Laboratory of Advanced Organic Chemistry, Department of Organic Chemistry and Physical Chemistry, Faculty of Chemical and Pharmaceutical Sciences; University of Chile, Santiago 8380000, Chile.
Laboratory of Molecular Pharmacology, Department of Pharmacological & Toxicological Chemistry, Faculty of Chemical and Pharmaceutical Sciences; University of Chile, Santiago 8380000, Chile.
Molecules. 2019 Feb 19;24(4):739. doi: 10.3390/molecules24040739.
New histone deacetylases (HDAC) inhibitors with low toxicity to non-cancerous cells, are a prevalent issue at present because these enzymes are actively involved in fibrotic diseases. We designed and synthesized a novel series of thiazolyl-coumarins, substituted at position 6 (R = H, Br, OCH₃), linked to classic zinc binding groups, such as hydroxamic and carboxylic acid moieties and alternative zinc binding groups such as disulfide and catechol. Their in vitro inhibitory activities against HDACs were evaluated. Disulfide and hydroxamic acid derivatives were the most potent ones. Assays with neonatal rat cardiac fibroblasts demonstrated low cytotoxic effects for all compounds. Regarding the parameters associated to cardiac fibrosis development, the compounds showed antiproliferative effects, and triggered a strong decrease on the expression levels of both α-SMA and procollagen I. In conclusion, the new thiazolyl-coumarin derivatives inhibit HDAC activity and decrease profibrotic effects on cardiac fibroblasts.
新型组蛋白去乙酰化酶（HDAC）抑制剂对非癌细胞的毒性较低，这是目前一个热门的研究课题，因为这些酶在纤维化疾病中起着积极的作用。我们设计并合成了一系列新型的噻唑基-香豆素，在 6 位取代（R = H、Br、OCH₃），连接到经典的锌结合基团，如羟肟酸和羧酸基团以及替代的锌结合基团，如二硫键和儿茶酚。评估了它们对 HDAC 的体外抑制活性。二硫键和羟肟酸衍生物是最有效的。对新生大鼠心肌成纤维细胞的测定表明，所有化合物的细胞毒性都较低。关于与心脏纤维化发展相关的参数，这些化合物表现出抗增殖作用，并强烈降低α-SMA 和原胶原蛋白 I 的表达水平。总之，新型噻唑基-香豆素衍生物抑制 HDAC 活性，并降低对心肌成纤维细胞的促纤维化作用。
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