Double-Strand DNA Breaks Induced by Paracyclophane Gold(I) Complexes.
Gold(I) complexes of ClickPhos [2.2]paracyclophane ligands were synthesized in excellent yields and fully characterized by spectroscopic methods as well as X-ray crystallography. The complexes exhibit a rigid ligand backbone and a triazolyl moiety and were systematically studied with respect to their cytotoxic properties. In combination with the ionic complex [(GemPhos)Au(tht)][ClO4] (tht=tetrahydrothiophene), in which the gold(I) atom exhibits a distorted trigonal coordination sphere of two phosphines and a labile tht ligand, their efficiency in cytotoxicity was investigated in HeLa, MCF7, and HCT116 cells as well as in a zebrafish model. Their cytotoxicity and their mechanisms of action are different and involve apoptosis, necrosis, and DNA damage. The compounds presented herein are potent metal-based cytostatics displaying LD50values from 3.5-38 μm in different tumor cell lines and induce double-strand DNA breaks (DSB) as shown by H2AX phosphorylation (γH2AX) at foci of DSBs.
Institute of Inorganic Chemistry, Karlsruhe Institute of Technology (KIT), Engesserstraße 15, 76131, Karlsruhe, Germany.
Sebastian
S
Bestgen
Institute of Toxicology and Genetics, Karlsruhe Institute of Technology (KIT), Hermann-von-Helmholtz-Platz 1, 76344, Eggenstein-Leopoldshafen, Germany.|Institute of Organic Chemistry, Karlsruhe Institute of Technology (KIT), Fritz-Haber-Weg 6, 76131, Karlsruhe, Germany.
Carmen
C
Seidl
Institute of Toxicology and Genetics, Karlsruhe Institute of Technology (KIT), Hermann-von-Helmholtz-Platz 1, 76344, Eggenstein-Leopoldshafen, Germany.
Thomas
T
Wiesner
Institute of Toxicology and Genetics, Karlsruhe Institute of Technology (KIT), Hermann-von-Helmholtz-Platz 1, 76344, Eggenstein-Leopoldshafen, Germany.
Andreas
A
Zimmer
Institute of Toxicology and Genetics, Karlsruhe Institute of Technology (KIT), Hermann-von-Helmholtz-Platz 1, 76344, Eggenstein-Leopoldshafen, Germany.
Martina
M
Falk
Institute of Applied Biosciences, Karlsruhe Institute of Technology (KIT), Adenauerring 20, 76131, Karlsruhe, Germany.
Beate
B
Köberle
Institute of Organic Chemistry, Karlsruhe Institute of Technology (KIT), Fritz-Haber-Weg 6, 76131, Karlsruhe, Germany.
Martina
M
Austeri
Institute of Organic Chemistry, Paderborn University, Warburger Str. 100, 33098, Paderborn, Germany.
Jan
J
Paradies
Institute of Toxicology and Genetics, Karlsruhe Institute of Technology (KIT), Hermann-von-Helmholtz-Platz 1, 76344, Eggenstein-Leopoldshafen, Germany.|Institute of Organic Chemistry, Karlsruhe Institute of Technology (KIT), Fritz-Haber-Weg 6, 76131, Karlsruhe, Germany.
Stefan
S
Bräse
Institute of Toxicology and Genetics, Karlsruhe Institute of Technology (KIT), Hermann-von-Helmholtz-Platz 1, 76344, Eggenstein-Leopoldshafen, Germany.|Institute of Organic Chemistry, Karlsruhe Institute of Technology (KIT), Fritz-Haber-Weg 6, 76131, Karlsruhe, Germany.
Ute
U
Schepers
Institute of Inorganic Chemistry, Karlsruhe Institute of Technology (KIT), Engesserstraße 15, 76131, Karlsruhe, Germany.
Peter W
http://orcid.org/0000-0002-0915-3893
PW
Roesky
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D056831:Coordination Complexes / Q000138:chemical synthesis / Q000737:chemistry* / Q000633:toxicity; D018360:Crystallography, X-Ray; D053903:DNA Breaks, Double-Stranded / Q000187:drug effects; D004988:Ethers, Cyclic / Q000737:chemistry; D006046:Gold / Q000737:chemistry*; D045325:HCT116 Cells; D006367:HeLa Cells; D006657:Histones / Q000378:metabolism; D006801:Humans; D007814:Larva / Q000187:drug effects / Q000502:physiology; D008024:Ligands; D061986:MCF-7 Cells; D008968:Molecular Conformation; D010720:Phosphines / Q000737:chemistry; D010766:Phosphorylation / Q000187:drug effects; D015027:Zebrafish / Q000254:growth & development
D056831:Coordination Complexes; D004988:Ethers, Cyclic; D006657:Histones; D008024:Ligands; D010720:Phosphines; D006046:Gold
antitumor agents; cytotoxicity; gold; paracyclophanes; phosphines