Diversity-oriented Synthesis And Biological Activity Of Natural Product-like Heterocyclic Libraries

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 derivativesIn 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 derivativesIn 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 derivativesIn 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 pyridoneIn 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...