类天然杂环化合物的多样性导向合成及其生物活性研究
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摘要
天然药物分子广泛存在于自然界,具有抗菌、抗肿瘤等多种药物活性,在药物研究中具有举足轻重的作用。以天然药物分子为导向,运用多样性导向合成策略,引入有机合成中绿色合成、手性合成等方法,设计具有潜在生物活性并常见于天然药物分子的具有分子多样性的类天然杂环化合物库,对其进行生物活性研究,是寻找优良先导化合物和候选药物分子的重要途径。
本文采用廉价易得的原料,以简洁高效、环境友好的合成方法设计合成了五类类天然杂环化合物,较系统地研究了它们的生物活性。其中活性研究涉及抗菌、抗肿瘤、荧光及药物安全性评价等方面。这对研究开发拥有自主知识产权的类天然杂环药物具有重要意义。
论文共分为六章：
第一章主要对几类常见于天然产物中并具有优良生物活性的分子及其生物活性(抗肿瘤、抗菌等)研究进展进行综述。介绍了多样性导向合成方法在药物研发中的作用及采用的重要合成子。
第二章研究多卤代吖啶酮类杂环化合物的制备与性质。探讨化合物对氢离子的荧光识别性能,结果显示化合物4a具有较好的pH荧光探针性能。抗肿瘤活性筛选显示其具有抗肿瘤活性,其中化合物4d、4o、5j、5k具有体外细胞抗肿瘤选择性(Scheme 1)。Scheme 1多卤代吖啶酮类化合物简洁制备及荧光、抗肿瘤活性
第三章设计合成了两类多卤代间苯二甲腈类衍生物,并对其进行抗菌、抗肿瘤活性测试。结果显示化合物3.4对革兰氏阳性菌和真菌具有较好的抑制作用,其中化合物3j的MIC值达0.4-0.5μg/mL,具有与抗菌药诺氟沙星和氟康唑相当的活性；化合物8对HL60等多种肿瘤细胞株显现较强的细胞毒活性,其中化合物8o的IC50值达0.02-3.7μg/mL,活性接近或者超过抗肿瘤药顺铂(Scheme 2)。Scheme 2多卤代间苯二甲腈衍生物简洁友好制备方法及抗菌抗肿瘤活性
第四章对简洁高效、环境友好的“无溶剂一锅法”制备的新型异喹啉酮/亚胺类化合物库进行了较系统的抗菌、抗肿瘤活性及急性毒性试验。经抗菌活性初筛发现该类化合物未表现体外抑菌活性,而大多数化合物均具有优良的体外抗肿瘤细胞毒活性。其中化合物5c的IC50值达0.005-3.4μg/ML,活性超过抗肿瘤药顺铂；化合物8j的IC50值达8.96-48.04μg/mL,代表化合物5c、6c和6h对小鼠肿瘤S180和H22显现体内抑制生长活性,而化合物6c和6h表现较低的急性毒性(Scheme 3)。Scheme 3多卤代异喹啉酮/亚胺一锅法平行制备及体内体外抗肿瘤活性
第五章发展了一种手性Evans助剂控制的手性双环吡啶酮立体选择性合成的新方法,该方法具有简洁高效、对映选择性高的特点,ee值高达83.7%-99.1%(Scheme 4)。Scheme 4 Evans手性助剂控制的手性双环吡啶酮选择性合成
第六章探索了以葡萄糖为原料制备具有两个固有手性中心侧链的嘧啶类化合物的方法,提出了该方法的反应过程模型(Scheme 5)。Scheme 5以葡萄糖为原料制备具有两个固有手性中心侧链的嘧啶化合物
Natural drug molecules are commonly found in nature, exhibit various biological and medicinal activities, including antibacterial, antitumour, and so on. Natural drugs research has a decisive function in drug discovery. This dissertation conducts research on natural drug molecules. The product-like heterocyclic molecules were designed and synthesed based on the excellent bioactive molecules skeleton which commonly in natural products. Diversity-Oriented Synthesis strategy and modern synthetic methods were applied such as the green chemistry, chiral synthesis, and so on. The physicochemical and biological characters of the highly functional natural product-like heterocyclic molecules libraries were evaluated. And thus, it is an important way to find lead compound and drug candidate.
Five types of natural product-like heterocyclic libraries were been designed and synthesed by cheap and easily available raw materials, green and brief chemical process. Meanwhile, biological actives were evaluated. The biological assessment refers to antibacterial, the in vitro and in vivo antitumour activities, fluorescence activity, drug safety evaluation, and so on. Consequently, this concise process presented herein has great potential to be applied to parallel synthesis and biological studies in drug discovery.
This dissertation is composed of six chapters.
In Chapters 1, a review of several excellent bioactive molecules which commonly in natural products molecules and their biological activity research progress (such as antitumor, antibacterial, etc.) were presented. Diversity-Oriented Synthesis strategy and the adopted synthons were described.
