The antimalarial and cytotoxic drug cryptolepine intercalates into DNA at cytosine-cytosine sites.
Cryptolepine, 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 approximately 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.
Lisgarten
John N
JN
Institut de Biologia Molecular de Barcelona, C.S.I.C., Jordi Girona 18, 08034 Barcelona, Spain.
Coll
Miquel
M
Portugal
Jose
J
Wright
Colin W
CW
Aymami
Juan
J
D000470:Alkaloids / Q000737:chemistry* / Q000378:metabolism*; D000962:Antimalarials / Q000737:chemistry / Q000378:metabolism*; D001483:Base Sequence; D001665:Binding Sites; D018360:Crystallography, X-Ray; D003596:Cytosine / Q000378:metabolism*; D004247:DNA / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D003956:Dialysis; D026121:Indole Alkaloids; D007211:Indoles / Q000737:chemistry* / Q000378:metabolism*; D007364:Intercalating Agents / Q000737:chemistry / Q000378:metabolism*; D008958:Models, Molecular; D008968:Molecular Conformation; D009690:Nucleic Acid Conformation; D010946:Plants, Medicinal / Q000737:chemistry; D011804:Quinolines / Q000737:chemistry* / Q000378:metabolism*; D012996:Solutions
D000470:Alkaloids; D000962:Antimalarials; D026121:Indole Alkaloids; D007211:Indoles; D007364:Intercalating Agents; D011804:Quinolines; D012996:Solutions; C024015:cryptolepine; D003596:Cytosine; D004247:DNA