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

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 O/Npropargyl 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 16, in which a Pt(IV) moiety is covalently connected with an O 2 -propargyl diazeniumdiolate moiety. It is found that 16 can be specifically reduced by cytoplasmic reductants in human ovarian cancer cells to liberate cisplatin, which subsequently stimulates the cleavage of O 2 -propargyl to release large amounts of NO in situ, thus generating synergistic and potent tumor suppression activity in vivo. Therefore, Pt(II)-triggered depropargylation and the integration concept might provide a general strategy for broad applicability of bioorthogonal cleavage chemistry in vivo.

Unleashing the Power of Bond Cleavage Chemistry in Living Systems

“…Finally, Huang et al used the Pt(IV) complex as a precatalyst, which can be selectively converted into Pt(II) in tumor cells, triggering the cleavage of O/N propargyl-caged prodrugs. 60 …”

“…Finally, Huang et al used the Pt(IV) complex as a precatalyst, which can be selectively converted into Pt(II) in tumor cells, triggering the cleavage of O/N propargyl-caged prodrugs. 60 In general, an advantage of transition-metal-triggered BCRs is that their reactivity/selectivity can be finely tuned by the metals or ligands utilized, which provides exciting chemical space for further exploration. Currently, although more than a stoichiometric amount of metal is often used, catalytic amounts of metal reagents may eventually be used to trigger BCRs in living systems.…”

“…In the latter work, the authors discovered that pentynoyl amides can be cleaved by the Pt catalyst, which added a new bioorthogonal caging group on the amide other than the carbamate group (Figure , entry 4). Finally, Huang et al used the Pt­(IV) complex as a precatalyst, which can be selectively converted into Pt­(II) in tumor cells, triggering the cleavage of O/N propargyl-caged prodrugs …”

Transition Metal Scaffolds Used To Bring New‐to‐Nature Reactions into Biological Systems

“…Due to the widespread usage of cisplatin as an effective anticancer agent, there has been a natural propensity to develop dual drug strategies that can also utilize the catalytic activity of platinum. For example, one strategy designed a prodrug that contains separate moieties containing both a masked platinum(IV) and a propargyl protected N ‐methylethanolamine diazeniumdiolate [71] . Upon platinum reduction by cancer‐specific reductases, the newly formed platinum(II) becomes active to facilitate prodrug depropargylation.…”

“…For example, one strategy designed a prodrug that contains separate moieties containing both a masked platinum(IV) and a propargyl protected N-methylethanolamine diazeniumdiolate. [71] Upon platinum reduction by cancer-specific reductases, the newly formed platinum(II) becomes active to facilitate prodrug depropargylation. This ultimately leads to the release of the diazeniumdiolate moiety, which spontaneously breaks down to produce nitrogen monoxide in situ.…”