Coralyne and related compounds as mammalian topoisomerase I and topoisomerase II poisons

Darshan Makhey, Barbara Gatto, Chiang Yu, Angela Liu, Leroy-Fong Liu, Edmond J. LaVoie

Research output: Contribution to journalArticle

83 Citations (Scopus)

Abstract

DNA topoisomerases are nuclear enzymes responsible for modifying the topological state of DNA. The development of agents capable of poisoning topoisomerases has proved to be an attractive approach in the search for novel cancer chemotherapeutics. Coralyne, an antileukemic alkaloid, has appreciable structural similarity to the potent topoisomerase I and II poison, nitidine. Analogues of coralyne were synthesized and evaluated for their activity as topoisomerase I and topoisomerase II poisons. These analogues were also evaluated for cytotoxicity in the human lymphoblast cell line, RPMI 8402, and its camptothecin-resistant variant, CPT-K5. The pharmacological activity of these analogues exhibited a strong dependence on the substitution pattern and the nature of substituents. Several 1- benzylisoquinolines and 3-phenylisoquinolines were also synthesized. These compounds, which incorporate only a portion of the ring structure of coralyne, were evaluated as topoisomerase poisons and for cytotoxicity. These structure-activity studies indicate that the structural rigidity associated with the coralyne ring system may be critical for pharmacological activity. The presence of a 3,4-methylenedioxy substituent on these coralyne analogues was generally associated with enhanced activity as a topoisomerase poison. 5,6-Dihydro-3,4-methylenedioxy-10,11-dimethoxydibenzo[a,g]quinolizinium chloride was the most potent topoisomerase I poison among the coralyne analogues evaluated, having similar activity to camptothecin. This analogues also possessed exceptional potency as a topoisomerase II poison. Despite the pronounced activity of several of these coralyne derivatives as topoisomerase I poisons, mine of these compounds had cytotoxic activity similar to camptothecin. Possible differences in cellular absorption between these coralyne analogs, which possess a quaternary ammonium group, and camptothecin may be responsible for the differences observed in their relative cytotoxicity.

Original languageEnglish
Pages (from-to)781-791
Number of pages11
JournalBioorganic and Medicinal Chemistry
Volume4
Issue number6
DOIs
Publication statusPublished - Jun 1996
Externally publishedYes

Fingerprint

coralyne
Type II DNA Topoisomerase
Type I DNA Topoisomerase
Poisons
Camptothecin
Cytotoxicity
DNA Topoisomerases
Benzylisoquinolines
Pharmacology
Ammonium Compounds
Alkaloids
Rigidity

ASJC Scopus subject areas

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

Cite this

Coralyne and related compounds as mammalian topoisomerase I and topoisomerase II poisons. / Makhey, Darshan; Gatto, Barbara; Yu, Chiang; Liu, Angela; Liu, Leroy-Fong; LaVoie, Edmond J.

In: Bioorganic and Medicinal Chemistry, Vol. 4, No. 6, 06.1996, p. 781-791.

Research output: Contribution to journalArticle

Makhey, Darshan ; Gatto, Barbara ; Yu, Chiang ; Liu, Angela ; Liu, Leroy-Fong ; LaVoie, Edmond J. / Coralyne and related compounds as mammalian topoisomerase I and topoisomerase II poisons. In: Bioorganic and Medicinal Chemistry. 1996 ; Vol. 4, No. 6. pp. 781-791.
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