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Total synthesis and biological evaluation of 22-hydroxyacuminatine.

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 pi-pi stacking is more important than hydrogen-bonding interactions in determining topoisomerase I inhibitor binding in the ternary cleavage complex.

SUBMITTER: Xiao X

PROVIDER: S-EPMC2532531 | biostudies-literature | 2006 Feb

REPOSITORIES: biostudies-literature

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Total synthesis and biological evaluation of 22-hydroxyacuminatine.

Xiao Xiangshu X Antony Smitha S Pommier Yves Y Cushman Mark M

Journal of medicinal chemistry 20060201 4

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 h ...[more]

PMID: 16480276

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