Department of Chemistry, National University of Singapore, 3 Science Drive 3, Singapore 117543, Singapore.
NUS Graduate School of Integrative Sciences and Engineering, National University of Singapore, 21 Lower Kent Ridge Rd, Singapore 119077, Singapore.
Inorg Chem. 2021 Feb 1;60(3):1823-1831. doi: 10.1021/acs.inorgchem.0c03299. Epub 2021 Jan 19.
A common challenge in Pt(IV) prodrug design is the limited repertoire of linkers available to connect the Pt(IV) scaffold with the bioactive payload. The commonly employed linkers are either too stable, leading to a linker artifact on the payload upon release, or too unstable, leading to premature release. In this study, we report the synthesis of a new class of Pt(IV) prodrugs using masked self-immolative 4-aminobenzyl linkers for controlled and traceless codrug delivery. Upon reduction of self-immolative Pt(IV) prodrugs, the detached axial ligands undergo decarboxylation and 1,6-elimination for payload release. Introduction of self-immolative linkers conferred good aqueous stability to the Pt(IV) codrug complex. Investigation revealed that efficient 1,6-elimination could be attributed to stabilization of the aza-quinone-methide intermediate. In particular, the self-immolative Pt(IV) prodrugs with cinnamate and coumarin derivatives were more potent than the coadministration of cisplatin with an unconjugated cinnamate or coumarin payload in vitro.
在 Pt(IV)前药设计中，将 Pt(IV)支架与生物活性有效载荷连接的连接子的选择有限，这是一个常见的挑战。常用的连接子要么太稳定，导致有效载荷在释放时出现连接子副产物，要么太不稳定，导致过早释放。在这项研究中，我们报告了使用掩蔽的自毁 4-氨基苄基连接子合成新型 Pt(IV)前药，用于控制和无痕共药传递。自毁性 Pt(IV)前药还原后，脱落的轴向配体发生脱羧和 1,6-消除，释放有效载荷。引入自毁性连接子可提高 Pt(IV)共药复合物的水稳定性。研究表明，有效的 1,6-消除可归因于氮杂醌甲亚胺中间体的稳定化。特别是，肉桂酸酯和香豆素衍生物的自毁性 Pt(IV)前药在体外比顺铂与未缀合的肉桂酸酯或香豆素有效载荷的联合给药更有效。
