title: Gold(I) N-heterocyclic carbene complexes with naphthalimide ligands as combined thioredoxin reductase inhibitors and DNA intercalators.
abstract: Organometallic conjugates consisting of a gold(I) N-heterocyclic carbene (NHC) moiety and a naphthalimide were prepared and investigated as cytotoxic agents that interact with both DNA and the disulfide reductase enzyme thioredoxin reductase (TrxR). The complexes were potent DNA intercalators related to their naphthalimide partial structure, inhibited TrxR as a consequence of the incorporation of the gold(I) moiety, and triggered efficient cytotoxic effects in MCF-7 breast and HT-29 colon adenocarcinoma cells. Strong effects on tumor cell metabolism were noted for the most cytotoxic complex, chlorido[1-(3'-(4''-ethylthio-1'',8''-naphthalimid-N''-yl))-propyl-3-methyl-imidazol-2-ylidene]gold(I) (4 d). In conclusion, the conjugation of naphthalimides with gold(I) NHC moieties provided a useful strategy for the design of bioorganometallic anticancer agents with multiple modes of action.
authors.affiliation: Institute of Medicinal and Pharmaceutical Chemistry, Technische Universität Braunschweig, Beethovenstr. 55, 38106 Braunschweig (Germany).
authors.forename: Andreas
authors.initials: A
authors.lastname: Meyer
authors.forename: Luciano
authors.initials: L
authors.lastname: Oehninger
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Geldmacher
authors.forename: Hamed
authors.initials: H
authors.lastname: Alborzinia
authors.forename: Stefan
authors.initials: S
authors.lastname: Wölfl
authors.forename: William S
authors.initials: WS
authors.lastname: Sheldrick
authors.forename: Ingo
authors.initials: I
authors.lastname: Ott
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D049109:Cell Proliferation / Q000187:drug effects; D056831:Coordination Complexes / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D004247:DNA / Q000737:chemistry* / Q000378:metabolism; D004354:Drug Screening Assays, Antitumor; D006046:Gold / Q000737:chemistry*; D019073:HT29 Cells; D006571:Heterocyclic Compounds / Q000737:chemistry; D006801:Humans; D007364:Intercalating Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D008024:Ligands; D061986:MCF-7 Cells; D008697:Methane / Q000031:analogs & derivatives / Q000737:chemistry; D053644:Naphthalimides / Q000737:chemistry*; D013880:Thioredoxin-Disulfide Reductase / Q000037:antagonists & inhibitors*
chemical_list: D000970:Antineoplastic Agents; D056831:Coordination Complexes; D006571:Heterocyclic Compounds; D007364:Intercalating Agents; D008024:Ligands; D053644:Naphthalimides; C030011:carbene; D006046:Gold; D004247:DNA; D013880:Thioredoxin-Disulfide Reductase; D008697:Methane
keywords: DNA; N-heterocyclic carbenes; gold; naphthalimides; thioredoxin reductase