Please use this identifier to cite or link to this item: http://rportal.lib.ntnu.edu.tw:80/handle/20.500.12235/101042
Title: 1. Design and Synthesis of Histone Deacetylase Inhibitors for Lung and Breast Cancer. 2. Asymmetric Aerobic Oxidation of α-Hydroxy Acid Derivatives Catalyzed by Reusable, Polystyrene Supported Chiral N-Salicylidine Oxidovanadium tert-Leucinates.
1. Design and Synthesis of Histone Deacetylase Inhibitors for Lung and Breast Cancer. 2. Asymmetric Aerobic Oxidation of α-Hydroxy Acid Derivatives Catalyzed by Reusable, Polystyrene Supported Chiral N-Salicylidine Oxidovanadium tert-Leucinates.
Authors: 李位仁
陳建添
Way-Zen Lee
Chien-Tien Chen
史南卡
Santosh Salunke
Keywords: 組蛋白去乙醯酶抑制劑
乳癌及肺癌
抗癌藥物
速配化學
細胞成像
不對稱氧化
動力光學對拆離
可回收手性氧釩金屬錯合物
四聚體
增效式的汞離子篩選
Histone deacetylase inhibitors
Lung and Breast cancer
Anti-tumor agents
Click Chemistry
Fluorescent HDACI-QD Conjugate
Cellular Imaging
Asymmetric
Kinetic Resolution
Chiral Mandelic acid derivatives
Reusable Chiral Vanadyl complexes
Tetramers
Hg(II)-specific detection and removal
Issue Date: 2011
Abstract: 我們開發出組蛋白去乙醯酶抑制劑的簡單製備方法。其中一種化合物OSU-HDAC-44,在NSCLC及異種移植具有抗腫瘤活性的效能。此化合物不只會抑制癌症細胞的生殖能力,並且在許多的NSCLC細胞株會引發細胞自毀,其效能是SAHA的三到四倍。此外其亦可藉由抑制癌細胞在生物體內的生長,而不影響到身體體重、器官及血液的狀態。另外新設計出的化合物對乳癌細胞也有抑制的活性。 N-hydroxy p-(acylamido)benzamide (HAAC) 是組蛋白去乙醯酶抑制劑,其可藉由控制賴胺酸N-端的去乙醯反應,造成含有腫瘤抑制基因之染色體位點的染色質濃縮及轉錄失活。在HDAC抑制劑的概念設計方面,我們以速配化學合成Dendron化合物,並藉由硫酯官能基將之接合在螢光CdSe/ZnS量子點上。螢光HDACI-CdSe/ZnS結合物可抑制A549肺癌細胞的生長。此外我們也利用共軛焦顯微圖像證明出此結合物會被傳遞至肺癌細胞核內。 在催化方面,我們將本實驗室所開發出的氧釩金屬錯合物藉由速配化學將之固定在疊氮聚苯乙烯的聚合物上(PSS),並成功將此聚苯乙烯聚合物的錯合物應用在-羥基酯類衍生物的不對稱催化空氣型氧化反應上面;且其鏡像超越值可高達99%,影響因子為41。值得一提的是此高分子類型催化劑可以藉由過濾的方式將之回收再利用。 最後我們利用Na-鉗合的C4-對稱四聚簇狀體來進行增效式的汞離子篩選。在含有十種大小接近之金屬離子水溶液中,可選擇性地辨識出汞離子並將它篩選出來。此外,所生成的Hg2+-鉗合的C4-對稱四聚簇狀體與硫酸鈉進行離子交換後,亦可再還原成Na+-鉗合的C4-對稱四聚簇狀體,並可繼續作為汞離子的特殊篩選傳送與回收。
We have developed short protocol for the preparation of compounds having histone deacetylase inhibition activities, as shown in chapter 1. Among these compounds, OSU-HDAC-44, displayed promising antitumor activities in non small lung cancer cell (NSCLC) and xenograft models. This compound not only repressed cell viability but also induced apoptosis in various NSCLC cell lines with 3-4 times greater potency than SAHA (known anticancer drug). In addition, submicromolar concentration of OSU-HDAC-44 exhibited prominently synergistic effects in combination with cisplatin on suppressing proliferation of NSCLC cell lines. Furthermore, it induced cell apoptosis and thereby inhibited tumor growth in vivo without adversely affected body weight, major organs and hematological parameters. Collectively, these results suggested that OSU-HDAC-44 is a promising HDAC inhibitor for NSCLC treatment. Additionally, we have also prepared two novel compounds for HDAC inhibition. Among these two molecules, one bearing tans-cyclopropyl moiety exhibited promising activities towards lung and breast cancer cells. N-hydroxy p-(acylamido)benzamide (HAAC) is a histone deacetylase (HDAC) inhibitor, which regulates deacetylation of the N-terminal group of lysine in histone, leading to chromatin compaction and transcriptional inactivation of chromosomal loci containing tumor suppressor genes. A new tri-antennary, N-hydroxy-p-(Acylamido) benzamide (HAAC) capped gallamide anchor with thiolate focal group is synthesized via click chemistry. The resulted highly hydrophilic dendron was efficiently anchored onto the surface of CdSe/ZnS core/shell nanoparticles in a covalent fashion, as evidenced by 1H NMR spectrum of the resultant nanohybrid with intact core fluorescent property. The