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Title

The antimalarial and cytotoxic drug cryptolepine intercalates into DNA at cytosine-cytosine sites

AuthorsLisgarten, John N.; Coll, Miquel ; Portugal, José ; Wright, Colin W.; Aymamí, Joan
Keywordscryptolepine
doxorubicin
DNA fragment
DNA
daunorubicin
cytosine
Issue Date2002
PublisherNature Publishing Group
CitationNature Structural Biology 9(1): 57-60 (2002)
AbstractCryptolepine, a naturally occurring indoloquinoline alkaloid used as an antimalarial drug in Central and Western Africa, has been found to bind to DNA in a formerly unknown intercalation mode. Evidence from competition dialysis assays demonstrates that cryptolepine is able to bind CG-rich sequences containing nonalternating CC sites. Here we show that cryptolepine interacts with the CC sites of the DNA fragment d(CCTAGG)2 in a base-stacking intercalation mode. This is the first DNA intercalator complex, from ∼90 solved by X-ray crystallography, to bind a nonalternating (pyrimidine-pyrimidine) DNA sequence. The asymmetry of the drug induces a perfect stacking with the asymmetric site, allowing for the stability of the complex in the absence of hydrogen bonding interactions. The crystal structure of this antimalarial drug-DNA complex provides evidence for the first nonalternating intercalation and, as such, provides a basis for the design of new anticancer or antimalarial drugs.
Publisher version (URL)http://dx.doi.org/10.1038/nsb729
URIhttp://hdl.handle.net/10261/108794
DOIhttp://dx.doi.org/10.1038/nsb729
Identifiersdoi: 10.1038/nsb729
issn: 1072-8368
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