Abstract
Genetic abnormalities have been conventionally considered as hallmarks of cancer. However, recent studies have demonstrated that epigenetic mechanisms are also implicated in the insurgence and development of cancer. Patterns of the epigenetic component include DNA methylation and histone modifications. Acetylation of histones is controlled by histone acetyltransferases (HATs) and histone deacetylases (HDACs). Imbalance of these two enzymatic systems is known to be a key factor in tumor progression. Because HDACs have been found to function incorrectly in cancer, various HDAC inhibitors (HDACIs) are being investigated to act as cancer chemotherapeutics. Herein, we report the synthesis, docking studies and biological activity of a series of hydroxamic acid-based HDACIs bearing an N1-aryl or N1-H pyrazole nucleus as surface recognition motif and a cinnamoyl group as a linker to the hydroxamic acid zinc-binding group (ZBG). Some of the tested compounds exhibited inhibitory properties towards HDACs and antiproliferative activity against neuroblastoma SH-SY5Y tumor cell line both at micromolar concentrations.
Highlights
The incidence of malignancies has dramatically risen in recent years
All reagents used for the development of the histone deacetylase (HDAC) inhibitors (HDACIs), including N-(3-dimethylaminopropyl)N -ethyl carbodiimide hydrochloride (EDCI), 1-hydroxybenzotriazole hydrate (HOBt) and various hydrazines, as well as all synthesis solvents and deuterated solvents employed for NMR analysis, were purchased from Sigma-Aldrich/Fluka (Milano, Italia) and used without further purification
Two sets of new hydroxamic acid-based derivatives endowed with a pyrazole capping group and a cinnamoyl linker were designed, synthesized, and evaluated as HDACIs
Summary
The incidence of malignancies has dramatically risen in recent years. According to the recent report (2018) of the World Health Organization, cancer is currently the second leading cause of death worldwide. The identification and improvement of new therapeutic strategies are urgently needed [1]. In this regard, it is well known the role of various histone deacetylase (HDAC) isoforms which act as epigenetic modulators of gene transcription and whose inhibition is crucial to identify novel anticancer agents. Imbalance of the activity of both histone acetyltransferase (HAT) and HDAC is strictly related to the insurgency and progression of tumors. These epigenetic markers have been the focus of drug discovery during the last decade. Histone deacetylase inhibitors (HDACIs) represent a promising new class of compounds for the treatment of cancer [3,4,5]
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