter, MDR1. These data indicate that substituted dibenzo[c,h]cinnolines can exhibit potent topoisomerase I-targeting activity and are capable of overcoming the multi-drug resistance associated with this efflux transporter.

Original languageEnglish
Pages (from-to)1475-1491
Number of pages17
JournalBioorganic and Medicinal Chemistry
Volume11
Issue number7
DOIs
Publication statusPublished - Apr 2003
Externally publishedYes

Fingerprint

Phenanthridines
Type I DNA Topoisomerase
Antineoplastic Agents
Cytotoxicity
Camptothecin
Cells
Derivatives
Cell Line
cinnoline
Multiple Drug Resistance
Structure-Activity Relationship
Tumor Cell Line
Inhibitory Concentration 50
Tumors
Pharmacology

ASJC Scopus subject areas

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

Cite this

Substituted dibenzo[c,h]cinnolines : Topoisomerase I-targeting anticancer agents. / Yu, Younong; Singh, Sudhir K.; Liu, Angela; Li, Tsai Kun; Liu, Leroy-Fong; LaVoie, Edmond J.

In: Bioorganic and Medicinal Chemistry, Vol. 11, No. 7, 04.2003, p. 1475-1491.

Research output: Contribution to journalArticle

Yu, Younong ; Singh, Sudhir K. ; Liu, Angela ; Li, Tsai Kun ; Liu, Leroy-Fong ; LaVoie, Edmond J. / Substituted dibenzo[c,h]cinnolines : Topoisomerase I-targeting anticancer agents. In: Bioorganic and Medicinal Chemistry. 2003 ; Vol. 11, No. 7. pp. 1475-1491.
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