General Strategy for Integrated Bioorthogonal Prodrugs: Pt(II)-Triggered Depropargylation Enables Controllable Drug Activation <i>In Vivo</i>

Abstract

Bioorthogonal decaging reactions for controllable drug activation within complex biological systems are highly desirable yet extremely challenging. Herein, we find a new class of Pt(II)-triggered bioorthogonal cleavage reactions in which Pt(II) but not Pt(IV) complexes effectively trigger the cleavage of <i>O</i>/<i>N</i>-propargyl in a variety of ranges of caged molecules under biocompatible conditions. Based on these findings, we propose a general strategy for integrated bioorthogonal prodrugs and accordingly design a prodrug <b>16</b>, in which a Pt(IV) moiety is covalently connected with an <i>O</i>²-propargyl diazeniumdiolate moiety. It is found that <b>16</b> can be specifically reduced by cytoplasmic reductants in human ovarian cancer cells to liberate cisplatin, which subsequently stimulates the cleavage of <i>O</i>²-propargyl to release large amounts of NO <i>in situ</i>, thus generating synergistic and potent tumor suppression activity <i>in vivo</i>. Therefore, Pt(II)-triggered depropargylation and the integration concept might provide a general strategy for broad applicability of bioorthogonal cleavage chemistry <i>in vivo</i>.