title: A novel suberoylanilide hydroxamic acid histone deacetylase inhibitor derivative, N25, exhibiting improved antitumor activity in both human U251 and H460 cells.
abstract: N1- (2, 5-dimethoxyphenyl)-N(8)-hydroxyoctanediamide (N25) is a novel SAHA cap derivative of HDACi, with a patent (No. CN 103159646). This invention is a hydroxamic acid compound with a structural formula of RNHCO(CH2)6CONHOH (wherein R=2, 5dimethoxyaniline), a pharmaceutically acceptable salt which is soluble. In the present study, we investigated the effects of N25 with regard to drug distribution and molecular docking, and anti-proliferation, apoptosis, cell cycling, and LD50. First, we designed a molecular approach for modeling selected SAHA derivatives based on available structural information regarding human HDAC8 in complex with SAHA (PDB code 1T69). N25 was found to be stabilized by direct interaction with the HDAC8. Anti-proliferative activity was observed in human glioma U251, U87, T98G cells and human lung cancer H460, A549, H1299 cells at moderate concentrations (0.5-30 μM). Compared with SAHA, N25 displayed an increased antitumor activity in U251 and H460 cells. We further analyzed cell death mechanisms activated by N25 in U251 and H460 cells. N25 significantly increased acetylation of Histone 3 and inhibited HDAC4. On RT-PCR analysis, N25 increased the mRNA levels of p21, however, decreased the levels of p53. These resulted in promotion of apoptosis, inducing G0/G1 arrest in U251 cells and G2/M arrest in H460 cells in a time-dependent and dose- dependent manner. In addition, N25 was able to distribute to brain tissue through the blood-brain barrier of mice (LD50: 240.840 mg/kg). In conclusion, our findings demonstrate that N25 will provide an invaluable tool to investigate the molecular mechanism with potential chemotherapeutic value in several malignancies, especially human glioma.
authors.affiliation: Department of Pharmacology, College of Pharmacy, Guangdong Pharmaceutical University, Guangzhou, China E-mail : fengbh@gdpu.edu.cn, fengbh2010@163.com.
authors.forename: Song
authors.initials: S
authors.lastname: Zhang
authors.forename: Wei-Bin
authors.initials: WB
authors.lastname: Huang
authors.forename: Li
authors.initials: L
authors.lastname: Wu
authors.forename: Lai-You
authors.initials: LY
authors.lastname: Wang
authors.forename: Lian-Bao
authors.initials: LB
authors.lastname: Ye
authors.forename: Bing-Hong
authors.initials: BH
authors.lastname: Feng
mesh_terms: D000107:Acetylation; D000813:Anilides / Q000493:pharmacokinetics / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D001932:Brain Neoplasms / Q000188:drug therapy*; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000096:biosynthesis / Q000235:genetics; D004354:Drug Screening Assays, Antitumor; D059585:G1 Phase Cell Cycle Checkpoints / Q000187:drug effects; D005910:Glioma / Q000188:drug therapy*; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006655:Histone Deacetylases; D006657:Histones / Q000378:metabolism; D006801:Humans; D006877:Hydroxamic Acids / Q000493:pharmacokinetics / Q000494:pharmacology*; D008175:Lung Neoplasms / Q000188:drug therapy*; D059566:M Phase Cell Cycle Checkpoints / Q000187:drug effects; D062105:Molecular Docking Simulation; D012097:Repressor Proteins / Q000037:antagonists & inhibitors; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis; D000077337:Vorinostat
chemical_list: D000813:Anilides; D000970:Antineoplastic Agents; D050759:Cyclin-Dependent Kinase Inhibitor p21; D056572:Histone Deacetylase Inhibitors; D006657:Histones; D006877:Hydroxamic Acids; C000597037:N1-(2,5-dimethoxyphenyl)-N8-hydroxyoctanediamide; D012097:Repressor Proteins; D016159:Tumor Suppressor Protein p53; D000077337:Vorinostat; C400300:HDAC4 protein, human; C409470:HDAC8 protein, human; D006655:Histone Deacetylases