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Issue 23, 2013
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Synthetic prodigiosenes and the influence of C-ring substitution on DNA cleavage, transmembrane chloride transport and basicity

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Abstract

Analogues of the tripyrrolic natural product prodigiosin bearing an additional methyl and a carbonyl group at the C-ring were synthesised and evaluated. In vitro anticancer activity screening (NCI) and the study of modes of action (copper-mediated cleavage of double-stranded DNA and transmembrane transport of chloride anions) showed that the presence of the methyl group is not detrimental to activity. Furthermore, although the presence of an ester conjugated to the prodigiosene C-ring seems to decrease both pKa and chloride transport efficiency compared to the natural product, these analogues still exhibit a high rate of chloride transport. All analogues exhibit good in vitro anticancer activity and reduced toxicity compared to the natural product: compare an acute systemic toxicity of 100 mg kg−1 in mice vs. 4 mg kg−1 for prodigiosin, pointing towards a larger therapeutic window than for the natural product.

Graphical abstract: Synthetic prodigiosenes and the influence of C-ring substitution on DNA cleavage, transmembrane chloride transport and basicity

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Publication details

The article was received on 07 Mar 2013, accepted on 24 Apr 2013 and first published on 03 May 2013


Article type: Paper
DOI: 10.1039/C3OB40477C
Citation: Org. Biomol. Chem., 2013,11, 3834-3845
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    Synthetic prodigiosenes and the influence of C-ring substitution on DNA cleavage, transmembrane chloride transport and basicity

    S. Rastogi, E. Marchal, I. Uddin, B. Groves, J. Colpitts, S. A. McFarland, J. T. Davis and A. Thompson, Org. Biomol. Chem., 2013, 11, 3834
    DOI: 10.1039/C3OB40477C

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