TY - JOUR
T1 - Stable anticancer gold(III)-porphyrin complexes
T2 - Effects of porphyrin structure
AU - Sun, Raymond Wai Yin
AU - Li, Carrie Ka Lei
AU - Ma, Edmond Dik Lung
AU - Yan, Jessie Jing
AU - Lok, Chun Nam
AU - Leung, Chung Hang
AU - Zhu, Nianyong
AU - Che, Chi Ming
N1 - Copyright:
Copyright 2010 Elsevier B.V., All rights reserved.
PY - 2010/3/8
Y1 - 2010/3/8
N2 - 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 IC50 values of [Au(Por)]+ (Por = porphyrinato ligand), which range from 0.033 to > 100 μM, 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-glucosylTPP)]Cl (2a; H2(4-glucosyl-TPP) = weso-tetrakis(4-β-D-glucosylphenyl) porphyrin) exhibits significant cytostatic activity to cancer cells (IC 50= 1.29.0 μM) without causing cell death and is much less toxic to lung fibroblast cells (IC50 > 100 μM). The gold(III)-porphyrin complexes induce S-phase cellcycle 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 105 to 4.1 x 106 dm3mol-1as determined by absorption titration. Complexes 2a and [Au(TMPyP)]Cl5 (4a; [H2TMPyP]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 [H2TMPyP]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 2 a and the parental gold(III)-porphyrin la 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.
AB - 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 IC50 values of [Au(Por)]+ (Por = porphyrinato ligand), which range from 0.033 to > 100 μM, 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-glucosylTPP)]Cl (2a; H2(4-glucosyl-TPP) = weso-tetrakis(4-β-D-glucosylphenyl) porphyrin) exhibits significant cytostatic activity to cancer cells (IC 50= 1.29.0 μM) without causing cell death and is much less toxic to lung fibroblast cells (IC50 > 100 μM). The gold(III)-porphyrin complexes induce S-phase cellcycle 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 105 to 4.1 x 106 dm3mol-1as determined by absorption titration. Complexes 2a and [Au(TMPyP)]Cl5 (4a; [H2TMPyP]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 [H2TMPyP]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 2 a and the parental gold(III)-porphyrin la 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.
KW - Antitumor agents
KW - Bioinorganic chemistry
KW - DNA
KW - G quadruplexes
KW - Porphyrinoids
UR - http://www.scopus.com/inward/record.url?scp=77649206626&partnerID=8YFLogxK
U2 - 10.1002/chem.200902741
DO - 10.1002/chem.200902741
M3 - Journal article
C2 - 20162647
AN - SCOPUS:77649206626
SN - 0947-6539
VL - 16
SP - 3097
EP - 3113
JO - Chemistry - A European Journal
JF - Chemistry - A European Journal
IS - 10
ER -