Biofunctional Synthetic Chemistry Laboratory, RIKEN Cluster for Pioneering Research, RIKEN, 2-1 Hirosawa, Wako-shi, Saitama, 351-0198, Japan.
GlycoTargeting Research Laboratory, RIKEN Baton Zone Program, RIKEN, 2-1 Hirosawa, Wako-shi, Saitama, 351-0198, Japan.
Angew Chem Int Ed Engl. 2021 May 25;60(22):12446-12454. doi: 10.1002/anie.202100369. Epub 2021 Apr 6.
An emerging approach in the field of targeted drug delivery is the establishment of abiotic metal-triggered prodrug mechanisms that can control the release of bioactive drugs. Currently, the design of prodrugs that use abiotic metals as a trigger relies heavily on uncaging strategies. Here, we introduce a strategy based on the gold-catalyzed activation of a phenanthridinium-based prodrug via hydroamination under physiological conditions. To make the prodrug strategy biocompatible, a gold artificial metalloenzyme (ArM) based on human serum albumin, rather than the free gold metal complex, was used as a trigger for prodrug activation. The albumin-based gold ArM protected the catalytic activity of the bound gold metal even in the presence of up to 1 mM glutathione in vitro. The drug synthesized via the gold ArM exerted a therapeutic effect in cell-based assays, highlighting the potential usefulness of the gold ArM in anticancer applications.
在靶向药物输送领域中，一种新兴的方法是建立非生物金属触发前药机制，以控制生物活性药物的释放。目前，使用非生物金属作为触发物的前药设计主要依赖于解笼策略。在这里，我们介绍了一种基于金催化的生理条件下通过氢胺化激活基于菲啶的前药的策略。为了使前药策略具有生物相容性，使用基于人血清白蛋白的金人工金属酶（ArM）而不是游离金金属配合物作为前药激活的触发物。基于白蛋白的金 ArM 即使在体外存在高达 1 mM 谷胱甘肽的情况下，也能保护结合金金属的催化活性。通过金 ArM 合成的药物在基于细胞的测定中发挥了治疗作用，突出了金 ArM 在抗癌应用中的潜在用途。
