Abstract
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.
Highlights
Cardiac fibrosis is characterized by the excessive deposition of collagens and extracellular matrix (ECM) proteins that lead to impaired organ function, and is the major factor in the progression of myocardial infarction and heart failure [1]
In hearts with heart failure, both HDAC1 and HDAC2 showed strong expression in Cardiac fibroblasts (CFs), HDAC2 maintained its expression in cardiomyocytes
These data suggest that HDAC1 and HDAC2 are mainly associated with the regulation of the biology of CFs in the heart [3,4,5]
Summary
Cardiac fibrosis is characterized by the excessive deposition of collagens and extracellular matrix (ECM) proteins that lead to impaired organ function, and is the major factor in the progression of myocardial infarction and heart failure [1]. The pattern expression analysis of HDAC1 and HDAC2 in hearts showed that. In hearts with heart failure, both HDAC1 and HDAC2 showed strong expression in CFs, HDAC2 maintained its expression in cardiomyocytes. Together, these data suggest that HDAC1 and HDAC2 are mainly associated with the regulation of the biology of CFs in the heart [3,4,5]
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