TCM active ingredient oxoglaucine metal complexes: crystal structure, cytotoxicity, and interaction with DNA.
The alkaloid oxoglaucine (OG), which is a bioactive component from traditional Chinese medicine (TCM), was synthesized by a two-step reaction and used as the ligand to react with transition metal salts to give four complexes: [OGH][AuCl(4)]·DMSO (1), [Zn(OG)(2)(H(2)O)(2)](NO(3))(2) (2), [Co(OG)(2)(H(2)O)(2)](ClO(4))(2) (3), and [Mn(OG)(2)(H(2)O)(2)](ClO(4))(2) (4). The crystal structures of the metal complexes were confirmed by single crystal X-ray diffraction. Complex 1 is an ionic compound consisting of a charged ligand [OGH](+) and a gold complex [AuCl(4)](-). Complexes 2-4 all have similar structures (inner-spheres), that is, octahedral geometry with two OG coordinating to one metal center and two aqua ligands occupying the two apical positions of the octahedron, and two NO(3)(-) or ClO(4)(-) as counteranions in the outer-sphere. The complexation of OG to metal ion was confirmed by ESI-MS, capillary electrophoresis and fluorescence polarization. The in vitro cytotoxicity of these complexes toward a various tumor cell lines was assayed by the MTT method. The results showed that most of these metal-oxoglaucine complexes exhibited enhanced cytotoxicity compared with oxoglaucine and the corresponding metal salts, with IC(50) values ranging from 1.4 to 32.7 μM for sensitive cancer cells, which clearly implied a positive synergistic effect. Moreover, these complexes appeared to be selectively active against certain cell lines. The interactions of oxoglaucine and its metal complexes with DNA and topoisomerase I were investigated by UV-vis, fluorescence, CD spectroscopy, viscosity, and agarose gel electrophoresis, and the results indicated that these OG-metal complexes interact with DNA mainly via intercalation. Complexes 2-4 are metallointercalators, but complex 1 is not. These metal complexes could effectively inhibit topoisomerase I even at low concentration. Cell cycle analysis revealed that 1-3 caused S-phase cell arrest.
State Key Laboratory Cultivation Base for the Chemistry and Molecular Engineering of Medicinal Resources, School of Chemistry & Chemical Engineering, Guangxi Normal University, Guilin, 541004, China. chenzfubc@yahoo.com
Zhen-Feng
ZF
Chen
Yan-Fang
YF
Shi
Yan-Cheng
YC
Liu
Xue
X
Hong
Bo
B
Geng
Yan
Y
Peng
Hong
H
Liang
D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000737:chemistry* / Q000494:pharmacology*; D001058:Apomorphine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D002417:Cattle; D002453:Cell Cycle / Q000187:drug effects; D002460:Cell Line; D056831:Coordination Complexes / Q000737:chemistry / Q000494:pharmacology; D018360:Crystallography, X-Ray; D004247:DNA / Q000378:metabolism; D004264:DNA Topoisomerases, Type I / Q000378:metabolism; D004365:Drugs, Chinese Herbal / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D008958:Models, Molecular; D009369:Neoplasms / Q000188:drug therapy; D059004:Topoisomerase I Inhibitors / Q000737:chemistry / Q000494:pharmacology; D028561:Transition Elements / Q000737:chemistry / Q000494:pharmacology
D000972:Antineoplastic Agents, Phytogenic; D056831:Coordination Complexes; D004365:Drugs, Chinese Herbal; D059004:Topoisomerase I Inhibitors; D028561:Transition Elements; C111587:oxoglaucine; D004247:DNA; C427203:calf thymus DNA; D004264:DNA Topoisomerases, Type I; D001058:Apomorphine