In Chapters 2, the preparation and characterization of polyhalo acridone was researched. The pH-sensitive fluorescence probe results show that compound 4a have good pH fluorescence probes properties. These compounds showed stronger cytotoxicity, and compounds 4d,4o,5j,5k have anti-tumor selectivity (Scheme 1). Scheme 1 Synthesis and fluorescence, antibacterial, antitumor activities of polyhalo acridone derivatives
In Chapters 3, two kinds of polyhalo isophthalonitrile derivatives were designed and synthesized, their bioactivities were screened. Compounds 3,4 showed stronger inhibition of gram-positive bacteria and fungi growth, and the antimicrobial ability of compound 3j was close to nofloxacin and fluconazole (MIC 0.4-0.5μg/mL). Compounds 8 showed stronger cytotoxicity against HL60 etc. cells, and the cytotoxicity of compound 8o approached or surpassed cisplatin (IC50 0.02-3.7μg/mL) (Scheme 2). Scheme 2 Synthesis and antibacterial, antitumor activities of polyhalo isophthalonitrile derivatives
In Chapters 4, the antibacterial, in vitro and in vivo antitumour activities of isoquinolin-1(2H)-one derivatives which prepared under solvent-free one-pot conditions and their acute toxicity were evaluated. The antibacterial was not found through preliminary screening. But the majority of compounds displayed superiorcytotoxicity compared to cisplatin. Compound 5c was found to be the most potent against the human tumor cell lines (IC50 0.005-3.4μg/mL), being 25-2000-fold more active than cisplatin except against the A431 and HepG2 cell lines. Compound 8j also showed good cytotoxic activity (IC50 8.96-48.04μg/mL). The representative compounds 5c,6c and 6h were also performed in mice bearing S180 go and H22 tumours. The results indicated that these three compounds inhibit S180 and H22 growth. In addition, compounds 6c and 6h have very low acute toxicities (Scheme 3). Scheme 3 Synthesis and in vitro and in vivo antitumour activity of isoquinolin-1(2H)-one derivatives
In Chapters 5, a succinct, efficient, high enantioselectivity process for stereoselective synthesis of bicyclic pyridone derivatives by chiral Evans auxiliary controlled were developed. The enantiomeric excess ratio reach 83.7%-99.1% (Scheme 4). Scheme 4 Synthesis of chiral bicyclic pyridone
In Chapters 6, a procedure for synthesis of chiral pyrimidine analogues was developed. The reaction process model of the methods was put forward (Scheme 5). Scheme 5 Synthesis of chiral pyrimidine analogues
本文采用廉价易得的原料,以简洁高效、环境友好的合成方法设计合成了五类类天然杂环化合物,较系统地研究了它们的生物活性。其中活性研究涉及抗菌、抗肿瘤、荧光及药物安全性评价等方面。这对研究开发拥有自主知识产权的类天然杂环药物具有重要意义。
论文共分为六章：
第一章主要对几类常见于天然产物中并具有优良生物活性的分子及其生物活性(抗肿瘤、抗菌等)研究进展进行综述。介绍了多样性导向合成方法在药物研发中的作用及采用的重要合成子。
第二章研究多卤代吖啶酮类杂环化合物的制备与性质。探讨化合物对氢离子的荧光识别性能,结果显示化合物4a具有较好的pH荧光探针性能。抗肿瘤活性筛选显示其具有抗肿瘤活性,其中化合物4d、4o、5j、5k具有体外细胞抗肿瘤选择性(Scheme 1)。Scheme 1多卤代吖啶酮类化合物简洁制备及荧光、抗肿瘤活性
第三章设计合成了两类多卤代间苯二甲腈类衍生物,并对其进行抗菌、抗肿瘤活性测试。结果显示化合物3.4对革兰氏阳性菌和真菌具有较好的抑制作用,其中化合物3j的MIC值达0.4-0.5μg/mL,具有与抗菌药诺氟沙星和氟康唑相当的活性；化合物8对HL60等多种肿瘤细胞株显现较强的细胞毒活性,其中化合物8o的IC50值达0.02-3.7μg/mL,活性接近或者超过抗肿瘤药顺铂(Scheme 2)。Scheme 2多卤代间苯二甲腈衍生物简洁友好制备方法及抗菌抗肿瘤活性
第四章对简洁高效、环境友好的“无溶剂一锅法”制备的新型异喹啉酮/亚胺类化合物库进行了较系统的抗菌、抗肿瘤活性及急性毒性试验。经抗菌活性初筛发现该类化合物未表现体外抑菌活性,而大多数化合物均具有优良的体外抗肿瘤细胞毒活性。其中化合物5c的IC50值达0.005-3.4μg/ML,活性超过抗肿瘤药顺铂；化合物8j的IC50值达8.96-48.04μg/mL,代表化合物5c、6c和6h对小鼠肿瘤S180和H22显现体内抑制生长活性,而化合物6c和6h表现较低的急性毒性(Scheme 3)。Scheme 3多卤代异喹啉酮/亚胺一锅法平行制备及体内体外抗肿瘤活性
第五章发展了一种手性Evans助剂控制的手性双环吡啶酮立体选择性合成的新方法,该方法具有简洁高效、对映选择性高的特点,ee值高达83.7%-99.1%(Scheme 4)。Scheme 4 Evans手性助剂控制的手性双环吡啶酮选择性合成
第六章探索了以葡萄糖为原料制备具有两个固有手性中心侧链的嘧啶类化合物的方法,提出了该方法的反应过程模型(Scheme 5)。Scheme 5以葡萄糖为原料制备具有两个固有手性中心侧链的嘧啶化合物
