Structure-activity relationships of benzimidazoles and related heterocycles as topoisomerase I poisons

Jung Sun Kim, Qun Sun, Barbara Gatto, Chiang Yu, Angela Liu, Leroy-Fong Liu, Edmond J. LaVoie

Research output: Contribution to journalArticle

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Abstract

A series of substituted 2-(4-methoxyphenyl)-1H-benzimidazoles were synthesized and evaluated as inhibitors of topoisomerase I. The presence of a 5-formyl-, 5-(aminocarbonyl)-, or 5-nitro group (i.e., substituents capable of acting as hydrogen bond accepters) correlated with the potential of select derivatives to inhibit topoisomerase I. In contrast to bi- and terbenzimidazoles, the substituted benzimidazoles that were active as topoisomerase I poisons exhibited minimum or no DNA binding affinity. 5-Nitro-2-(4-methoxyphenyl)-1H-benzimidazole exhibited the highest activity and was significantly more active than the 4-nitro positional isomer. The 5- and 6-nitro derivatives of 2-(4-methoxyphenyl)benzoxazole, 2-(4-methoxyphenyl)benzothiazole, and 2-(4-methoxyphenyl)indole were synthesized and their relative activity as topoisomerase I inhibitors determined. None of these heterocyclic analogues were effective in significantly inhibiting cleavable-complex formation in the presence of DNA and topoisomerase I, suggesting a high degree of structural specificity associated with the interaction of these substituted benzimidazoles with the enzyme or the enzyme-DNA complex. In evaluating their cytotoxicity, these new topoisomerase I poisons also exhibited no significant cross-resistance against cell lines that express camptothecin-resistant topoisomerase I.

Original languageEnglish
Pages (from-to)621-630
Number of pages10
JournalBioorganic and Medicinal Chemistry
Volume4
Issue number4
DOIs
Publication statusPublished - Apr 1996
Externally publishedYes

Fingerprint

Benzimidazoles
Type I DNA Topoisomerase
Poisons
Structure-Activity Relationship
Topoisomerase I Inhibitors
Benzoxazoles
Derivatives
Camptothecin
DNA
Enzymes
Cytotoxicity
Isomers
Hydrogen
Hydrogen bonds
Cells
Cell Line

ASJC Scopus subject areas

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

Cite this

Structure-activity relationships of benzimidazoles and related heterocycles as topoisomerase I poisons. / Kim, Jung Sun; Sun, Qun; Gatto, Barbara; Yu, Chiang; Liu, Angela; Liu, Leroy-Fong; LaVoie, Edmond J.

In: Bioorganic and Medicinal Chemistry, Vol. 4, No. 4, 04.1996, p. 621-630.

Research output: Contribution to journalArticle

Kim, Jung Sun ; Sun, Qun ; Gatto, Barbara ; Yu, Chiang ; Liu, Angela ; Liu, Leroy-Fong ; LaVoie, Edmond J. / Structure-activity relationships of benzimidazoles and related heterocycles as topoisomerase I poisons. In: Bioorganic and Medicinal Chemistry. 1996 ; Vol. 4, No. 4. pp. 621-630.
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