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Article: Anticancer cyclometalated [AuIIIm(C∧N∧C)mL]n+ compounds: Synthesis and cytotoxic properties

TitleAnticancer cyclometalated [AuIIIm(C∧N∧C)mL]n+ compounds: Synthesis and cytotoxic properties
Authors
KeywordsAatitumor agents
Bioinorganic chemistry
DNA
Gold
Ligand effects
Issue Date2006
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, 2006, v. 12 n. 20, p. 5253-5266 How to Cite?
AbstractA series of cyclometalated gold(III) compounds [Aum-(C ∧N∧C)mL]n+ (m = 1-3; n=0-3: HC∧N∧CH=2,6-diphenylpyridine) was prepared by ligand substitution reaction of L with N-donor or phosphine ligands. The [Aum(C∧N∧C)mL]n+ compounds are stable in solution in the presence of glutathione. Crystal structures of the gold(in) compounds containing bridging bi- and tridentate phosphino ligands reveal the presence of weak intramolecular JI-JT stacking between the [Au(C∧N∧C)]+ units. Results of MTT assays demonstrated that the [Aum(C∧N ∧C)mL]n+ compounds containing nontoxic N-donor auxiliary ligands (2) exert anticancer potency comparable to that of cisplatin, with IC50 values ranging from 1.5 to 84 μM. The use of [Au(C∧N∧C)(1-methylimidazole)]+ (2a) as a model compound revealed that the gold(III)-induced cytotoxicity occurs through an apoptotic cell-death pathway. The cell-free interaction of 2 a with double-stranded DNA was also examined. Absorption titration showed that 2 a binds to calfthymus DNA (ctDNA) with a binding constant of 4.5 × 10 5 dm3 mol-1 at 298 K. Evidence from gel-mobility-shift assays and viscosity measurements supports an intercalating binding mode for the 2a-DNA interaction. Cell-cycle analysis revealed that 2 a causes S-phase cell arrest after incubation for 24 and 48 hours. The cytotoxicity of 3b-g toward cancer cells (IC50-0.04-4.3 μM) correlates to that of the metal-free phosphine ligands (IC50=0.1-38.0 μM), with [Au2(C∧N∧C) 2(μ-dppp)]2+ (3d) and dppp (dppp = 1,2- bis(diphenylphosphino)propane) being the most cytotoxic gold(III) and metal-free compounds, respectively. Compound 3d shows a cytotoxicity at least ten-fold higher than the other gold(III) analogues; in vitro cellular-uptake experiments reveal similar absorptions for all the gold(III) compounds into nasopharyngeal carcinoma cells (SUNE1) (1.18-3.81 ng/cell; c.f., 3d = 2.04ng/cell), suggesting the presence of non-gold-mediated cytotoxicity. Unlike 2 a, both gold(III) compounds [Au(C∧N∧C)(PPh3)]- (3a) (PPh3 = triphenylphosphine) and [Au2(C ∧N∧C)2(μ-dpPP)]2+ (3d) interact only weakly with ctDNA and do not arrest the cell cycle. © 2006 Wiley-VCH Verlag GmbH & Co. KGaA.
Persistent Identifierhttp://hdl.handle.net/10722/70411
ISSN
2015 Impact Factor: 5.771
2015 SCImago Journal Rankings: 2.323
ISI Accession Number ID
References

 