Natural drug molecules are commonly found in nature, exhibit various biological and medicinal activities, including antibacterial, antitumour, and so on. Natural drugs research has a decisive function in drug discovery. This dissertation conducts research on natural drug molecules. The product-like heterocyclic molecules were designed and synthesed based on the excellent bioactive molecules skeleton which commonly in natural products. Diversity-Oriented Synthesis strategy and modern synthetic methods were applied such as the green chemistry, chiral synthesis, and so on. The physicochemical and biological characters of the highly functional natural product-like heterocyclic molecules libraries were evaluated. And thus, it is an important way to find lead compound and drug candidate.
Five types of natural product-like heterocyclic libraries were been designed and synthesed by cheap and easily available raw materials, green and brief chemical process. Meanwhile, biological actives were evaluated. The biological assessment refers to antibacterial, the in vitro and in vivo antitumour activities, fluorescence activity, drug safety evaluation, and so on. Consequently, this concise process presented herein has great potential to be applied to parallel synthesis and biological studies in drug discovery.
This dissertation is composed of six chapters.
In Chapters 1, a review of several excellent bioactive molecules which commonly in natural products molecules and their biological activity research progress (such as antitumor, antibacterial, etc.) were presented. Diversity-Oriented Synthesis strategy and the adopted synthons were described.
In Chapters 2, the preparation and characterization of polyhalo acridone was researched. The pH-sensitive fluorescence probe results show that compound 4a have good pH fluorescence probes properties. These compounds showed stronger cytotoxicity, and compounds 4d,4o,5j,5k have anti-tumor selectivity (Scheme 1). Scheme 1 Synthesis and fluorescence, antibacterial, antitumor activities of polyhalo acridone derivatives
In Chapters 3, two kinds of polyhalo isophthalonitrile derivatives were designed and synthesized, their bioactivities were screened. Compounds 3,4 showed stronger inhibition of gram-positive bacteria and fungi growth, and the antimicrobial ability of compound 3j was close to nofloxacin and fluconazole (MIC 0.4-0.5μg/mL). Compounds 8 showed stronger cytotoxicity against HL60 etc. cells, and the cytotoxicity of compound 8o approached or surpassed cisplatin (IC50 0.02-3.7μg/mL) (Scheme 2). Scheme 2 Synthesis and antibacterial, antitumor activities of polyhalo isophthalonitrile derivatives
In Chapters 4, the antibacterial, in vitro and in vivo antitumour activities of isoquinolin-1(2H)-one derivatives which prepared under solvent-free one-pot conditions and their acute toxicity were evaluated. The antibacterial was not found through preliminary screening. But the majority of compounds displayed superiorcytotoxicity compared to cisplatin. Compound 5c was found to be the most potent against the human tumor cell lines (IC50 0.005-3.4μg/mL), being 25-2000-fold more active than cisplatin except against the A431 and HepG2 cell lines. Compound 8j also showed good cytotoxic activity (IC50 8.96-48.04μg/mL). The representative compounds 5c,6c and 6h were also performed in mice bearing S180 go and H22 tumours. The results indicated that these three compounds inhibit S180 and H22 growth. In addition, compounds 6c and 6h have very low acute toxicities (Scheme 3). Scheme 3 Synthesis and in vitro and in vivo antitumour activity of isoquinolin-1(2H)-one derivatives
In Chapters 5, a succinct, efficient, high enantioselectivity process for stereoselective synthesis of bicyclic pyridone derivatives by chiral Evans auxiliary controlled were developed. The enantiomeric excess ratio reach 83.7%-99.1% (Scheme 4). Scheme 4 Synthesis of chiral bicyclic pyridone
In Chapters 6, a procedure for synthesis of chiral pyrimidine analogues was developed. The reaction process model of the methods was put forward (Scheme 5). Scheme 5 Synthesis of chiral pyrimidine analogues
引文
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