Design, synthesis, and affinity evaluations of PP2A-targeting spiroketal derivatives based on structure-activity relationship studies of marine toxin okadaic acid fragments

IF 3.1 4区医学 Q3 CHEMISTRY, MEDICINAL

Medicinal Chemistry Research Pub Date : 2025-07-23 DOI:10.1007/s00044-025-03448-8

Li Sheng, Rajiv Bhalla

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Abstract

Protein phosphatase 2A (PP2A), a member of the phosphoprotein phosphatase (PPP) family, plays a pivotal role in regulating tau dephosphorylation, thereby maintaining the functional integrity of this brain-specific protein in microtubule assembly. Progressive downregulation of PP2A has been implicated in the pathogenesis of Alzheimer’s disease (AD). The identification of high-affinity PP2A ligands presents a promising avenue for monitoring early-stage dementia progression through alternative molecular mechanisms. Utilizing the catalytic binding pocket model of PP1 as a structural surrogate for PPPs, three distinct fragments derived from various natural PP2A inhibitors were found to exhibit equivalent binding functionality. Building upon this framework in small-molecule design, a synthetic spiroketal compound was developed based on the C1–C14 acidic fragment of okadaic acid (OA), a PP2A-selective inhibitor. This compound emerges as a promising candidate for further therapeutic and diagnostic investigation.

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基于海洋毒素冈田酸片段构效关系的pp2a靶向螺旋酮衍生物的设计、合成及亲和性评价

蛋白磷酸酶2A （PP2A）是磷酸蛋白磷酸酶（PPP）家族的一员，在调节tau去磷酸化中发挥关键作用，从而维持这种脑特异性蛋白在微管组装中的功能完整性。PP2A的进行性下调与阿尔茨海默病（AD）的发病机制有关。高亲和力PP2A配体的鉴定为通过替代分子机制监测早期痴呆进展提供了一条有希望的途径。利用PP1的催化结合口袋模型作为PPPs的结构替代物，发现来自不同天然PP2A抑制剂的三个不同片段具有相同的结合功能。基于这一小分子设计框架，以pp2a选择性抑制剂冈田酸（OA）的C1-C14酸性片段为基础，合成了螺旋酮化合物。该化合物成为进一步治疗和诊断研究的有希望的候选物。

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来源期刊

Medicinal Chemistry Research 医学-医药化学

CiteScore

4.70

自引率

3.80%

发文量

162

审稿时长

5.0 months

期刊介绍： Medicinal Chemistry Research (MCRE) publishes papers on a wide range of topics, favoring research with significant, new, and up-to-date information. Although the journal has a demanding peer review process, MCRE still boasts rapid publication, due in part, to the length of the submissions. The journal publishes significant research on various topics, many of which emphasize the structure-activity relationships of molecular biology.