Chao S.-W.Chen L.-C.Yu C.-C.Liu C.-Y.Lin T.E.JIH-HWA GUHWang C.-Y.Chen C.-Y.Hsu K.-C.Huang W.-J.2021-06-022021-06-0220182235234https://www.scopus.com/inward/record.uri?eid=2-s2.0-85036670008&doi=10.1016%2fj.ejmech.2017.11.092&partnerID=40&md5=221249fc4e540262ed511c1ab774bea4https://scholars.lib.ntu.edu.tw/handle/123456789/564766Histone 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 SASHistone deacetylase; Indole; Isozyme; Molecular docking; Structure activity relationship[SDGs]SDG3histone 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, Culturedjournal article10.1016/j.ejmech.2017.11.092292230962-s2.0-85036670008