Discovery of aliphatic-chain hydroxamates containing indole derivatives with potent class I histone deacetylase inhibitory activities
Journal
European Journal of Medicinal Chemistry
Journal Volume
143
Pages
792-805
Date Issued
2018
Author(s)
Abstract
Histone deacetylase (HDAC) is a validated drug target for various diseases. This study combined indole recognition cap with SAHA, an FDA-approved HDAC inhibitor used to treat cutaneous T-cell lymphoma (CTCL). The structure activity relationship of the resulting compounds that inhibited HDAC was disclosed as well. Some compounds exhibited much stronger inhibitory activities than SAHA. We identified two meta-series compounds 6j and 6k with a two-carbon linker had IC50 values of 3.9 and 4.5 nM for HDAC1, respectively. In contrast, the same oriented compounds with longer carbon chain linkers showed weaker inhibition. The result suggests that the linker chain length greatly contributed to enzyme inhibitory potency. In addition, comparison of enzyme-inhibiting activity between the compounds and SAHA showed that compounds 6j and 6k displayed higher inhibiting activity for class I (HDAC1, -2, -3 and -8). The molecular docking and structure analysis revealed structural differences with the inhibitor cap and metal-binding regions between the HDAC isozymes that affect interactions with the inhibitors and play a key role for selectivity. Further biological evaluation showed multiple cellular effects associated with compounds 6j- and 6k-induced HDAC inhibitory activity. ? 2017 Elsevier Masson SAS
Subjects
Histone deacetylase; Indole; Isozyme; Molecular docking; Structure activity relationship
SDGs
Other Subjects
histone deacetylase 1; histone deacetylase 2; histone deacetylase 3; histone deacetylase 4; histone deacetylase 5; histone deacetylase 6; histone deacetylase 7; histone deacetylase 8; histone deacetylase 9; histone deacetylase inhibitor; hydroxamic acid derivative; indole derivative; n hydroxy 7 [2 [2 (5,6,7 trimethoxy 1h indol 1 yl)ethoxy]phenylcarbamoyl]heptanamide; n hydroxy 7 [2 [3 (5,6,7 trimethoxy 1h indol 1 yl)propoxy]phenylcarbamoyl]heptanamide; n hydroxy 7 [2 [4 (5,6,7 trimethoxy 1h indol 1 yl)butoxy]phenylcarbamoyl]heptanamide; n hydroxy 7 [3 [2 (1h indol 1 yl)ethoxy]phenylcarbamoyl]heptanamide; n hydroxy 7 [3 [2 (5 bromo 1h indol 1 yl)ethoxy]phenylcarbamoyl]heptanamide; n hydroxy 7 [3 [2 (5 methoxy 1h indol 1 yl)ethoxy]phenylcarbamoyl]heptanamide; n hydroxy 7 [3 [2 (5,6,7 methoxy 1h indol 1 yl)ethoxy]phenylcarbamoyl]heptanamide; n hydroxy 7 [3 [2 (5,6,7 trimethoxy 1h indol 1 yl)ethoxy]phenylcarbamoyl]heptanamide; n hydroxy 7 [3 [2 (6 methoxy 1h indol 1 yl)ethoxy]phenylcarbamoyl]heptanamide; n hydroxy 7 [3 [2 (7 methoxy 1h indol 1 yl)ethoxy]phenylcarbamoyl]heptanamide; n hydroxy 7 [3 [3 (5,6,7 trimethoxy 1h indol 1 yl)propoxy]phenylcarbamoyl]heptanamide; n hydroxy 7 [3 [4 (5,6,7 trimethoxy 1h indol 1 yl)butoxy]phenylcarbamoyl]heptanamide; n hydroxy 7 [4 [2 (5,6,7 trimethoxy 1h indol 1 yl)ethoxy]phenylcarbamoyl]heptanamide; n hydroxy 7 [4 [3 (5,6,7 trimethoxy 1h indol 1 yl)propoxy]phenylcarbamoyl]heptanamide; n hydroxy 7 [4 [4 (5,6,7 trimethoxy 1h indol 1 yl)butoxy]phenylcarbamoyl]heptanamide; n hydroxy 8 [3 [2 (5 methoxy 1h indol 1 yl)ethoxy]phenylcarbamoyl]heptanamide; n hydroxy 9 [3 [2 (5 methoxy 1h indol 1 yl)ethoxy]phenylcarbamoyl]nonanamide; unclassified drug; vorinostat; antineoplastic agent; HDAC1 protein, human; histone deacetylase 1; histone deacetylase inhibitor; hydroxamic acid; indole; indole derivative; lissamine rhodamine B; rhodamine; A-549 cell line; apoptosis; Article; cell cycle progression; cell death; cell growth; cell membrane permeability; comparative study; cutaneous T cell lymphoma; cytotoxicity; drug potency; drug targeting; electrospray mass spectrometry; enzyme active site; enzyme binding; enzyme inhibition; food and drug administration; HeLa cell line; high performance liquid chromatography; histone acetylation; human; human cell; hydrogen bond; IC50; metal binding; molecular docking; sequence analysis; sequence homology; structure activity relation; structure analysis; Western blotting; cell proliferation; chemical structure; chemistry; dose response; drug development; drug effects; drug screening; synthesis; tumor cell culture; Antineoplastic Agents; Cell Proliferation; Dose-Response Relationship, Drug; Drug Discovery; Drug Screening Assays, Antitumor; Histone Deacetylase 1; Histone Deacetylase Inhibitors; Humans; Hydroxamic Acids; Indoles; Molecular Structure; Rhodamines; Structure-Activity Relationship; Tumor Cells, Cultured
Type
journal article