Abstract
Histone deacetylases (HDACs) belong to a family of enzymes that remove acetyl groups from the ɛ-amino of histone and nonhistone proteins. Additionally, HDACs participate in the genesis and development of cancer diseases as promising therapeutic targets to treat cancer. Therefore, in this work, we designed and evaluated a set of hydroxamic acid derivatives that contain a hydrophobic moiety as antiproliferative HDAC inhibitors. For the chemical structure design, in silico tools (molecular docking, molecular dynamic (MD) simulations, ADME/Tox properties were used to target Zn2+ atoms and HDAC hydrophobic cavities. The most promising compounds were assayed in different cancer cell lines, including hepatocellular carcinoma (HepG2), pancreatic cancer (MIA PaCa-2), breast cancer (MCF-7 and HCC1954), renal cancer (RCC4-VHL and RCC4-VA) and neuroblastoma (SH-SY5Y). Molecular docking and MD simulations coupled to the MMGBSA approach showed that the target compounds have affinity for HDAC1, HDAC6 and HDAC8. Of all the compounds evaluated, YSL-109 showed the best activity against hepatocellular carcinoma (HepG2 cell line, IC50 = 3.39 µM), breast cancer (MCF-7 cell line, IC50 = 3.41 µM; HCC1954 cell line, IC50 = 3.41 µM) and neuroblastoma (SH-SY5Y cell line, IC50 = 6.42 µM). In vitro inhibition assays of compound YSL-109 against the HDACs showed IC50 values of 259.439 µM for HDAC1, 0.537 nM for HDAC6 and 2.24 µM for HDAC8.
Highlights
Histone deacetylases (HDACs) belong to a family of enzymes that remove acetyl groups from the ɛ-amino of histone and nonhistone proteins
Selective HDAC1 inhibitors can be obtained by exploiting the foot pocket (14 Å channel), which is observed in class I HDACs but not in class IIa33, which is important for the correct catalytic activity of the enzyme[34]
It possesses a tunnel that is wider and more shallow[7,37], structural data supported by X-ray diffraction studies placed at Protein Data Base (PDB): 5EDU (Human), 5EEF, 5EEI, 5EEK, 5EEM, 5EEN, 5EF7, 5EF8, 5EF8, 5EFG 5EFH, 5EFJ, 5EFK and 5EFN (Danio), and it has been suggested that the use of bulky and aromatic moieties would increase the selectivity for HDAC618,26
Summary
Histone deacetylases (HDACs) belong to a family of enzymes that remove acetyl groups from the ɛ-amino of histone and nonhistone proteins. These HDACs have been linked to cancer progression and development[19] and are related to neurodegenerative diseases[7,18,20,21] These differences suggest the importance in the development of isoform-selective HDAC inhibitors (HDACi) to enhance drug efficacy and decrease side effects[22,23]. Structural insights into the binding differences among HDAC isoforms that permits the design of new HDACi with improved affinity and selectivity need to be explored. In this sense, several structural studies have been performed revealing particular differences among HDAC isoforms. It possesses a tunnel that is wider and more shallow[7,37], structural data supported by X-ray diffraction studies placed at Protein Data Base (PDB): 5EDU (Human), 5EEF, 5EEI, 5EEK, 5EEM, 5EEN, 5EF7, 5EF8, 5EF8, 5EFG 5EFH, 5EFJ, 5EFK and 5EFN (Danio), and it has been suggested that the use of bulky and aromatic moieties would increase the selectivity for HDAC618,26
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