Conjugating Biotin to Ruthenium(II) Arene Units via Phosphine Ligand Functionalization

Two-step functionalization of 4-diphenylphosphino benzoic acid with biotin afforded 2-(biotinyloxy)ethyl 4-(diphenylphosphanyl)benzoate (LP), that was subsequently used to synthesize the Ru(II) arene complexes [RuCl2(η6-p-cymene)(LP)] (1), [Ru(C2O4)(η6-p-cymene)(LP)] (2) and [Ru(curc)(η6-p-cymene)(LP)]NO3 ([3]NO3), the latter incorporating curcumin (curcH) as an additional bioactive fragment. [Ru(curc)(η6-p-cymene)(PPh3)]NO3 ([4]NO3) was also prepared as a reference compound. Compounds 2 and [3]NO3 exhibited excellent stability in water/DMSO solution while being slowly activated in the cell culture medium over 72 hours. Together with LP, they were therefore assessed for their antiproliferative activity towards a panel of cancer cell lines, with different levels of biotin transporter expression. The apparent affinity of the compounds towards avidin varies, and their antiproliferative activity does not correlate with biotin transporter expression, although it is systematically enhanced when biotin-free cell culture medium is used.