【作者】 罗阳；

【导师】 何菱；

【作者基本信息】 四川大学 ， 药物化学， 2021， 硕士

【摘要】 氮氧杂螺二烯酮类衍生物的设计、合成及抗肿瘤活性研究螺环结构与单环结构或平面芳香结构相比,拥有更大的空间三维结构。尤其杂螺环结构可借助其生物电子等排体,在一定程度上改变药物分子与靶点的相互作用以及物化性质,如水溶性、log P、代谢稳定性,改善药效、提供优势构象。同时,基于螺环二烯酮骨架构建的多种新型衍生物可用于治疗多种疾病。因此,螺环骨架作为药物分子的核心结构,受到人们的关注。课题组前期工作表明1-氧-4-氮杂螺癸二烯酮衍生物对于肺癌细胞系A549、人乳腺癌细胞MDA-MB-231和宫颈癌细胞系Hela具有较好的抗肿瘤活性,IC₅₀值部分可达到10 nmol·L^-1,但是该系列化合物的作用靶点未知,同时也存在部分化合物水溶性差,毒副作用较大和一些化合物稳定性差等问题。鉴于以上问题,作者对前期研究的骨架进行结构修饰:引入羰基增强水溶性和作用亲和力,对前期骨架分子进行成环修饰,以降低Michael受体的活性,在保留双烯酮结构的前提下,提高化合物的稳定性,降低化合物的毒性。作者共合成22个目标化合物,酰基磺酰胺类螺环化合物对Hela细胞具有较好的抑制活性。急毒实验表明结构修饰后降低了此类化合物的毒性。体内外抗肿瘤实验表明此类化合物可以抑制肿瘤细胞的增殖。细胞凋亡和细胞周期阻滞实验表明,此类化合物可以促进癌细胞的早期凋亡,并对细胞周期S期具有阻滞作用。分子水平靶点测试结果表明此类化合物的作用靶点可能是基质金属蛋白酶。微波促进含氮五元杂环衍生物的合成N-取代-2-吡咯烷酮、N-取代-3-吡唑烷酮和N-取代异吲哚啉-1-酮结构单元是一类重要的模块,广泛存在于药物分子、生物活性分子和功能材料中。作者探索了一种微波促进伯胺与γ-卤素羧酸衍生物一锅合成N-取代γ-丁内酰胺的简便方法,此方法无需溶剂,只需添加适量有机碱（DIPEA）作为附酸剂即可在5-20 min内完成反应,对于亲核性适中的伯胺几乎没有副反应的发生,反应产率高,反应液只需简单的快速柱层析即可达到纯化目的。对于亲核性较弱的芳香伯胺,借助离子液体也可提高反应产率。作者共计合成51个五元含氮杂环化合物,其中N-取代-2-吡咯烷酮衍生物36个,N-取代异吲哚啉-1-酮衍生物11个,N-取代-3-吡唑烷酮衍生物4个。借助微波实现了N-取代-2-吡咯烷酮衍生物、N-取代异吲哚啉-1-酮衍生物和3-吡唑烷酮衍生物三类化合物简单、快速、高产率的合成,底物适用范围广,后处理简单。吡咯烷酮三氟乙氧基化方法学研究从农药,材料科学到药物研究,含氟化合物都具有重要的意义。由于三氟乙氧基具有良好的的代谢稳定性、极高的电负性和优良的亲脂性可以改善药物分子的吸收、分布、代谢和排泄（ADME）性质,探索引入三氟乙氧基的新的方法具有应用价值。然而,目前所报道的方法均基于芳香化合物的三氟乙氧基化,仅一例文献报道脂肪族的预活化的羰基α-位的三氟乙氧基化。作者针对所合成的N-取代2-吡咯烷酮化合物进一步衍生,经一锅两步串联反应实现γ-三氟乙氧基取代的α,β-不饱和-γ-丁内酰胺衍生物的合成。此方法未见文献报道,具有独特的新颖性,为金属催化的α,β-不饱和-γ-丁内酰胺衍生物的γ位三氟乙氧基化研究提供参考。更多还原

