Defining the Anti-Cancer Activity of Tricarbonyl Rhenium Complexes: Induction of G2/M Cell Cycle Arrest and Blockade of Aurora-A Kinase Phosphorylation.
Rhenium and ruthenium complexes containing N-heterocylic carbene (NHC) ligands and conjugated to indomethacin were prepared. The anticancer properties were probed against pancreatic cell lines, revealing a remarkable activity of the rhenium fragment as anticancer agent. The ruthenium complexes were found to be inactive against the same pancreatic cancer cell lines, either alone or in conjugation with indomethacin. An in-depth biological study revealed the origin of the anticancer properties of the rhenium tricarbonyl fragment, of which a complete elucidation had yet to be achieved. It was found that the rhenium complexes induce cell cycle arrest at the G2/M phase by inhibiting the phosphorylation of Aurora-A kinase. A preliminary study on the structure-activity relationship on a large family of these complexes revealed that the anticancer properties are mainly associated with the lability of the ancillary ligand, with inert complexes showing limited to no anticancer properties.
Curtin Institute of Functional Molecules and Interfaces, Department of Chemistry, Curtin University, Kent Street, Bentley, 6102 WA, Australia.
Peter V
http://orcid.org/0000-0002-5701-3203
PV
Simpson
Metabolic Signalling Group, School of Biomedical Sciences, Curtin Health Innovation Research Institute, Curtin University, Perth, Western Australia, 6102, Australia.
Ilaria
I
Casari
Metabolic Signalling Group, School of Biomedical Sciences, Curtin Health Innovation Research Institute, Curtin University, Perth, Western Australia, 6102, Australia.
Silvano
S
Paternoster
School of Chemistry and Biochemistry, University of Western Australia, Crawley, 6009 WA, Australia.
Brian W
BW
Skelton
Metabolic Signalling Group, School of Biomedical Sciences, Curtin Health Innovation Research Institute, Curtin University, Perth, Western Australia, 6102, Australia.
Marco
http://orcid.org/0000-0002-9801-7235
M
Falasca
Curtin Institute of Functional Molecules and Interfaces, Department of Chemistry, Curtin University, Kent Street, Bentley, 6102 WA, Australia.
Massimiliano
http://orcid.org/0000-0001-6949-4019
M
Massi
D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000633:toxicity; D064096:Aurora Kinase A / Q000037:antagonists & inhibitors / Q000378:metabolism*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D056831:Coordination Complexes / Q000138:chemical synthesis / Q000737:chemistry* / Q000633:toxicity; D018360:Crystallography, X-Ray; D059565:G2 Phase Cell Cycle Checkpoints / Q000187:drug effects; D057809:HEK293 Cells; D006801:Humans; D008024:Ligands; D059566:M Phase Cell Cycle Checkpoints / Q000187:drug effects; D008697:Methane / Q000031:analogs & derivatives / Q000737:chemistry; D008968:Molecular Conformation; D010766:Phosphorylation / Q000187:drug effects; D012428:Ruthenium / Q000737:chemistry*; D013329:Structure-Activity Relationship
D000970:Antineoplastic Agents; D056831:Coordination Complexes; D008024:Ligands; C030011:carbene; D012428:Ruthenium; D064096:Aurora Kinase A; D008697:Methane
N-heterocyclic carbenes; antitumor agents; cancer; carbenes; rhenium