Alteration of steric hindrance modulates glutathione resistance and cytotoxicity of three structurally related Ru(II)-p-cymene complexes.
The effect of steric hindrance on reactivity towards biomolecules while designing Ru(II)-η(6)-p-cymene based anticancer agents seems to be an important parameter in improving the activity and inducing resistance against glutathione (GSH) deactivation. Herein we present the structure, hydrolysis, anticancer activity and the effect of steric hindrance on deactivation by glutathione for three complexes, [Ru(II)(η(6)-p-cym)(L1)(Cl)](PF6) (1), [Ru(II)(η(6)-p-cym)(L2)(Cl)](PF6) (2) and [Ru(II)(η(6)-p-cym)(L3)(Cl)](PF6) (3). The ligands L1-L3 are Schiff bases which show increasing substitution in a benzene ring, such that two ortho hydrogens are replaced by -methyl in 2 and by -isopropyl in 3. The cytotoxicity results strongly suggest that controlling the rate of hydrolysis through tuning of steric hindrance may be a feasible pathway to derive GSH resistant anticancer agents. The cellular studies show that all the three complexes show good blood compatibility (haemolysis <3%) and induce cellular death through caspase activation via the mitochondrial pathway. They have anti-angiogenic activity and prevent the healing of treated cells.
Department of Chemical Sciences, Indian Institute of Science Education and Research Kolkata, Mohanpur Campus, 741246, India. a.mukherjee@iiserkol.ac.in.
Kallol
K
Purkait
Saptarshi
S
Chatterjee
Subhendu
S
Karmakar
Arindam
A
Mukherjee
D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000378:metabolism / Q000633:toxicity; D017209:Apoptosis / Q000187:drug effects; D053179:Caspase 7 / Q000378:metabolism; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D056831:Coordination Complexes / Q000737:chemistry* / Q000378:metabolism / Q000633:toxicity; D000081007:Cymenes; D053938:DNA Fragmentation / Q000187:drug effects; D004912:Erythrocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D005978:Glutathione / Q000737:chemistry*; D006207:Half-Life; D006461:Hemolysis / Q000187:drug effects; D006801:Humans; D006868:Hydrolysis; D061986:MCF-7 Cells; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D051379:Mice; D008968:Molecular Conformation; D039821:Monoterpenes / Q000737:chemistry; D012428:Ruthenium / Q000737:chemistry*; D012545:Schiff Bases / Q000737:chemistry
D000970:Antineoplastic Agents; D056831:Coordination Complexes; D000081007:Cymenes; D039821:Monoterpenes; D012545:Schiff Bases; C007210:4-cymene; D012428:Ruthenium; D053179:Caspase 7; D005978:Glutathione