title: Harnessing chemoselective imine ligation for tethering bioactive molecules to platinum(IV) prodrugs.
abstract: Platinum(II) anticancer drugs are among the most effective and often used chemotherapeutic drugs. In recent years, there has been increasing interest in exploiting inert platinum(IV) scaffolds as a prodrug strategy to mitigate the limitations of platinum(II) anticancer complexes. In this prodrug strategy, the axial ligands are released concomitantly upon intracellular reduction to the active platinum(II) congener, offering the possibility of conjugating bioactive co-drugs which may synergistically enhance cytotoxicity on cancer cells. Existing techniques of tethering bioactive molecules to the axial positions of platinum(IV) prodrugs suffer from limited scope, poor yields and low reliability. This report explores the applications of current chemoselective ligation chemistries to platinum(IV) anticancer complexes with the aim of addressing the aforementioned limitations. Here, we describe the synthesis of a platinum(IV) complex bearing an aromatic aldehyde functionality and explored the scope of imine ligation with various hydrazide and aminooxy functionalized substrates. As a proof of concept, we tethered a six sequence long peptide mimetic (AMVSEF) of the anti-inflammatory protein, ANXA1.
authors.affiliation: Department of Chemistry, National University of Singapore, 3 Science Drive 3, Singapore 117543, Singapore.
authors.forename: Daniel Yuan Qiang
authors.initials: DY
authors.lastname: Wong
authors.forename: Jia Yi
authors.initials: JY
authors.lastname: Lau
authors.forename: Wee Han
authors.initials: WH
authors.lastname: Ang
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry*; D006835:Hydrazones / Q000737:chemistry; D007097:Imines / Q000737:chemistry*; D009942:Organometallic Compounds / Q000737:chemistry; D010091:Oximes / Q000737:chemistry; D057786:Peptidomimetics / Q000737:chemistry; D010984:Platinum / Q000737:chemistry*; D011355:Prodrugs / Q000737:chemistry*; D013379:Substrate Specificity
chemical_list: D000970:Antineoplastic Agents; D006835:Hydrazones; D007097:Imines; D009942:Organometallic Compounds; D010091:Oximes; D057786:Peptidomimetics; D011355:Prodrugs; D010984:Platinum