Construction and application of a Rh-Pt DNA metalloinsertor conjugate

Abstract

The success of cisplatin as an anticancer agent has led to the development of a multitude of inorg. complexes for chemotherapy. In particular, rhodium metalloinsertor complexes, which selectively target base pair mismatches in DNA, have been shown to exhibit exceptional and selective cytotoxic activity in cancer cells that are deficient in mismatch repair (MMR). Here, we have synthesized and characterized a bifunctional metalloinsertor conjugate (RhPt), consisting of a rhodium mismatch recognition component tethered to a deriv. of the chemotherapeutic oxaliplatin. The RhPt complex exhibits dual binding to a DNA duplex contg. a mismatch, first through metalloinsertion at the mismatched site followed by the formation of covalent Pt-DNA adducts. It was found that RhPt displays enhanced cytotoxicity in MMR-deficient HCT116O cells compared to cisplatin and oxaliplatin as well as relative to the individual subunits. Cytotoxicity assays with caspase and poly-ADP ribose polymerase inhibitors revealed that RhPt induces apoptotic cell death, rather than the necrotic pathway triggered by metalloinsertors. Cellular uptake was probed using inductively coupled plasma mass spectrometry, and it was found that RhPt exhibits increased cellular uptake compared to control complexes, likely contributing to its enhanced activity. This and other Rh-Pt complexes will be discussed in the application of bifunctional complexes as chemotherapeutic agents.

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