【作者】 韩超；

【导师】 陶京朝；

【作者基本信息】 郑州大学 ， 有机化学， 2014， 博士

【摘要】 吡咯烷-2,4-二酮(特氨酸,Tetramic acid)及其衍生物普遍存在于许多天然产物中,大多数从天然产物中分离出来的特氨酸衍生物都有很好的生物活性,如抗菌,抗肿瘤,抗病毒等,某些特氨酸衍生的生物活性分子已进入临床研究阶段。鉴于特氨酸五元杂环上有多个活性反应位点,基于该结构单元的天然产物修饰,结构改造以及构效关系等方面的研究,成为当前新药开发的研究热点。多组分反应策略由于其连续、简便、高效的优点,特别是可以快速、大量地合成具有结构多样性和复杂性的化合物,用于优化和筛选具有药理活性苗头的先导化合物,引起了化学和药学工作者的极大兴趣。本论文以特氨酸为反应底物,采用“一锅”多组分反应的合成策略,设计合成了四个系列共126种可能具有潜在生物活性,含有毗咯-2-酮结构单元的吲哚螺吡喃、吲哚螺二氢吡啶、苯二氮卓和取代吡唑类化合物。通过IR、NMR、HRMS和／或X-射线晶体结构测定表征了新化合物的结构,并考察了其中部分化合物的生物活性,探讨了构效关系。研究主要包括以下几部分内容：第一部分在无催化剂条件下,以特氨酸衍生物、取代靛红和丙二腈为底物,采用“一锅”多组分反应策略,简便、高效地合成了24种未见于文献报道的新型吲哚-螺-吡喃并吡咯类杂环衍生物。首次以N-(S)-苯乙基特氨酸为原料,通过“一锅”三组分反应和柱层析分离方法,实现了含手性季碳中心的新型吲哚螺吡喃类化合物非对映选择性合成和非对映异构体的分离。评价了所合成杂环化合物对Raji细胞的体外抗肿瘤活性,发现大部分化合物表现出较好的抑制活性。特别是当吲哚环上的6-位被溴取代时活性最好(IC50=17.56μM),与阳性对照物顺铂的抑制活性相当。第二部分开发了一种以取代靛红,特氨酸衍生物,取代苯胺和丙二腈作为反应底物,DMAP催化的“一锅”四组分反应新方法,成功合成了28个未见于文献报道的新型吲哚-螺-二氢吡啶并吡咯类杂环化合物。与传统的三组分反应方法相比,本工作开发的“一锅”四组分反应原料简单易得,不需要预合成中间体烯胺,从而使操作简单,提高了反应效率。而且该四组分反应条件温和,使用50%乙醇水溶液做溶剂,降低了对环境的污染。第三部分以3-乙酰基特氨酸衍生物为原料,通过缩合环化反应,合成了28种未见报道的新型吡咯烷酮并吡唑化合物。通过琼脂糖凝胶电泳法,初步研究了部分吡唑衍生物与金属离子的配合物对质粒DNA(pUC19)的切割活性,优化了切割条件,发现当配体的吡唑环上无取代基时,对DNA切割活性最好。评价了部分化合物的体外抗BVDV病毒活性,结果表明,部分化合物表现出对BVDV病毒的较好的抑制活性,其中化合物4f的活性最好(EC50=0.12μM)。第四部分通过特氨酸,芳香醛和邻苯二胺的“一锅”三组分反应,在温和条件下,成功合成了26种未见于文献报道的毗咯并1,5-苯并二氮杂卓衍生物,经IR, NMR, HRMS表征了新化合物的结构。实现了由廉价易得的原料,简便、快速、洁净地合成结构复杂的苯并二氮卓类化合物的绿色合成。评价了18种所合成的毗咯并苯二氮杂卓类化合物的抗BVDV病毒活性。发现当卓环上取代苯基上的取代基为强给电子取代基(OMe或NMe2)时,相应化合物表现出很好的抗BVDV病毒活性。特别是当吡咯环的5-位被苄基取代,并且卓环上苯基的对位是二甲胺基时活性最好(131, EC50=0.12优于阳性对照物利巴韦林的活性(Ribavirin, EC50=1.30μM)。第五部分以手性5-取代-(S)-特氨酸、靛红和丙二腈或者氰乙酸乙酯为底物,通过水相三组分“一锅”法反应,在无催化剂条件下,非对映选择性合成了20种新型吲哚螺毗喃类化合物。通过IR,二维NMR和HRMS基本确定了两个非对映异构体的绝对构型,研究了不同的取代基对产物立体选择性的影响。更多还原

