Synthetic Diastereomers of the Fungal Cycloheptapeptide Paraisariamide A Retain Ternatin-Like Biological Activity

IF 3.9 3区医学 Q2 CHEMISTRY, MEDICINAL

ACS Medicinal Chemistry Letters Pub Date : 2026-08-13 Epub Date: 2026-07-01 DOI:10.1021/acsmedchemlett.6c00180

Sophia E. Bonar, Daphne R. Mattos, Takumi Arai, Yui Tagami, Dean A. Buch, Richard M. Tehan, Kerry L. McPhail, Shinya Oishi, Jane E. Ishmael

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Abstract

Paraisariamides (Psds) are a family of fungal N-methylated cyclic heptapeptides with structural similarity to the translation eukaryotic elongation factor 1A inhibitor ternatin. Initial characterization of the eight known Psds A–H revealed a complex biological activity profile; Psd A and Psds E–H showed differential cytotoxicity to HCT116 colon cancer cells, whereas Psds B–D were inactive. Here, we report that Psd A is a weak inhibitor of total protein synthesis and that three synthetic diastereomers of Psd A retain comparable pharmacological activity. Psd A and all structural variants decreased the level of expression of extracellular Gaussia luciferase in a phenotypic assay that senses endoplasmic reticulum stress in living cells. Inhibition of cellular secretion was fully reversible; however, the three Psd A diastereomers were all eventually cytotoxic to HCT116 colon cancer cells. The stereochemistry of Psd A, a weak cytotoxin relative to Psds E–H, is anticipated to inform future structure–activity relationship studies of these ternatin-like molecules.

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真菌环七肽副伞虫酰胺A非对映体的合成

Paraisariamides （pds）是真菌n -甲基化环七肽家族，其结构与翻译真核延伸因子1A抑制剂ternatin相似。8种已知psd a - h的初步表征揭示了复杂的生物活性谱；Psd A和Psd E-H对HCT116结肠癌细胞具有不同的细胞毒性，而Psd B-D对HCT116结肠癌细胞无活性。在这里，我们报道了Psd A是总蛋白合成的弱抑制剂，并且Psd A的三种合成非对映体保持相当的药理活性。在一项表型测定中，Psd A和所有结构变异降低了细胞外高斯荧光素酶的表达水平，该表型测定可感知活细胞内质网应激。细胞分泌抑制是完全可逆的；然而，三种Psd A非对映体最终都对HCT116结肠癌细胞具有细胞毒性。PsdA是相对于Psds E-H的一种弱细胞毒素，其立体化学性质有望为未来研究该类分子的结构-活性关系提供信息。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

ACS Medicinal Chemistry Letters CHEMISTRY, MEDICINAL-

CiteScore

7.30

自引率

2.40%

发文量

328

审稿时长

1 months

期刊介绍： ACS Medicinal Chemistry Letters is interested in receiving manuscripts that discuss various aspects of medicinal chemistry. The journal will publish studies that pertain to a broad range of subject matter, including compound design and optimization, biological evaluation, drug delivery, imaging agents, and pharmacology of both small and large bioactive molecules. Specific areas include but are not limited to: Identification, synthesis, and optimization of lead biologically active molecules and drugs (small molecules and biologics) Biological characterization of new molecular entities in the context of drug discovery Computational, cheminformatics, and structural studies for the identification or SAR analysis of bioactive molecules, ligands and their targets, etc. Novel and improved methodologies, including radiation biochemistry, with broad application to medicinal chemistry Discovery technologies for biologically active molecules from both synthetic and natural (plant and other) sources Pharmacokinetic/pharmacodynamic studies that address mechanisms underlying drug disposition and response Pharmacogenetic and pharmacogenomic studies used to enhance drug design and the translation of medicinal chemistry into the clinic Mechanistic drug metabolism and regulation of metabolic enzyme gene expression Chemistry patents relevant to the medicinal chemistry field.