SYNTHESIS AND TESTING OF NOVEL VORINOSTAT? DERIVATIVES FOR INCREASED BIOAVAILABI

新型伏立诺他的合成和测试？

• 批准号: 8359822
• 负责人: Ellis Benjamin
• 金额: $ 10.77万
• 依托单位: UNIV OF ARKANSAS FOR MED SCIS
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-05-01 至 2012-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8359822
• 关键词: Animals; Apoptosis; Arkansas; Biological; Biological Assay; Biological Availability; Biomedical Research; Carbon; Cell Cycle; Cell Proliferation; Cells; Cutaneous; Epigenetic Process; Esters; Excision; Flow Cytometry; Funding; G1 Phase; Gene Expression; Goals; Grant; Half-Life; Histone Deacetylase Inhibitor; Histones; Hydroxamic Acids; Imides; Immune Tolerance; Link; Lysine; Mass Fragmentography; Molecular; Mus; NMR Spectroscopy; National Center for Research Resources; Polyethylene Glycols; Principal Investigator; Proteins; Research; Research Infrastructure; Resources; Source; T-Cell Lymphoma; T-Lymphocyte; Testing; United States National Institutes of Health; Vorinostat; cancer cell; cellular targeting; cost; design; improved; in vivo; neoplastic cell; novel; tumor

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Histone deacetylase (HDAC) inhibitors are epigenetic modifiers which obstruct the removal of an acetyl groups from an ¿-N-acetyl lysine on both histone or non-histone proteins. By altering gene expression, one result is cell cycle blockage at the G1 phase. Synthetic HDAC inhibitors are being tested for multiple biomedical applications including inhibition of tumor cell proliferation and the induction of immune tolerance. Unfortunately, histone deacetylase inhibitors efficacy has been limited by their short half-life in vivo. The goal of this proposed research is to increase the bioavailability of HDAC inhibitors in vivo by the derivization of Vorinostat¿ a class 1 HDAC inhibitor. We will start with Vorinostat, and attempt to modify it for increased stability and enhanced tumor targeting capacity. Although Vorinstat, has been approved as a treatment for cutaneous T-cell lymphoma, animal studies have found that this HDAC inhibitor breaks down within minutes thereby reducing its bioavailability. Structurally, Vorinostat maintains a carbon linker, and a hydrophobic cap, and a Zn2+-chelating hydroxamic acid. Although the hydroxamic acid is the functional region of Vorinostat its ability to be catalyzed under biological conditions decreases the half-life of Vorinostat in vivo. This project will synthesis and biologically evaluate novel N-hydroxy cyclic imides, N-alkyloxy esters, and polyethylene glycol (PEG)-linked Vorinstat derivatives designed for increased bioavailability by enhancing molecular stability of the hydroxamic acid and cellular targeting of Vorinostat derivatives. Targeting of the Vorinostat derivatives should allow for improved efficacy due to direct interaction with only the desired cancer cells. Structural confirmation and stability studies of the Vorinostat derivatives will use gas chromatography mass spectrometry (GCMS), infrared (IR), and nuclear magnetic resonance (NMR) spectroscopy. Two general protein assays (Apoptosis and Cell Proliferation Analysis) will be conducted for all Vorinostat derivatives in which EL4 cells (mouse T cell lymophoma) will determine specific biological activity using flow cytometry.

该子项目是利用资源的众多研究子项目之一 由 NIH/NCRR 资助的中心拨款提供。子项目的主要支持 并且子项目的主要研究者可能是由其他来源提供的， 包括其他 NIH 来源。 子项目可能列出的总成本 代表子项目使用的中心基础设施的估计数量， NCRR 赠款不直接向子项目或子项目工作人员提供资金。 组蛋白脱乙酰酶 (HDAC) 抑制剂是表观遗传修饰剂，可阻碍组蛋白或非组蛋白上 ¿-N-乙酰基赖氨酸中乙酰基的去除。 通过改变基因表达，一个结果是细胞周期被阻断在 G1 期。 合成 HDAC 抑制剂正在测试多种生物医学应用，包括抑制肿瘤细胞增殖和诱导免疫耐受。 不幸的是，组蛋白脱乙酰酶抑制剂的功效因其体内半衰期短而受到限制。 这项研究的目标是通过衍生 1 类 HDAC 抑制剂伏立诺他来提高 HDAC 抑制剂的体内生物利用度。 我们将从伏立诺他开始，并尝试对其进行修改以提高稳定性和增强肿瘤靶向能力。 尽管 Vorinstat 已被批准用于治疗皮肤 T 细胞淋巴瘤，但动物研究发现这种 HDAC 抑制剂会在几分钟内分解，从而降低其生物利用度。 在结构上，伏立诺他保留了碳连接体、疏水帽和 Zn2+ 螯合异羟肟酸。 尽管异羟肟酸是伏立诺他的功能区域，但其在生物条件下的催化能力会缩短伏立诺他的体内半衰期。 该项目将合成和生物学评估新型 N-羟基环状酰亚胺、N-烷氧基酯和聚乙二醇 (PEG) 连接的伏林司他衍生物，这些衍生物旨在通过增强异羟肟酸的分子稳定性和伏立诺他衍生物的细胞靶向性来提高生物利用度。 由于仅与所需的癌细胞直接相互作用，伏立诺他衍生物的靶向应可提高疗效。 伏立诺他衍生物的结构确认和稳定性研究将使用气相色谱质谱（GCMS）、红外（IR）和核磁共振（NMR）光谱。 将对所有伏立诺他衍生物进行两种常规蛋白质测定（细胞凋亡和细胞增殖分析），其中 EL4 细胞（小鼠 T 细胞淋巴瘤）将使用流式细胞术测定特定的生物活性。