Department of Cellular, Computational And Integrative Biology, (CIBIO), Via Sommarive 9, I-38123 Povo, TN, Italy.
Chemistry Department, Università Statale di Milano, Via Golgi 19, I-20133 Milan, Italy.
Bioorg Med Chem Lett. 2021 May 15;40:127929. doi: 10.1016/j.bmcl.2021.127929. Epub 2021 Mar 9.
A small set of trehalose-centered putative autophagy inducers was rationally designed and synthesized, with the aim to identify more potent and bioavailable autophagy inducers than free trehalose, and to acquire information about their molecular mechanism of action. Several robust, high yield routes to key trehalose intermediates and small molecule prodrugs (2-5), putative probes (6-10) and inorganic nanovectors (12a - thiol-PEG-triazole-trehalose constructs 11) were successfully executed, and compounds were tested for their autophagy-inducing properties. While small molecules 2-11 showed no pro-autophagic behavior at sub-millimolar concentrations, trehalose-bearing PEG-AuNPs 12a caused measurable autophagy induction at an estimated 40 μM trehalose concentration without any significant toxicity at the same concentration.
一组由海藻糖为核心的假定自噬诱导剂被合理设计和合成，旨在鉴定比游离海藻糖更有效和更具生物利用度的自噬诱导剂，并获得关于它们作用机制的信息。成功执行了几种稳健、高产的关键海藻糖中间体和小分子前药（2-5）、假定探针（6-10）和无机纳米载体（12a-巯基-PEG-三唑-海藻糖构建体 11）的路线，并且测试了化合物的自噬诱导特性。虽然小分子 2-11 在亚毫摩尔浓度下没有表现出促进自噬的行为，但带有海藻糖的 PEG-AuNPs 12a 在估计 40μM 海藻糖浓度下引起了可测量的自噬诱导，而在相同浓度下没有明显的毒性。
