Substituted benz[a]acridines and benz[c]acridines as mammalian topoisomerase poisons

Darshan Makhey, Chiang Yu, Angela Liu, Leroy-Fong Liu, Edmond J. Lavoie

Research output: Contribution to journalArticle

38 Citations (Scopus)

Abstract

Coralyne and several other synthetic benzo[a,g]quinolizium derivatives related to protoberberine alkaloids have exhibited activity as topoisomerase poisons. These compounds are characterized by the presence of a positively charged iminium group, which has been postulated to be associated with their pharmacological properties. The objective of the present study was to devise stable noncharged bioisosteres of these compounds. Several similarly substituted benz[a]acridine and benz[c]acridine derivatives were synthesized and their relative activity as topoisomerase poisons was determined. While the benz[c]acridine derivatives evaluated as part of this study were devoid of topoisomerase poisoning activity, several dihydrobenz[a]acridines were able to enhance DNA cleavage in the presence of topo I. In contrast to certain protoberberine derivatives that did exhibit activity as topo II poisons, none of the benz[a]acridines derivatives enhanced DNA cleavage in the presence of topo II. Among the benz[a]acridines studied, 5,6-dihydro-3,4- methylenedioxy-9,10-dimethoxybenz[a]acridine, 13e, was the most potent topo I poison, with comparable potency to coralyne. These data suggest that heterocyclic compounds structurally related to coralyne can exhibit potent topo I posioning activity despite the absence of an iminium cation within their structure. In comparison to coralyne or other protoberberine derivatives, these benz[a]acridine derivatives possess distinctly different physicochemical properties and represent a novel series of topo I poisons. (C) 2000 Elsevier Science Ltd.

Original languageEnglish
Pages (from-to)1171-1182
Number of pages12
JournalBioorganic and Medicinal Chemistry
Volume8
Issue number5
DOIs
Publication statusPublished - May 2000
Externally publishedYes

Fingerprint

coralyne
Poisons
Derivatives
Acridines
DNA Cleavage
Heterocyclic Compounds
Alkaloids
Poisoning
Cations
DNA
benz(a)acridine
benz(c)acridine
Pharmacology

ASJC Scopus subject areas

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

Cite this

Substituted benz[a]acridines and benz[c]acridines as mammalian topoisomerase poisons. / Makhey, Darshan; Yu, Chiang; Liu, Angela; Liu, Leroy-Fong; Lavoie, Edmond J.

In: Bioorganic and Medicinal Chemistry, Vol. 8, No. 5, 05.2000, p. 1171-1182.

Research output: Contribution to journalArticle

Makhey, Darshan ; Yu, Chiang ; Liu, Angela ; Liu, Leroy-Fong ; Lavoie, Edmond J. / Substituted benz[a]acridines and benz[c]acridines as mammalian topoisomerase poisons. In: Bioorganic and Medicinal Chemistry. 2000 ; Vol. 8, No. 5. pp. 1171-1182.
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