title: Stable anticancer gold(III)-porphyrin complexes: effects of porphyrin structure.
abstract: In the design of physiologically stable anticancer gold(III) complexes, we have employed strongly chelating porphyrinato ligands to stabilize a gold(III) ion [Chem. Commun. 2003, 1718; Coord. Chem. Rev. 2009, 253, 1682]. In this work, a family of gold(III) tetraarylporphyrins with porphyrinato ligands containing different peripheral substituents on the meso-aryl rings were prepared, and these complexes were used to study the structure-bioactivity relationship. The cytotoxic IC(50) values of [Au(Por)](+) (Por=porphyrinato ligand), which range from 0.033 to >100 microM, correlate with their lipophilicity and cellular uptake. Some of them induce apoptosis and display preferential cytotoxicity toward cancer cells than to normal noncancerous cells. A new gold(III)-porphyrin with saccharide conjugation [Au(4-glucosyl-TPP)]Cl (2a; H(2)(4-glucosyl-TPP)=meso-tetrakis(4-beta-D-glucosylphenyl)porphyrin) exhibits significant cytostatic activity to cancer cells (IC(50)=1.2-9.0 microM) without causing cell death and is much less toxic to lung fibroblast cells (IC(50)>100 microM). The gold(III)-porphyrin complexes induce S-phase cell-cycle arrest of cancer cells as indicated by flow cytometric analysis, suggesting that the anticancer activity may be, in part, due to termination of DNA replication. The gold(III)-porphyrin complexes can bind to DNA in vitro with binding constants in the range of 4.9 x 10(5) to 4.1 x 10(6) dm(3) mol(-1) as determined by absorption titration. Complexes 2a and [Au(TMPyP)]Cl(5) (4a; [H(2)TMPyP](4+)=meso-tetrakis(N-methylpyridinium-4-yl)porphyrin) interact with DNA in a manner similar to the DNA intercalator ethidium bromide as revealed by gel mobility shift assays and viscosity measurements. Both of them also inhibited the topoisomerase I induced relaxation of supercoiled DNA. Complex 4a, a gold(III) derivative of the known G-quadruplex-interactive porphyrin [H(2)TMPyP](4+), can similarly inhibit the amplification of a DNA substrate containing G-quadruplex structures in a polymerase chain reaction stop assay. In contrast to these reported complexes, complex 2a and the parental gold(III)-porphyrin 1a do not display a significant inhibitory effect (<10%) on telomerase. Based on the results of protein expression analysis and computational docking experiments, the anti-apoptotic bcl-2 protein is a potential target for those gold(III)-porphyrin complexes with apoptosis-inducing properties. Complex 2a also displays prominent anti-angiogenic properties in vitro. Taken together, the enhanced stabilization of the gold(III) ion and the ease of structural modification render porphyrins an attractive ligand system in the development of physiologically stable gold(III) complexes with anticancer and anti-angiogenic activities.
authors.affiliation: Department of Chemistry and Open Laboratory of Chemical Biology of the Institute of Molecular Technology for Drug Discovery and Synthesis, The University of Hong Kong, Pokfulam Road, Hong Kong, China.
authors.forename: Raymond Wai-Yin
authors.initials: RW
authors.lastname: Sun
authors.forename: Carrie Ka-Lei
authors.initials: CK
authors.lastname: Li
authors.forename: Dik-Lung
authors.initials: DL
authors.lastname: Ma
authors.forename: Jessie Jing
authors.initials: JJ
authors.lastname: Yan
authors.forename: Chun-Nam
authors.initials: CN
authors.lastname: Lok
authors.forename: Chung-Hang
authors.initials: CH
authors.lastname: Leung
authors.forename: Nianyong
authors.initials: N
authors.lastname: Zhu
authors.forename: Chi-Ming
authors.initials: CM
authors.lastname: Che
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology*; D001665:Binding Sites; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D018360:Crystallography, X-Ray; D004247:DNA / Q000737:chemistry* / Q000378:metabolism; D054856:G-Quadruplexes / Q000187:drug effects; D006046:Gold / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D008024:Ligands; D051379:Mice; D050607:Organogold Compounds / Q000737:chemistry* / Q000494:pharmacology*; D011166:Porphyrins / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D008024:Ligands; D050607:Organogold Compounds; D011166:Porphyrins; C021096:tetra(4-N-methylpyridyl)porphine; D006046:Gold; D004247:DNA