【摘要】：多環(huán)吡啶、多環(huán)吲哚等天然雜環(huán)化合物具有優(yōu)良的抗菌、抗腫瘤、抗HIV等生物活性。以天然藥物分子為先導(dǎo),采用多樣性導(dǎo)向合成策略,簡捷高效地設(shè)計合成具有分子多樣性的類天然雜環(huán)化合物并進行生物活性研究,對研究開發(fā)自主知識產(chǎn)權(quán)的藥物具有重要意義。 本文以雜環(huán)烯酮縮胺及硝基葡烯糖為主要合成砌塊,設(shè)計合成三大類共十二類類天然雜環(huán)化合物,總計353個化合物。對部分化合物進行了抗菌、抗腫瘤、熒光及細胞成像等生物活性的研究。 一、多環(huán)毗啶類化合物的合成及性質(zhì) 茚并喹啉類化合物：通過串聯(lián)反應(yīng)一步法合成分子多樣性多環(huán)茚并喹啉化合物。產(chǎn)物經(jīng)體外抗瘤活性篩選,其中10c和10r具有較好細胞毒活性(Scheme1)。 多環(huán)咕噸酮及雙環(huán)吡啶類化合物：構(gòu)建多環(huán)咕噸酮化合物庫及雙環(huán)吡啶化合物庫并對其進行熒光光譜性質(zhì)及細胞成像的研究。部分化合物具有較好的pH熒光探針性能及較好的生物相容性和細胞穿透性(Scheme2)。 吡啶并香豆素類化合物：構(gòu)建吡啶并香豆素化合物庫(Scheme3)。咪唑并吡啶類化合物：構(gòu)建了咪唑并吡啶類化合物庫(Scheme4)。 嘧啶/苯并二氮雜(?)類化合物：合成手性側(cè)鏈嘧啶/苯并二氮雜(?)類化合物庫(Scheme5)。 二、多環(huán)吲哚類化合物：螺環(huán)吲哚酮化合物和多鹵代吲哚化合物的合成 螺環(huán)吲哚酮化合物：高立體/區(qū)域選擇性合成螺環(huán)吲哚酮化合物庫(Scheme6)。 多鹵代吲哚化合物：構(gòu)建了多鹵代吲哚化合物庫(Scheme7)。 三、α-位取代雜環(huán)烯酮縮胺的合成 2-亞磷酸二乙酯基雜環(huán)烯酮縮胺：發(fā)展了一種以Mn(OAc)2/KMnO4復(fù)合催化體系代替Mn(OAc)3合成2-亞磷酸二乙酯基二甲縮硫醚的方法(Scheme8)。 Z構(gòu)型雜環(huán)烯酮縮胺化合物：構(gòu)建了2-吡唑啉酮基雜環(huán)烯酮縮胺化合物庫及2-香豆素基雜環(huán)烯酮縮胺化合物庫(Scheme9)。 2-亞硝基雜環(huán)烯酮縮胺類化合物：發(fā)展了一種新型有機亞硝基化試劑并構(gòu)建了2-亞硝基雜環(huán)烯酮縮胺化合物庫(Scheme10)。
[Abstract]:Polycyclic pyridine, polycyclic indole and other natural heterocyclic compounds have excellent antibacterial, anti-tumor, anti-HIV and other biological activities. Taking the natural drug molecule as the leader and adopting the strategy of diversity oriented synthesis, the natural heterocyclic compounds with molecular diversity were designed and synthesized in a simple and efficient manner and their biological activities were studied. It is of great significance for the research and development of drugs with independent intellectual property rights. In this paper, twelve kinds of natural heterocyclic compounds were designed and synthesized with heterocyclic ketenamine and nitroglutene as main synthetic blocks, with a total of 353 compounds. The biological activities of some compounds such as antibacterial, anti-tumor, fluorescence and cell imaging were studied. Synthesis and properties of first, polycyclic pyridine compounds; Indenoquinoline compounds: synthesis of polycyclic ninhydrin quinoline compounds by a one-step series reaction. The antitumor activity of the product was screened in vitro, of which 10c and 10r had good cytotoxic activity (Scheme1). Polycyclic ton-one and bicyclic pyridine compounds: the polycyclic ton-one library and the bicyclic pyridine compound library were constructed and their fluorescence spectra and cellular imaging were studied. Some of the compounds have better pH fluorescence probe properties, better biocompatibility and cell penetration (Scheme2). Pyridine coumarin compounds: a pyridine coumarin compound library (Scheme3) was constructed. Imidazolidopyridine compounds: a library of imidazolidopyridine compounds (Scheme4) was constructed. Pyrimidine / benzodiazide (?) Synthesis of chiral side chain pyrimidine / benzodiazide (?) Like compound library (Scheme5). Synthesis of polycyclic indole compounds: spirocyclic indole compounds and polyhalogenated indole compounds: high stereoselective synthesis of spirocyclic indole compounds (Scheme6). Polyhalogenated indole compounds: a polyhalogenated indole compound library (Scheme7) was constructed. Synthesis of tri-position substituted heterocyclic ketene amine; diethyl 2-phosphate heterocyclic ketene amine: a method for synthesis of 2-diethyl 2-phosphate diethyl ester dimethyl sulfides by using Mn (OAc) 2/KMnO4 complex catalyst system instead of Mn (OAc) _ 3 has been developed (Scheme8). Z configuration heterocyclic ketene ketenamine compound: 2-pyrazoline keto-heterocyclic ketene condensate compound library and 2-coumarin heterocyclic ketene condensate compound library (Scheme9). Amines: a new organic nitrite reagent was developed and a 2-nitroso-heterocyclic ketene condensate compound library (Scheme10) was constructed.
【學(xué)位授予單位】：云南大學(xué)
【學(xué)位級別】：博士
【學(xué)位授予年份】：2013
【分類號】：O626

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