【Abstract】 Design,Synthesis and Anti-tumor Activity of Azaspirodienone DerivativesThe spiro structure has a larger three-dimensional structure than single ring structure or a planar aromatic structure.The heterocyclic spiro ring structure is regarded as the bio-isostere of certain groups,which changes the physical and chemical properties of the drug molecule,such as water solubility,log P,and metabolic stability,improving drug efficacy and providing advantageous conformation.The spiro skeleton can also be used as the core structure of drug molecules,and a variety of new derivatives based on the spiro dienone skeleton can be used to treat a variety of diseases.The previous work of our research group showed that1-oxo-4-azaspirodecadienone derivatives have good anti-tumor activity against lung cancer cell A549,human breast cancer cell MDA-MB-231 and cervical cancer cell Hela,The IC₅₀value can reach 10 nmol·L^-1,but the target point of this series of compounds is unknown.At the same time,some compounds have poor water solubility,large toxic and side effects,and poor stability of some chemicals.In view of the above problems,the author modified the structure of the previous study’s skeleton:introducing carbonyl groups to enhance water solubility and interaction affinity,and modifying the previous skeleton molecules to reduce the activity of the Michael acceptor.Improve the stability of the compound and reduce the toxicity of the compound on the premise of retaining the diketene structure.The author synthesized a total of 22 target compounds.The acylsulfonamide spirocyclic compounds have good inhibitory activity on Hela cells.Acute toxicity experiments show that the structural modification reduces the toxicity of these compounds.In vivo and in vitro anti-tumor experiments show that these compounds can inhibit the proliferation of tumor cells.Apoptosis and cell cycle arrest experiments show that these compounds can promote early apoptosis of cancer cells and block the S phase of the cell cycle.The results of molecular target testing indicate that the target of such compounds may be matrix metalloproteinases.Microwave Promotes the Synthesis of Nitrogen-containing Five-membered Heterocyclic DerivativesN-substituted-2-pyrrolidone,N-substituted-3-pyrazolidinone and N-substituted isoindolin-1-one structural units are an important module widely found in drug molecules,biologically active molecules and functional materials.The author explored a microwave-promoted one-pot synthesis of N-substituted lactams with primary amines andγ-halogen carboxylic acid derivatives.This method does not require solvents and only needs to add an appropriate amount of organic base（DIPEA）as an acid attachment.The reaction is completed within 5-20minutes.There are almost no side reactions for primary amines with moderate nucleophilicity,and the reaction yield is high.The reaction solution can be purified by simple flash column chromatography.For aromatic primary amines with weaker nucleophilicity,the reaction yield can also be improved with the involved of ionic liquids.The author synthesized a total of 51 five-membered nitrogen-containing heterocyclic compounds,including 36 N-substituted-2-pyrrolidone derivatives,11 N-substituted isoindolin-1-one derivatives,and N-substituted-3-pyrazolidinones 4 derivatives.The simple,rapid and high-yield synthesis of N-substituted-2-pyrrolidone derivatives,N-substituted isoindolin-1-one derivatives and 3-pyrazolidinone derivatives is achieved by microwave,suitable for a variety of substrates and simple post-processing.Study on the Methodology of Pyrrolidone TrifluoroethoxylationFrom pesticides,materials science to drug research,fluorine-containing compounds are of great significance.Because trifluoroethoxy has good metabolic stability,extremely high electronegativity and excellent lipophilicity,it can improve the absorption,distribution,metabolism and excretion（ADME）properties of drug molecules.Exploring the new method of introducing trifluoroethoxy group has application research value.However,the currently reported methods are all based on the trifluorooxylation of aromatic compounds,and only one case reports the trifluoroethoxylation of aliphatic pre-activated carbonyl groups at theα-position.The author further derives the synthesized N-substituted 2-pyrrolidone compounds and realizes the synthesis ofγ-trifluoroethoxy substitutedα,β-unsaturated-γ-butyrolactam deriva-tives through a one-pot two-step tandem reaction.This method is very novel.It has unique novelty and provides a good reference for the research on the trifluoroethoxylation of theγ-position of the metal-catalyzedα,β-unsaturated-γ-butyrolactam derivatives.更多还原