title: Construction and application of a Rh-Pt DNA metalloinsertor conjugate.
abstract: We report the synthesis and characterization of a bimetallic conjugate (RhPt) in which an oxaliplatin derivative is tethered to a rhodium metalloinsertor through an aminomalonate leaving group ligand. The complex interacts with DNA through metalloinsertion at a base pair mismatch followed by formation of a covalent Pt-DNA adduct. Characterization of RhPt in mismatch repair-deficient HCT116O cells reveals increased cytotoxicity compared to cisplatin and oxaliplatin as well as relative to the unconjugated rhodium and platinum counterparts. Caspase and poly-ADP ribose polymerase inhibition assays indicate that RhPt induces apoptotic cell death. Inductively coupled plasma mass spectrometry (ICP-MS) experiments reveal that RhPt exhibits enhanced cellular uptake properties that contribute to its increased efficacy.
authors.affiliation: Division of Chemistry and Chemical Engineering, California Institute of Technology , Pasadena, California 91125, United States.
authors.forename: Alyson G
authors.initials: AG
authors.lastname: Weidmann
authors.forename: Jacqueline K
authors.initials: JK
authors.lastname: Barton
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis*; D020137:Base Pair Mismatch; D061945:Caspase Inhibitors / Q000494:pharmacology; D002945:Cisplatin / Q000494:pharmacology; D004247:DNA / Q000737:chemistry*; D045325:HCT116 Cells; D006801:Humans; D009944:Organoplatinum Compounds / Q000138:chemical synthesis* / Q000494:pharmacology; D000077150:Oxaliplatin; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D012238:Rhodium / Q000737:chemistry*; D013054:Spectrophotometry, Atomic
chemical_list: D000970:Antineoplastic Agents; D061945:Caspase Inhibitors; D009944:Organoplatinum Compounds; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D000077150:Oxaliplatin; D004247:DNA; D012238:Rhodium; D002945:Cisplatin