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

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/N-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 16, in which a Pt­(IV) moiety is covalently connected with an O2-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 O2-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.在复杂生物系统中实现可控药物激活的生物正交脱笼反应（Bioorthogonal decaging reactions），既是学界高度渴求的研究方向，同时也极具挑战性。本研究中，我们发现了一类全新的铂(II)（Pt(II)）触发型生物正交裂解反应：在生物相容条件下，仅铂(II)而非铂(IV)（Pt(IV)）配合物可有效触发多种笼状分子中O/N-炔丙基的裂解过程。基于上述发现，我们提出了一种适用于整合型生物正交前药（prodrug）的通用策略，并据此设计了前药16：该前药中铂(IV)基团与O2-炔丙基二氮烯二醇盐（diazeniumdiolate）基团以共价键相连。研究发现，前药16可在人卵巢癌细胞内被胞质还原剂特异性还原，释放顺铂（cisplatin）；顺铂随后可触发O2-炔丙基的裂解，原位释放大量一氧化氮（NO），进而在体内产生协同强效的肿瘤抑制活性。综上，铂(II)触发的去炔丙基化反应及其整合设计理念，可为生物正交裂解化学在体内的广泛应用提供通用解决方案。