Caffeine-based gold(I) N-heterocyclic carbenes as possible anticancer agents: synthesis and biological properties.
A new series of gold(I) N-heterocyclic carbene (NHC) complexes based on xanthine ligands have been synthesized and characterized by mass spectrometry, NMR, and X-ray diffraction. The compounds have been tested for their antiproliferative properties in human cancer cells and nontumorigenic cells in vitro, as well as for their toxicity in healthy tissues ex vivo. The bis-carbene complex [Au(caffein-2-ylidene)2][BF4] (complex 4) appeared to be selective for human ovarian cancer cell lines and poorly toxic in healthy organs. To gain preliminary insights into their actual mechanism of action, two biologically relevant in cellulo targets were studied, namely, DNA (more precisely a higher-order DNA structure termed G-quadruplex DNA that plays key roles in oncogenetic regulation) and a pivotal enzyme of the DNA damage response (DDR) machinery (poly-(adenosine diphosphate (ADP)-ribose) polymerase 1 (PARP-1), strongly involved in the cancer resistance mechanism). Our results indicate that complex 4 acts as an efficient and selective G-quadruplex ligand while being a modest PARP-1 inhibitor (i.e., poor DDR impairing agent) and thus provide preliminary insights into the molecular mechanism that underlies its antiproliferative behavior.
Dept. Pharmacokinetics, Toxicology and Targeting, Research Institute of Pharmacy, University of Groningen , Antonius Deusinglaan 1, 9713 AV Groningen, The Netherlands.
Benoît
B
Bertrand
Loic
L
Stefan
Marc
M
Pirrotta
David
D
Monchaud
Ewen
E
Bodio
Philippe
P
Richard
Pierre
P
Le Gendre
Elena
E
Warmerdam
Marina H
MH
de Jager
Geny M M
GM
Groothuis
Michel
M
Picquet
Angela
A
Casini
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D002110:Caffeine / Q000737:chemistry*; D002460:Cell Line; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D006046:Gold / Q000737:chemistry*; D006571:Heterocyclic Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D020128:Inhibitory Concentration 50; D008024:Ligands; D008697:Methane / Q000031:analogs & derivatives* / Q000737:chemistry; D015394:Molecular Structure; D019820:Xanthine / Q000737:chemistry
D000970:Antineoplastic Agents; D006571:Heterocyclic Compounds; D008024:Ligands; D019820:Xanthine; C030011:carbene; D002110:Caffeine; D006046:Gold; D008697:Methane