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Sci. Pharm. 2011, 79(4), 729-748; doi:10.3797/scipharm.1107-19

Attenuation of Cytotoxic Natural Product DNA Intercalating Agents by Caffeine

1
Department of Chemistry, University of Alabama in Huntsville, Huntsville, Alabama 35899, USA
2
Department of Biological Sciences, University of Alabama in Huntsville, Huntsville, Alabama 35899, USA
*
Author to whom correspondence should be addressed.
Received: 14 July 2011 / Accepted: 17 September 2011 / Published: 17 September 2011
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Abstract

Many anti-tumor drugs function by intercalating into DNA. The xanthine alkaloid caffeine can also intercalate into DNA as well as form π-π molecular complexes with other planar alkaloids and anti-tumor drugs. The presence of caffeine could interfere with the intercalating anti-tumor drug by forming π-π molecular complexes with the drug, thereby blocking the planar aromatic drugs from intercalating into the DNA and ultimately lowering the toxicity of the drug to the cancer cells. The cytotoxic activities of several known DNA intercalators (berberine, camptothecin, chelerythrine, doxorubicin, ellipticine, and sanguinar-ine) on MCF-7 breast cancer cells, both with and without caffeine present (200 μg/mL) were determined. Significant attenuation of the cytotoxicities by caffeine was found. Computational molecular modeling studies involving the intercalating anti-tumor drugs with caffeine were also carried out using density functional theory (DFT) and the recently developed M06 functional. Relatively strong π–π interaction energies between caffeine and the intercalators were found, suggesting an “interceptor” role of caffeine protecting the DNA from intercalation.
Keywords: Caffeine; DNA Intercalation; Cytotoxicity; π–π Complex; Density Functional Theory Caffeine; DNA Intercalation; Cytotoxicity; π–π Complex; Density Functional Theory
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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MDPI and ACS Style

HILL, G.M.; MORIARITY, D.M.; SETZER, W.N. Attenuation of Cytotoxic Natural Product DNA Intercalating Agents by Caffeine. Sci. Pharm. 2011, 79, 729-748.

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