【Abstract】 Tetramic acid (2,4-pyrrolidinedione) and its derivatives have been found to be a key substructure in many natural products. The naturally occurring tetramic acids have attracted a great deal of interest. The majority of the tetramic acid derivatives to date exhibit good biological activity, such as antibiotic, antineoplastic, anti-tumor, and antiviral activity. The multi reactive center containing structure of tetramic acid has caused researchers to study a large number of total synthesis, structural modification and structure-activity relationship.Multicomponent reactions (MCRs) is the ’one-pot’ method for the synthesis of compounds by taking more than three substrates into a reactor without separating intermediate products. The strategies of MCRs offer significant advantages over conventional linear-type syntheses for their high degree of atom economy, ease of execution, and broad applications characters, which are particularly useful to generate diverse chemical libraries of’drug like’ molecules for biological screening.In this dissertation, much attention has been focused on the MCRs in the synthesis of pyrrolidinone-containing spirooxindole heterocycles, including 1,4-dihydropyridine derivatives and 4H-pyran derivatives, pyrrolidinone fused benzodiazepine derivatives and parazole fused pyrrolidinone derivatives. All the new compounds synthesized were characterized by IR, NMR, HRMS, as well as X-ray single crystal diffraction. The biological activities of some of the synthesized compounds and structure-activity relationship were evaluated. The whole work is mainly composed of the following five parts:Part Ⅰ:A simple and efficient ’one-pot’ three-component reaction for assembling novel spirooxindole 4H-pyran derivatives was developed and used to prepare a series of biologically important compounds. We attempted a ’one-pot’ reaction of tetramic acid, isatin, and malononitrile without any catalysts. The cytotoxic activities of these new pyrans derivatives were evaluated in vitro. Most of the tested compounds exhibited significant cytotoxicities to Raji cell lines.Part Ⅱ:A series of novel spirooxindole 1,4-dihydropyridine compounds were synthesized via’one-pot’ four-component reactions of substituted aniline, tetramic acid, isatin, and malononitrile. The reaction could be easily performed in aqueous ethanol with 4-DMAP as catalyst. Particularly valuable features of this method include environmentally benign character, high yields processing and straightforward procedure. Plausible mechanism of the reaction is also presented.Part Ⅲ:A series of novel pyrazole fused heterocyclic derivatives were synthesized and their catalytic DNA cleavage abilities and anti-BVDV activities were also evaluated. The interaction of plasmid pUC19 DNA with ligands in the presence of Cu2+ complexes respectively was monitored by Agarose gel electrophoresis and UV-Visible spectroscopy. The studies on anti-viral activities against bovine viral diarrhea virus (BVDV) demonstrated that some of the pyrazole derivatives showed pronounced anti-BVDV activity.Part IV:An efficient and clean three-component ’one-pot’ reaction was developed for the convenient and cheap synthesis of benzodiazepine derivatives. Both sets of reaction were conducted in the presence of acetic acid catalyst in ethanol. The present new synthesis method shows attractive green chemistry characteristics, such as concise’one-pot’conditions, easy work-up/purification. The studies on anti-viral activities against bovine viral diarrhea virus (BVDV) demonstrated that some of the benzodiazepine derivatives showed pronounced anti-BVDV activity.Part V:A fast and convenient protocol for the diasteroselective synthesis of novel spirooxindoles 4H-pyran derivatives was developed by the three-component reactions of isatin, malononitrile or ethyl cyanoacetate, and chiral 5-substituted tetramic acid in water in absence of catalyst. The present new synthesis shows attractive green chemistry characteristics, such as the use of water as reaction media, short reaction periods, easy work-up/purification, and reduced waste production. At the same time, the effects of different substituents on the diastereoselectivity and the isolation of the two diasteromers were also studied.更多还原