The substitutionally-inert ruthenium(II) polypyridyl complex (RPC) [Ru(dip)3]2+ (4) exhibits potent cytotoxic effects and functions via arrest of normal microtubule (MT) dynamics. MTs are polymers of the tubulin heterodimer and are designed to rapidly form and disassemble as a function of numerous cellular signals. RPC 4 stabilizes MTs in a manner that can result in cellular misfunction and cell death. Efforts to determine the stoichiometry of the RPC binding with tubulin in vitro were hampered by the poor solubility of RPC 4, which resulted in both specific and non-specific binding to tubulin. In an effort to reduce non-specific binding we systematically reduced the lipophilicity of the RPC by changing dip ligands to phen ligands making [Ru(dip)2phen]2+ (3), [Ru(phen)2dip]2+ (2) and [Ru(phen)3]2+ (1). Cytotoxicity studies with cultured mammalian cell lines revealed 3 to be similar to 4 in cytotoxicity and a decrease in cytotoxicity on going to 2 and then 1. The octanol/water partition coefficient (logP) was determined for these RPCs and as expected logP decreases 4&gt;3&gt;2&gt;1. Because of the enhanced solubility of 3 over 4 in aqueous solutions and retention of good cytotoxicity, 3 may be the ideal complex for scientific study and ultimately, potential medicinal applications and is being used for stoichiometry studies.

Lipophilic Ru(II) polypyridyl complexes that target microtubules as promising new anti-cancer agents

ACS Spring Meeting 2021

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