water-miscible nanohybrid which bears peripheral HAAC as the HDAC inhibitor was found smoothly uptaken by lung cancer cells and translocated inside cell nucleus in 2-3 hours, as evidenced by confocal microscopic analysis. In addition, Nano-HAAC displayed promising activities towards A549 and H1299 lung cancer cell lines. Nanohybrid-HAAC at 20 nM induced cell cycle arrest at G2/M and eventually led to apoptotic cell death of lung cancer cell lines, demonstrating that nanohybrid-HAAC is much more potent in inhibiting lung cancer cell growth than parental HTPB. In addition, nanohybrid-HAAC was more effective than the parental HTPB to increase the acetylation of histone proteins and non-histone proteins. Our results provided the compelling evidences that encapsulation of quantum dots with triantennary dendritic HDAC inhibitors represent a feasible and novel strategy for drug delivery preserving the biological effects of drug. In chapter 3, we have documented the first successful synthesis of heterogeneous chiral vanadium complexes through direct immobilization of C5-propargyl ether modified, chiral N-Salicylidine oxidovanadium tert-leucinates onto 4-azidomethyl-substituted polystyrene by click chemistry. This protocol offers promising alternative to synthesize polymer bound catalyst which is prepared by immobilization of ligands followed by metallation. The grafting occurred cleanly, under mild conditions, affording heterogeneous chiral vanadium (V) catalysts with excellent vanadium loadings. The resulting polystyrene-supported (PSS) catalysts were then successfully used in asymmetric, aerobic oxidation of α-hydroxy carboxylic acid derivatives with excellent enantioselectivities (up to 99% ee, krel up to 41). In addition, practical scale synthesis of optically pure, mandelic acid derivatives can be made with only 3 mol% loading of PSS catalyst in CHCl3.These PSS catalysts can be readily recovered by filtration and reused for at least four consecutive runs without discernible loss of reactivity and enantioselectivity. In chapter 4, we have demonstrated a unique green protocol forhighly sensitive and specific Hg(II) recognition and transport from an aqueous solution containing ten different M+ and M2+ of similar size by utilizing two tailor-made, C4-symmetric Na+-bound tetramers based on simple chiral oxidovanadium(V) methoxide complexes. Exclusive swapping of Na+ by Hg2+ in these tetramers can be achieved readily in reasonable time scale with discernible δ changes of their 51V signals by 5 ppm and Δε change of their CD-ORD spectra by 8-49% at 267-272 and 400-417 nm. The structural identify was subsequently confirmed by X-ray crystallographic analysis. Furthermore, the original Na+-bound cluster can be regenerated by simply treating the corresponding Hg2+ Cluster in CDCl3 with a saturated, aqueous solution of Na2SO4 in 5 min. Reusability and sustainability of the sodium clusters make the newly developed system unique and highly desirable for the Hg2+-specific recovery and storage as HgSO4. Our experimental findings offer new and tailor-made opportunity for rapid, easy, and economical diagnosis and removal of toxic metal ions from highly contaminated environmental sewage.
URI: http://etds.lib.ntnu.edu.tw/cgi-bin/gs32/gsweb.cgi?o=dstdcdr&s=%22http://etds.lib.ntnu.edu.tw/cgi-bin/gs32/gsweb.cgi?o=dstdcdr&s=id=%22GN0894420094%22.&%22.id.&
http://rportal.lib.ntnu.edu.tw:80/handle/20.500.12235/101042
Other Identifiers: GN0894420094
Appears in Collections:學位論文

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