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|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.
Histone deacetylase inhibitors
Lung and Breast cancer
Fluorescent HDACI-QD Conjugate
Chiral Mandelic acid derivatives
Reusable Chiral Vanadyl complexes
Hg(II)-specific detection and removal
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。
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.
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