Is the reactivity of M(II)-arene complexes of 3-hydroxy-2(1H)-pyridones to biomolecules the anticancer activity determining parameter?
Hydroxypyr(id)ones are versatile ligands for the synthesis of organometallic anticancer agents, equipping them with fine-tunable pharmacological properties. Herein, we report on the preparation, mode of action, and in vitro anticancer activity of Ru(II)- and Os(II)-arene complexes with alkoxycarbonylmethyl-3-hydroxy-2-pyridone ligands. The hydrolysis and binding to amino acids proceed quickly, as characterized by NMR spectroscopy and ESI mass spectrometry. However, the reaction with amino acids causes cleavage of the pyridone ligands from the metal center because the amino acids act as multidentate ligands. A similar behavior was also observed during the reactions with the model proteins ubiquitin and cytochrome c, yielding mainly [protein + M(eta(6)-p-cymene)] adducts (M = Ru, Os). Notably the ligand cleavage of the Os derivative was significantly slower than of its Ru analogue, which could explain its higher activity in in vitro anticancer assays. Furthermore, the reaction of the compounds to 5'-GMP was characterized and coordination to the N7 of the guanine moiety was demonstrated by (1)H NMR spectroscopy and X-ray diffraction analysis. CDK2/Cyclin A protein kinase inhibition studies revealed potent activity of the Ru and Os complexes.
Hanif
Muhammad
M
University of Vienna, Institute of Inorganic Chemistry, Waehringer Str. 42, A-1090 Vienna, Austria.
Henke
Helena
H
Meier
Samuel M
SM
Martic
Sanela
S
Labib
Mahmoud
M
Kandioller
Wolfgang
W
Jakupec
Michael A
MA
Arion
Vladimir B
VB
Kraatz
Heinz-Bernhard
HB
Keppler
Bernhard K
BK
Hartinger
Christian G
CG
D000596:Amino Acids / Q000378:metabolism; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D045744:Cell Line, Tumor; D018360:Crystallography, X-Ray; D051357:Cyclin-Dependent Kinase 2 / Q000037:antagonists & inhibitors / Q000378:metabolism; D045304:Cytochromes c / Q000378:metabolism; D004247:DNA / Q000378:metabolism; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D008958:Models, Molecular; D009369:Neoplasms / Q000188:drug therapy; D017892:Osmium Compounds / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D011728:Pyridones / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D017975:Ruthenium Compounds / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D025801:Ubiquitin / Q000378:metabolism
D000596:Amino Acids; D000970:Antineoplastic Agents; D017892:Osmium Compounds; D011728:Pyridones; D017975:Ruthenium Compounds; D025801:Ubiquitin; C017679:2-hydroxypyridine; D045304:Cytochromes c; D004247:DNA; D051357:Cyclin-Dependent Kinase 2