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Article: Stable anticancer gold(III)-porphyrin complexes: Effects of porphyrin structure

TitleStable anticancer gold(III)-porphyrin complexes: Effects of porphyrin structure
Authors
KeywordsAntitumor agents
Bioinorganic chemistry
DNA
G quadruplexes
Porphyrinoids
Issue Date2010
PublisherWiley - V C H Verlag GmbH & Co KGaA. The Journal's web site is located at http://www.wiley-vch.de/home/chemistry
Citation
Chemistry - A European Journal, 2010, v. 16 n. 10, p. 3097-3113 How to Cite?
AbstractIn 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. © 2010 Wiley-VCH Verlag GmbH & Co. KGaA.
Persistent Identifierhttp://hdl.handle.net/10722/69039
ISSN
2015 Impact Factor: 5.771
2015 SCImago Journal Rankings: 2.323
ISI Accession Number ID
Funding AgencyGrant Number
University of Hong Kong
University Grants Council (HKSAR, China)AoE/P-10/01
Funding Information:

We acknowledge support from The University of Hong Kong (University Development Fund) and the Area of Excellence Scheme (AoE/P-10/01) administered by the University Grants Council (HKSAR, China). We thank Dr. Fuyi Zhang for the preparation of glycosylated porphyrins.

References
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DC FieldValueLanguage
dc.contributor.authorSun, RWYen_HK
dc.contributor.authorLi, CKLen_HK
dc.contributor.authorMa, DLen_HK
dc.contributor.authorYan, JJen_HK
dc.contributor.authorLok, CNen_HK
dc.contributor.authorLeung, CHen_HK
dc.contributor.authorZhu, Nen_HK
dc.contributor.authorChe, CMen_HK
dc.date.accessioned2010-09-06T06:09:59Z-
dc.date.available2010-09-06T06:09:59Z-
dc.date.issued2010en_HK
dc.identifier.citationChemistry - A European Journal, 2010, v. 16 n. 10, p. 3097-3113en_HK
dc.identifier.issn0947-6539en_HK
dc.identifier.urihttp://hdl.handle.net/10722/69039-
dc.description.abstractIn 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. © 2010 Wiley-VCH Verlag GmbH & Co. KGaA.en_HK
dc.languageengen_HK
dc.publisherWiley - V C H Verlag GmbH & Co KGaA. The Journal's web site is located at http://www.wiley-vch.de/home/chemistryen_HK
dc.relation.ispartofChemistry - A European Journalen_HK
dc.subjectAntitumor agentsen_HK
dc.subjectBioinorganic chemistryen_HK
dc.subjectDNAen_HK
dc.subjectG quadruplexesen_HK
dc.subjectPorphyrinoidsen_HK
dc.subject.meshAntineoplastic Agents - chemistry - pharmacology-
dc.subject.meshDNA - chemistry - metabolism-
dc.subject.meshGold - chemistry - pharmacology-
dc.subject.meshOrganogold Compounds - chemistry - pharmacology-
dc.subject.meshPorphyrins - chemistry - metabolism - pharmacology-
dc.titleStable anticancer gold(III)-porphyrin complexes: Effects of porphyrin structureen_HK
dc.typeArticleen_HK
dc.identifier.openurlhttp://library.hku.hk:4550/resserv?sid=HKU:IR&issn=0947-6539&volume=16&issue=10&spage=3097&epage=3113&date=2010&atitle=Stable+anticancer+gold(III)-porphyrin+complexes:+effects+of+porphyrin+structureen_HK
dc.identifier.emailSun, RWY: rwysun@hku.hken_HK
dc.identifier.emailMa, DL: edmondma@hku.hken_HK
dc.identifier.emailLok, CN: cnlok@hku.hken_HK
dc.identifier.emailLeung, CH: duncanl@hkucc.hku.hken_HK
dc.identifier.emailZhu, N: nzhu@hkucc.hku.hken_HK
dc.identifier.emailChe, CM: cmche@hku.hken_HK
dc.identifier.authoritySun, RWY=rp00781en_HK
dc.identifier.authorityMa, DL=rp00760en_HK
dc.identifier.authorityLok, CN=rp00752en_HK
dc.identifier.authorityLeung, CH=rp00730en_HK
dc.identifier.authorityZhu, N=rp00845en_HK
dc.identifier.authorityChe, CM=rp00670en_HK
dc.description.naturelink_to_subscribed_fulltext-
dc.identifier.doi10.1002/chem.200902741en_HK
dc.identifier.pmid20162647-
dc.identifier.scopuseid_2-s2.0-77649206626en_HK
dc.identifier.hkuros169869en_HK
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-77649206626&selection=ref&src=s&origin=recordpageen_HK
dc.identifier.volume16en_HK
dc.identifier.issue10en_HK
dc.identifier.spage3097en_HK
dc.identifier.epage3113en_HK
dc.identifier.eissn1521-3765-
dc.identifier.isiWOS:000275943400017-
dc.publisher.placeGermanyen_HK
dc.relation.projectInstitute of molecular technology for drug discovery and synthesis-
dc.identifier.scopusauthoridSun, RWY=26325835800en_HK
dc.identifier.scopusauthoridLi, CKL=14037827700en_HK
dc.identifier.scopusauthoridMa, DL=7402075538en_HK
dc.identifier.scopusauthoridYan, JJ=35752634300en_HK
dc.identifier.scopusauthoridLok, CN=7006410829en_HK
dc.identifier.scopusauthoridLeung, CH=7402612570en_HK
dc.identifier.scopusauthoridZhu, N=7201449530en_HK
dc.identifier.scopusauthoridChe, CM=7102442791en_HK

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