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  • 學位論文

(I) 1,3-雙氧環己烷基、1,3-雙硫環己烷基和1,3-氧硫環己烷基核苷及核苷酸類似物之設計與合成 (II) 新穎非典型抗精神病試劑之研發: 具有1,3-雙氧環己烷基或1,3-氧硫環己烷基雙芳香環哌啶類似物之合成及應用

(I) Design and Synthesis of 1,3-Dioxolanyl, 1,3-Dithiolanyl and 1,3-Oxathiolanyl Nucleoside and Nucleotide Analogues (II) Development of Novel Atypical Antipsychotic Agents: Synthesis and Biological Evaluation of 1,3-Dioxolanyl or 1,3-Oxathiolanyl Diarylmethylene-Piperidine Analogues

指導教授 : 劉行讓
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摘要


以具抗病毒潛力化合物BCH-189的骨架為藍本,利用我們已經建立之合成3'-異原子取代基的雙去氧核醣核苷及其核苷酸類似物的嶄新途徑,在循理性合成設計的策略下,一系列的核苷及其核苷酸類似物已順利完成製備,同時所得之部分類似物可進一步經由化學鍵結成為環狀核苷酸類似物,以期能獲得更佳之抗病毒活性。此外經由部分策略上的修飾,上述合成方法亦可用來合成2'-異原子取代基的雙去氧核醣核苷及其核苷酸類似物。一部份含3'-異原子取代基的核苷類似物亦進一步轉換成相對之單磷酸鹽基化合物以探討其抗病毒活性。藉由類似的合成途徑,以抗病毒藥物HPMPA及PMEA之骨架為基礎,一系列成環且具磷酸根之核苷化合物也以成功製得。 截至目前為止,上述所合成之新穎化合物已陸續接受多種抗病毒活性測試。雖然目前尚未發現對某些特定的病毒具高度活性,我們仍將繼續進行其他種類病毒的測試,尤其是對HBV及HIV兩種特定病毒。我們對此兩項病毒的測試抱高度的期望,因為這些化合物原本即為針對此二病毒所設計。除此之外,這些化合物也具有抗血管增生的活性,在這當中又以化合物109效果較佳,其針對血管調控因子的移行及管柱成型都呈現出良好競爭力。 除了製備上述具有潛在療效的化合物外,在以結構為基礎的循理性合成設計下我們也完成了一系列具抗精神病活性的類似物。以雙芳香環哌啶類似物化合物133的骨架為出發點,藉由收斂性的合成策略,具有1,3-雙氧戊環基或1,3-氧硫戊環基的多種類似物已經製備完成,體外活性測試的初步結果顯示這些化合物具有高度的活性。據此我們將進一步研發,期許獲得一新穎之抗精神病藥物。

並列摘要


Starting from the potent antiviral agent BCH-189 and taking a rational structure-based design approach, a series of nucleotide and nucleoside analogues were designed and a novel synthetic protocol amenable towards Structure-Activity Relationship study purposes was established. Using this synthetic process, a series of 3'-heteroatom substituted dideoxynucleosides as well as their corresponding nucleotides were generated. Additionally and with minor modifications, the abovementioned process was amended to allow for the synthesis of 2'-heteroatom substituted dideoxynucleosides and nucleotides, both series of which were also arrived at chemically. Representative members of the 3'-heteroatom containing nucleosides mentioned above were further elaborated to the corresponding mono-phosphonate to investigate a recent hypothesis in antiviral prodrug design. In a similar structure-based approach starting with well known antiviral agents HPMPA and PMEA, cyclic and phosphonate-containing nucleosides were conceptualized, a synthetic route towards their generation delineated, and members thereof arrived at synthetically. Most of the derivatives arrived at in the abovementioned synthetic work were subjected to antiviral potential evaluation against viruses responsible for a wide range of viral indications of significance. Although significant antiviral activity from these cell based assays has yet to emerge, those against HBV and HIV, the two specific targets of this sub-project, are eagerly anticipated. Otherwise each of these derivatives exhibited a unique antiangiogenic profile. In the presence of all, compound 109 showed the better in vitro potency against VEGF migration or tube formation. Apart from the aforementioned work towards the generation of novel and potentially therapeutically useful antiviral agents, a project relying on a rational structure-based design of novel antipsychotic agents was achieved. Starting from diarylmethylene-piperidine derivative 133, a known molecule possessing antipsychotic properties, a series of 1,3-dioxolane and 1,3-oxathiolane containing derivatives were designed and synthesized via a highly convergent synthetic protocol. In vitro assays of these compounds yielded several promising lead structures amenable towards the development of novel antipsychotic therapeutics.

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