Journal
JOURNAL OF BIOLOGICAL INORGANIC CHEMISTRY
Volume 17, Issue 2, Pages 247-261Publisher
SPRINGER
DOI: 10.1007/s00775-011-0846-z
Keywords
Anticancer drug; Liriodenine; Gold compound; X-ray crystallography; DNA binding
Funding
- National Basic Research Program of China [2009CB526503, 2010CB534911]
- National Natural Science Foundation of China [20861002]
- Natural Science Foundation of Guangxi Province [0991012Z, 0991003, 2010GXNSFF013001]
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Liriodenine, an oxoaporphine alkaloid with anticancer activity isolated from Zanthoxylum nitidum (rutaceous anticancer traditional Chinese medicine), was selected as a bioactive ligand to react with HAuCl4 and NaAuCl4 to afford [LH][AuCl4] (1) and [AuCl3L] (2), respectively (where L is liriodenine). The structures of 1 and 2 were characterized by IR spectroscopy, electrospray ionization mass spectrometry, H-1-NMR spectroscopy, and elemental analysis. The single-crystal X-ray diffraction analysis of 1 revealed that it is an ionic compound consisting of protonated liriodenine cation [LH](+) and [AuCl4](-) anion. The spectroscopic analysis showed that 2 is a coordination compound, in which one liriodenine coordinates to gold via its 7-N donor. In aqueous solution, 1 is relatively stable, but 2 undergoes rapid hydrolysis. The in vitro cytotoxicity towards five human tumor cell lines shows that 1 and 2 manifest roughly similar biological behavior and appreciable antiproliferative properties, with IC50 values falling in the 2-16 mu M range. The flow-cytometric analysis of 1 and 2 suggests that both compounds induced an S-phase arrest. Compounds 1 and 2 significantly poison topoisomerase I in vitro at low concentration (25 mu M or less). DNA binding studies indicate that both 1 and 2 interact with DNA mainly via intercalation between the neighboring base pairs of the DNA double helix. Electrostatic interactions of 1 and 2 with the polyanionic DNA phosphate backbone may reinforce the intercalation because both 1 and 2 are composed of planar cationic species.
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