DC FieldValueLanguage
dc.contributor.authorLi, CKLen_HK
dc.contributor.authorSun, RWYen_HK
dc.contributor.authorKui, SCFen_HK
dc.contributor.authorZhu, Nen_HK
dc.contributor.authorChe, CMen_HK
dc.date.accessioned2010-09-06T06:22:37Z-
dc.date.available2010-09-06T06:22:37Z-
dc.date.issued2006en_HK
dc.identifier.citationChemistry - A European Journal, 2006, v. 12 n. 20, p. 5253-5266en_HK
dc.identifier.issn0947-6539en_HK
dc.identifier.urihttp://hdl.handle.net/10722/70411-
dc.description.abstractA series of cyclometalated gold(III) compounds [Aum-(C ∧N∧C)mL]n+ (m = 1-3; n=0-3: HC∧N∧CH=2,6-diphenylpyridine) was prepared by ligand substitution reaction of L with N-donor or phosphine ligands. The [Aum(C∧N∧C)mL]n+ compounds are stable in solution in the presence of glutathione. Crystal structures of the gold(in) compounds containing bridging bi- and tridentate phosphino ligands reveal the presence of weak intramolecular JI-JT stacking between the [Au(C∧N∧C)]+ units. Results of MTT assays demonstrated that the [Aum(C∧N ∧C)mL]n+ compounds containing nontoxic N-donor auxiliary ligands (2) exert anticancer potency comparable to that of cisplatin, with IC50 values ranging from 1.5 to 84 μM. The use of [Au(C∧N∧C)(1-methylimidazole)]+ (2a) as a model compound revealed that the gold(III)-induced cytotoxicity occurs through an apoptotic cell-death pathway. The cell-free interaction of 2 a with double-stranded DNA was also examined. Absorption titration showed that 2 a binds to calfthymus DNA (ctDNA) with a binding constant of 4.5 × 10 5 dm3 mol-1 at 298 K. Evidence from gel-mobility-shift assays and viscosity measurements supports an intercalating binding mode for the 2a-DNA interaction. Cell-cycle analysis revealed that 2 a causes S-phase cell arrest after incubation for 24 and 48 hours. The cytotoxicity of 3b-g toward cancer cells (IC50-0.04-4.3 μM) correlates to that of the metal-free phosphine ligands (IC50=0.1-38.0 μM), with [Au2(C∧N∧C) 2(μ-dppp)]2+ (3d) and dppp (dppp = 1,2- bis(diphenylphosphino)propane) being the most cytotoxic gold(III) and metal-free compounds, respectively. Compound 3d shows a cytotoxicity at least ten-fold higher than the other gold(III) analogues; in vitro cellular-uptake experiments reveal similar absorptions for all the gold(III) compounds into nasopharyngeal carcinoma cells (SUNE1) (1.18-3.81 ng/cell; c.f., 3d = 2.04ng/cell), suggesting the presence of non-gold-mediated cytotoxicity. Unlike 2 a, both gold(III) compounds [Au(C∧N∧C)(PPh3)]- (3a) (PPh3 = triphenylphosphine) and [Au2(C ∧N∧C)2(μ-dpPP)]2+ (3d) interact only weakly with ctDNA and do not arrest the cell cycle. © 2006 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.subjectAatitumor agentsen_HK
dc.subjectBioinorganic chemistryen_HK
dc.subjectDNAen_HK
dc.subjectGolden_HK
dc.subjectLigand effectsen_HK
dc.subject.meshAntineoplastic Agents - chemical synthesis - pharmacology-
dc.subject.meshDNA, Neoplasm - drug effects - metabolism-
dc.subject.meshIntercalating Agents - chemical synthesis - pharmacology-
dc.subject.meshLigands-
dc.subject.meshOrganogold Compounds - chemical synthesis - pharmacology-
dc.titleAnticancer cyclometalated [AuIIIm(C∧N∧C)mL]n+ compounds: Synthesis and cytotoxic propertiesen_HK
dc.typeArticleen_HK
dc.identifier.openurlhttp://library.hku.hk:4550/resserv?sid=HKU:IR&issn=0947-6539&volume=12&issue=20&spage=5253&epage=5266&date=2006&atitle=Anticancer+cyclometalated+[AuIIIm(C+∧N∧C)mL]n++compounds:+Synthesis+and+cytotoxic+propertiesen_HK
dc.identifier.emailSun, RWY: rwysun@hku.hken_HK
dc.identifier.emailKui, SCF: stevenku@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.authorityKui, SCF=rp00715en_HK
dc.identifier.authorityZhu, N=rp00845en_HK
dc.identifier.authorityChe, CM=rp00670en_HK
dc.description.naturelink_to_subscribed_fulltext-
dc.identifier.doi10.1002/chem.200600117en_HK
dc.identifier.pmid16642532-
dc.identifier.scopuseid_2-s2.0-33745930511en_HK
dc.identifier.hkuros126782en_HK
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-33745930511&selection=ref&src=s&origin=recordpageen_HK
dc.identifier.volume12en_HK
dc.identifier.issue20en_HK
dc.identifier.spage5253en_HK
dc.identifier.epage5266en_HK
dc.identifier.isiWOS:000239105500011-
dc.publisher.placeGermanyen_HK
dc.identifier.scopusauthoridLi, CKL=14037827700en_HK
dc.identifier.scopusauthoridSun, RWY=26325835800en_HK
dc.identifier.scopusauthoridKui, SCF=6506763660en_HK
dc.identifier.scopusauthoridZhu, N=7201449530en_HK
dc.identifier.scopusauthoridChe, CM=7102442791en_HK

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