Total synthesis and biological evaluation of 22-hydroxyacuminatine

Xiangshu Xiao, Smitha Antony, Yves Pommier, Mark Cushman

Research output: Contribution to journalArticle

51 Citations (Scopus)

Abstract

A total synthesis of 22-hydroxyacuminatine, a cytotoxic alkaloid isolated from Camptotheca acuminata, is reported. The key step in the synthesis involves the reaction of 2,3-dihydro-1H-pyrrolo[3,4-b]quinoline with a brominated phthalide to generate a substituted pentacyclic 12H-5,11a-diazadibenzo[b,h] fluoren-11-one intermediate. Despite its structural resemblance to camptothecin and luotonin A, a biological evaluation of 22-hydroxyacuminatine in a topoisomerase I-deficient cell line P388/CPT45 has confirmed that the observed cytotoxicity is not due to topoisomerase I inhibition, even though 22-hydroxyacuminatine has a hydroxyl group that can theoretically hydrogen bond to Asp533. This result is consistent with the hypothesis that π-π stacking is more important than hydrogen-bonding interactions in determining topoisomerase I inhibitor binding in the ternary cleavage complex.

Original languageEnglish (US)
Pages (from-to)1408-1412
Number of pages5
JournalJournal of Medicinal Chemistry
Volume49
Issue number4
DOIs
StatePublished - Feb 23 2006
Externally publishedYes

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Type I DNA Topoisomerase
Camptotheca
Hydrogen bonds
Topoisomerase I Inhibitors
Camptothecin
Hydrogen Bonding
Cytotoxicity
Alkaloids
Hydroxyl Radical
Hydrogen
Cells
Cell Line
22-hydroxyacuminatine
luotonin A
phthalide
quinoline

ASJC Scopus subject areas

  • Organic Chemistry

Cite this

Total synthesis and biological evaluation of 22-hydroxyacuminatine. / Xiao, Xiangshu; Antony, Smitha; Pommier, Yves; Cushman, Mark.

In: Journal of Medicinal Chemistry, Vol. 49, No. 4, 23.02.2006, p. 1408-1412.

Research output: Contribution to journalArticle

Xiao, Xiangshu ; Antony, Smitha ; Pommier, Yves ; Cushman, Mark. / Total synthesis and biological evaluation of 22-hydroxyacuminatine. In: Journal of Medicinal Chemistry. 2006 ; Vol. 49, No. 4. pp. 1408-1412.
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