Kakde Badrinath N, An Sung Wan, Jebaraj Yaashmin Shiny, Neelam Sudha, Wolf Matthias T F, Tambar Uttam K
Department of Biochemistry, The University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, Texas 75390-9038, United States.
Department of Pediatrics, The University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, Texas 75390-9063, United States.
ACS Med Chem Lett. 2024 Nov 12;15(12):2220-2224. doi: 10.1021/acsmedchemlett.4c00497. eCollection 2024 Dec 12.
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 () and the first reported syntheses of (±)-ganocochlearin A () and (±)-cochlearol Y () through a strategy that includes a Robinson annulation and unexpected oxidative aromatization. We also access tricyclic intermediate that represents a formal synthesis of ganocins A-C and ganocochlearins C-D. We investigated the activity of these synthesized compounds 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.
耳蜗醇类和甘诺耳蜗素类是在肾脏疾病模型中具有独特抗纤维化和肾脏保护活性的天然产物。它们是针对通常以肾纤维化为特征的肾脏疾病进行药物干预的极具吸引力的先导化合物。我们报道了通过包括罗宾逊环化反应和意外氧化芳构化反应的策略，对（±）-耳蜗醇T（）进行的四步合成，以及首次报道的（±）-甘诺耳蜗素A（）和（±）-耳蜗醇Y（）的合成。我们还获得了三环中间体，该中间体代表了对甘诺菌素A-C和甘诺耳蜗素C-D的形式合成。我们通过用TGF-β1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和蛋白质印迹研究评估对纤维化的影响。我们检测到所有三种天然产物的纤维化标志物的mRNA基因和蛋白质表达均显著降低。
