【作者】 吴倩；

【导师】 尹大力； 谢平；

【作者基本信息】 北京协和医学院 ， 药物化学， 2012， 博士

【摘要】 新型抗肾衰药物的设计与合成慢性肾衰竭(CRF)是我国最为常见的难治性疾病之一。目前,透析治疗是治疗CRF的有效手段,但其依赖透析机器的医疗条件,且存在着心血管并发症高、顺应性差和经济负担重等问题,在我国的应用仍十分有限。因此,新型抗肾衰药物的研制和开发显得尤为重要。XLF-343为我所自主研发的治疗肾衰的一类新药,目前已经完成I期临床实验,由于其具有溶解性较差、生物利用度较低的缺点,因此我们以该香豆素类化合物为先导物进行结构改造,设计并合成了28个目标化合物,经核磁共振氢谱和质谱确定了其结构,并对目标化合物的T β RⅡ磷酸化抑制作用以及对顺铂造成的小鼠肾损伤的保护作用筛选,得到了部分化合物的药理活性结果。为今后总结其构效关系,寻找新药提供了有益的参考。吡咯并喹啉类活性天然产物的全合成研究海洋天然产物Ammosamide B,Plakinidine D和Lymphostin为结构独特的吡咯[4,3,2-de]喹啉类生物碱,这类天然产物具有较强的抗肿瘤活性,最近研究发现Ammosamide B对人结肠癌HCT-116细胞具有很强的选择性抑制作用,作用于肌球蛋白；Plakinidine D对人类结肠癌细胞株HCT-116具有细胞毒作用；而Lymphostin在最近研究报道中发现具有潜在的mTOR抑制活性。但这类天然产物结构复杂,骨架上普遍存在多个化学敏感的官能团,因而合成困难。本论文根据对上述天然产物的逆合成分析,尝试用价廉易得原料1,5-二氟-2,4-二硝基苯,经中间体4,6-二硝基-1,3-苯二胺的芳环亲电环合反应,探索这类天然产物基本骨架的高效、快捷的合成方法。本论文主要完成了以下工作：1)以1,5-二氟-2,4-二硝基苯为起始原料通过5步反应成功完成了天然产物Ammosamide B的全合成,总收率为9.7%,其中关键反应为4,6-二硝基-1,3-苯二胺与α-酮戊二酸二甲酯在三氟乙酸条件下经一步反应成功构建吡咯环和喹啉环,大大缩减了反应步骤,实现了吡咯[4,3,2-de]喹啉骨架结构的高效、快捷的合成,目标化合物的1H-NMR, i3C-NMR, HRESI-MS谱与文献报道的天然产物一致；2)以1,5-二氟-2,4-二硝基苯和吲哚醌为原料,参考Ammosamide B吡咯并喹啉骨架合成方法,经一步反应合成了Plakinidine D的基本骨架,后经PMB保护、环合等7步反应,得到了天然产物Plakinidine D的中间体。3)在Ammosamide B全合成基础上尝试了Lymphostin的全合成研究,为该类化合物的后续研究工作奠定了基础。合成目标化合物以及中间体均已送药理活性筛选,本论文研究工作为今后开展吡咯[4,3,2-de]喹啉类生物碱的合成以及结构与活性关系研究奠定了基础。更多还原

【Abstract】 Chronic renal failure (CRF) is one of the most common refractory disease in our country. At present, kidney dialysis is an effective method of treating kidney failure, but its application is limited because of the cardiovascular complications and heavy economic burden. As a result, it is particularly important to find new drugs. XLF-343was first studied as a new drug for renal failure by us. But its poor solubility spured us to designe and synthesize28new compounds based on the lead compound XLF-343. All of the compounds have been determined by1H-NMR and LC-MS. In addition, the derivatives were tested for anti-renal activity and some compounds demonstrated inhibitory activity to renal failure. All of these researches have great value for summarizing the structure-activity relationship in order to find new drug of good activity and high bioavailability in treating chronic renal failure. Marine natural products Ammosamide B, Plakinidine D and Lymphostin are structurally unique pyrrolo[4,3,2-de]quinoline akaloids which exhibit excellent antitumor activities. Wherein the myosin targeted Ammosamide B exhibited significant in vitro cytotoxicity against human colon adenocarcinoma HCT-116cells; Plakinidine D was reported to have potent in vitro cytotoxicity against the human colon tumor cell line HCT-116, and recently Lymphostin was found to exhibite potent mTOR inhibitory activity. Nevertheless, the synthesis of the three compounds remained synthetically challenging as all of them share the same complicating structure skeleton and densely pack arrays of chemically sensitive functional groups. In this thesis, based on retrosynthetic analysis of the core structure of the natural products, we have studied a novel and efficient synthesis method in construction of pyrrolo[4,3,2-de]quinoline framework through the intramolecular electrophilic cyclization from commercially available1,5-difluoro-2,4-dinitrobenzene.This dissertation finished the following work:1) We have successfully accomplished the total synthesis of Ammosamide B in only5steps albeit in moderate overall yield (9.7%). The key step of the route involves the condensation of1,3-diamine-4,6-dinitrobenzene derivative with dimethyl2-ketoglutaconate, which effectively constructs the pyrrolidinone ring and the quinoline ring in a single step. This study proved novel method for rapidly and efficient synthesis of pyrroloquinoline alkaloids and their analogues.2) Based on the similar consideration, we have studied the total synthesis of Plakinidine D, and constructed the core of this natural product via intramolecular electrophilic cyclization reaction by using1,5-difluoro-2,4-dinitrobenzene and isatin as the starting material, and successfully synthesized the analogue of Plakinidine D in seven steps.3) Besides we have tried the total synthesis of Lymphostin which laid foundation for further study.4) The primary cytotoxicity of the compounds have been tested.This essay would allow access to the preparation of a variety of structural analogues for investigation of pharmacological structure-activity relationships.更多还原