Attaching
peptides to metallodrugs may result in improved
biological properties of the complexes. The potential use of
cell penetrating peptides (CPPs) as cell delivery vectors is attractive, since directed cell uptake of (metallo)drugs remains a major challenge in anticancer
drug design. In this work, we report the synthesis of
peptide conjugates of the organometallic Os(II) anticancer complex [(η(6)-
biphenyl)Os(
picolinate)Cl] with different
arginine (Arg) chain lengths. Complexes conjugated to Arg(5) or Arg(8) at the 5-position of the
picoline ring increase Os uptake into A2780 human
ovarian cancer cells by ca. 2× and 10×, respectively, whereas a single Arg had no effect. Furthermore, a 15-fold increase in binding of Os to
DNA, a potential target for these complexes, was observed for Arg(8) compared to the Arg(1) conjugate. The Arg(5) and Arg(8) conjugates exhibited fast kinetics of binding to
calf thymus DNA and an ability to precipitate
DNA at very low concentrations. In serum-free medium, the Arg(8) complex was cytotoxic (IC(50) 33 μM) and appears to be a rare example of a bioactive organometallic
peptide conjugate. Experiments on CHO cells deficient in DNA repair suggested that unrepaired DNA damage contributes to the cytotoxicity of the Arg(5) and Arg(8) conjugates. These studies demonstrate the potential for use of cell- and nucleus-penetrating
peptides in targeting organometallic arene anticancer complexes.