Total synthesis and biological evaluation of 22-hydroxyacuminatine

Xiangshu Xiao, Smitha Antony, Yves Pommier, Mark Cushman

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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
Publication statusPublished - Feb 23 2006
Externally publishedYes

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ASJC Scopus subject areas

  • Organic Chemistry

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