title: Synthesis, Biological Evaluation, and Computer-Aided Drug Designing of New Derivatives of Hyperactive Suberoylanilide Hydroxamic Acid Histone Deacetylase Inhibitors.
abstract: The synthesis and biological evaluation of a novel series of compounds based on suberoylanilide hydroxamic acid (SAHA) had been designed as potential histone deacetylase inhibitors (HDACis). Molecular docking studies indicated that our derivatives had better fitting in the binding sites of HDAC8 than SAHA. Compounds 1-5 were synthesized through the synthetic routes. In biological test, compounds also showed good inhibitory activity in HDAC enzyme assay and more potent growth inhibition in human glioma cell lines (MGR2, U251, and U373). A representative compound, N3F, exhibited better inhibitory effect (HDAC, IC50  = 0.1187 μm; U251, IC50  = 0.8949 μm) and lower toxicity for human normal cells (LO2, IC50  = 172.5 μm and MRC5, IC50  = 213.6 μm) compared with SAHA (HDAC, IC50  = 0.8717 μm; U251, IC50  = 8.938 μm; LO2, IC50  = 86.52 μm and MRC5, IC50  = 81.02 μm). In addition, N3F obviously increased Beclin-1 and Caspase-3 and 9 as well as inhibited Bcl-2 in U251 cells. All of our results indicated that these SAHA cap derivatives could serve as potential lead compounds for further optimization. In addition, N3F and N2E both displayed promising profile as antitumor candidates for the treatment of human glioma.
authors.affiliation: Department of Pharmacology, College of Pharmacy, Guangdong Pharmaceutical University, Guangdong, China.
authors.forename: Song
authors.initials: S
authors.lastname: Zhang
authors.affiliation: Department of Pharmacology, College of Pharmacy, Guangdong Pharmaceutical University, Guangdong, China.
authors.forename: Weibin
authors.initials: W
authors.lastname: Huang
authors.affiliation: Brain Tumor Program, Texas Children's Cancer Center Department of Pediatrics, Baylor College of Medicine, 1102 Bates St., Ste. 1030.07, Houston, TX, 77030, USA.
authors.forename: Xiaonan
authors.initials: X
authors.lastname: Li
authors.affiliation: Department of Pharmacology, College of Pharmacy, Guangdong Pharmaceutical University, Guangdong, China.
authors.forename: Zhicheng
authors.initials: Z
authors.lastname: Yang
authors.affiliation: Department of Pharmacology, College of Pharmacy, Guangdong Pharmaceutical University, Guangdong, China.
authors.forename: Binghong
authors.initials: B
authors.lastname: Feng
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D000071186:Beclin-1; D053148:Caspase 3 / Q000378:metabolism; D053453:Caspase 9 / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D017076:Computer-Aided Design; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D005910:Glioma / Q000188:drug therapy / Q000378:metabolism; D056572:Histone Deacetylase Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D006655:Histone Deacetylases / Q000378:metabolism; D006801:Humans; D006877:Hydroxamic Acids / Q000737:chemistry* / Q000494:pharmacology*; D008565:Membrane Proteins / Q000378:metabolism; D062105:Molecular Docking Simulation; D012097:Repressor Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D000077337:Vorinostat
chemical_list: D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; C491997:BECN1 protein, human; D000071186:Beclin-1; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D008565:Membrane Proteins; D012097:Repressor Proteins; D000077337:Vorinostat; D053148:Caspase 3; D053453:Caspase 9; C409470:HDAC8 protein, human; D006655:Histone Deacetylases
keywords: Bcl-2; Beclin-1; Caspase-3, 9; histone deacetylase inhibitor; human normal cells (LO2 and MRC5); proliferation inhibition of human glioma cells