Chemical Synthesis and Antifibrotic Properties of (±)-Cochlearol T, (±)-Ganocochlearin A, and (±)-Cochlearol Y

IF 4 3区医学 Q2 CHEMISTRY, MEDICINAL

ACS Medicinal Chemistry Letters Pub Date : 2024-11-12 DOI:10.1021/acsmedchemlett.4c0049710.1021/acsmedchemlett.4c00497

Badrinath N. Kakde, Sung Wan An, Yaashmin Shiny Jebaraj, Sudha Neelam, Matthias T. F. Wolf* and Uttam K. Tambar*,

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Abstract

The cochlearols and ganocochlearins are natural products with unique antifibrotic and renoprotective activities in models of kidney disease. They represent compelling lead compounds for pharmacological intervention against kidney disease, often characterized by renal fibrosis. We report a four-step synthesis of (±)-cochlearol T (1) and the first reported syntheses of (±)-ganocochlearin A (2) and (±)-cochlearol Y (3) through a strategy that includes a Robinson annulation and unexpected oxidative aromatization. We also access tricyclic intermediate 12 that represents a formal synthesis of ganocins A–C and ganocochlearins C–D. We investigated the activity of these synthesized compounds in vitro by inducing fibrosis in a human kidney cell line with TGF-β1. The effect on fibrosis was assessed by qPCR and Western blot studies. We detected significantly lower mRNA gene and protein expression of fibrosis markers for all three natural products.

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（±）-Cochlearol T、（±）-Ganocochlearin A和（±）-Cochlearol Y的化学合成及抗纤维化性能

耳蜗醇和胆蜗学习素是天然产物，在肾脏疾病模型中具有独特的抗纤维化和肾保护活性。它们代表了对肾脏疾病进行药物干预的引人注目的先导化合物，通常以肾纤维化为特征。我们报道了（±）-cochlearol T(1)的四步合成和（±）-ganocochlearin a(2)和（±）-cochlearol Y(3)的首次报道，合成策略包括罗宾逊环化和意外的氧化芳构化。我们还获得了代表ganocins a - c和ganocochlearins C-D正式合成的三环中间体12。我们通过TGF-β1在体外诱导人肾细胞系纤维化来研究这些合成化合物的活性。通过qPCR和Western blot研究评估其对纤维化的影响。我们检测到所有三种天然产物的纤维化标志物的mRNA基因和蛋白质表达显著降低。

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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.