Edupuganti Veera V Shivaji R, Matikonda Siddharth S, Lawer Aggie, Fairhall Jessica M, Lewin Harrison M, Kueh Jui Thiang Brian, Tyndall Joel D A, Gamble Allan B
School of Pharmacy, University of Otago, 18 Frederick Street, Dunedin, 9054, New Zealand.
Department of Chemistry, University of Otago, Union Place, Dunedin, 9016, New Zealand.
Chemistry. 2025 Jun 3;31(31):e202501278. doi: 10.1002/chem.202501278. Epub 2025 Apr 28.
Self-immolative linkers that use p-amino/hydroxy-benzyloxycarbonyl (PABC/PHBC) spacers are essential to the mechanism of many prodrugs. However, a highly reactive (aza)quinone methide is generated as a potential toxic byproduct. To remove the methide as it forms, we synthesized a series of novel tripartite prodrugs, comprising different triggers (nitro, amide, azide, boronate) and a PABC/PHBC-type self-immolative spacer with an integrated nucleophile (amine). Upon reductive, hydrolytic, or oxidative-trigger activation, the release of the cargo is facilitated via a 1,6-elimination that generates a reactive (aza)quinone methide. With the built-in nucleophile, the (aza)quinone methide is rapidly self-quenched to generate tetrahydroisoquinolines (THIQs). One of the selected THIQs does not exhibit an anti-proliferative effect on the A431 mammalian tumor cell line. The new prodrug strategy has broad scope, enabling the use of a trigger that matches the targeted stimulus, while allowing for a diverse range of drug/cargo attachment. This proof-of-concept study adds a new linker strategy that quenches the electrophilic (aza)quinone methide generated in many self-immolative linker systems and could find applications in prodrug and antibody-drug conjugate strategies, or as a linker for probes in chemical biology.
使用对氨基/羟基苄氧羰基（PABC/PHBC）间隔基的自毁型连接子对许多前药的作用机制至关重要。然而，会生成一种高反应性的（氮杂）醌甲基化物作为潜在的有毒副产物。为了在（氮杂）醌甲基化物形成时将其去除，我们合成了一系列新型三联前药，其包含不同的触发基团（硝基、酰胺、叠氮化物、硼酸酯）以及带有整合亲核试剂（胺）的PABC/PHBC型自毁型间隔基。在还原、水解或氧化触发激活后，通过1,6-消除促进货物释放，该消除反应会生成反应性的（氮杂）醌甲基化物。借助内置的亲核试剂，（氮杂）醌甲基化物会迅速自我淬灭以生成四氢异喹啉（THIQs）。所选择的一种THIQs对A431哺乳动物肿瘤细胞系没有抗增殖作用。这种新的前药策略具有广泛的应用范围，能够使用与靶向刺激相匹配的触发基团，同时允许进行多种药物/货物连接。这项概念验证研究增加了一种新的连接子策略，该策略可淬灭许多自毁型连接子系统中产生的亲电（氮杂）醌甲基化物，并可能在prodrug和抗体-药物偶联策略中找到应用，或用作化学生物学中探针的连接子。
