TY - JOUR
T1 - Functionalization of ruthenium(II)(ų6-p-cymene)(3-hydroxy-2-pyridone) complexes with (thio)morpholine
T2 - Synthesis and bioanalytical studies
AU - Hanif, Muhammad
AU - Meier, Samuel M.
AU - Adhireksan, Zenita
AU - Henke, Helena
AU - Martic, Sanela
AU - Movassaghi, Sanam
AU - Labib, Mahmoud
AU - Kandioller, Wolfgang
AU - Jamieson, Stephen M.F.
AU - Hejl, Michaela
AU - Jakupec, Michael A.
AU - Kraatz, Heinz Bernhard
AU - Davey, Curt A.
AU - Keppler, Bernhard K.
AU - Hartinger, Christian G.
N1 - Funding Information:
We thank the Genesis Oncology Trust (GOT-1263-RPG), the Austrian Science Fund (Schrödinger Fellowship for M.H. J3288-N28), and COST CM1105 for financial support. We gratefully acknowledge Prof. Markus Galanski for recording the 2D NMR spectra. C.A.D. and Z.A. thank M. Wang, V. Olieric, and staff at the Swiss Light Source (Paul Scherrer Institute, Villigen, Switzerland), and are grateful for financial support from the Singapore Ministry of Education Academic Research Fund Tier 2 Program (grant 19/08), the Ministry of Health National Medical Research Council (grant NMRC/1312/2011), and the Ministry of Education Academic Research Fund Tier 3 Program (grant MOE2012-T3-1-001).
Publisher Copyright:
© 2017 Wiley-VCH Verlag GmbH&Co. KGaA, Weinheim.
PY - 2017/6/1
Y1 - 2017/6/1
N2 - Hydroxypyr(id)ones constitute an emerging platform for the design of drug molecules, owing to their favorable biocompatibility and toxicity profiles. Herein, [RuII(ų6-p-cymene)] complexes with 3-hydroxy-2-pyridinone functionalized with morpholine and thiomorpholine, as a means often used in medicinal chemistry to alter the physicochemical properties of drug compounds, are reported. The compounds underwent hydrolysis of the Ru@Cl bond and the aqua species were stable for up to 48 h in aqueous solution, as observed by 1H NMR spectroscopy and ESI-MS. The compounds formed adducts with amino acids and proteins through cleavage of the pyridinone ligand. Binding experiments to the nucleosome core particle by means of X-ray crystallography revealed similar reactivity and exclusive binding to histidine moieties of the histone proteins. Preliminary cyclin-dependent kinase 2 (CDK2)/cyclinA kinase inhibitory studies revealed promising activity similar to that of structurally related organometallic compounds.
AB - Hydroxypyr(id)ones constitute an emerging platform for the design of drug molecules, owing to their favorable biocompatibility and toxicity profiles. Herein, [RuII(ų6-p-cymene)] complexes with 3-hydroxy-2-pyridinone functionalized with morpholine and thiomorpholine, as a means often used in medicinal chemistry to alter the physicochemical properties of drug compounds, are reported. The compounds underwent hydrolysis of the Ru@Cl bond and the aqua species were stable for up to 48 h in aqueous solution, as observed by 1H NMR spectroscopy and ESI-MS. The compounds formed adducts with amino acids and proteins through cleavage of the pyridinone ligand. Binding experiments to the nucleosome core particle by means of X-ray crystallography revealed similar reactivity and exclusive binding to histidine moieties of the histone proteins. Preliminary cyclin-dependent kinase 2 (CDK2)/cyclinA kinase inhibitory studies revealed promising activity similar to that of structurally related organometallic compounds.
KW - Antitumor agents
KW - Bioorganometallic chemistry
KW - Medicinal chemistry
KW - Ruthenium
KW - Synthesis design
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U2 - 10.1002/cplu.201700050
DO - 10.1002/cplu.201700050
M3 - Article
C2 - 31961568
AN - SCOPUS:85017343914
SN - 2192-6506
VL - 82
SP - 841
EP - 847
JO - ChemPlusChem
JF - ChemPlusChem
IS - 6
ER -