多取代2-吡啶酮衍生物的合成及其抗胰腺癌活性研究

发布时间：2018-03-30 00:32

  本文选题：2-吡啶酮衍生物　切入点：抗胰腺癌　出处：《南京大学》2014年硕士论文

【摘要】：胰腺癌是一种恶性程度极高的肿瘤,在全球每年导致超过22万人死亡。胰腺癌缺乏特异性症状,早期发现十分困难。由于病情发展速度快,死亡率极高,胰腺癌患者的中位生存期不超过6个月,而5年以上生存率仅为3%,因此胰腺癌是整个医学界已知的预后判断最差的恶性肿瘤之一。目前,对于胰腺癌尚无有效的治疗措施,手术切除仍然是唯一有效的治疗手段,但仅15-20%的胰腺癌患者可以接受根治性切除手术,并且术后容易复发和转移。放疗和化疗是胰腺癌治疗中重要的辅助手段,对于改善病人生存质量、延长生存时间有一定作用。吉西他滨是用于胰腺癌化疗的主要药物,但由于胰腺癌的耐药性,该药的总体有效率不足20%,因此亟需找到能够有效抑制胰腺癌的药物。为了寻找一种具有对胰腺癌细胞选择性抑制作用的先导化合物,本文采用全新的方法合成了一系列多取代2-吡啶酮类衍生物。采用MTT法,对所合成化合物在有营养条件和乏营养条件下对于胰腺癌细胞PANC-1的抑制作用进行了评价。一、多取代2-吡啶酮类衍生物的合成前期工作中,在研究多环异戊烯化酰化间苯三酚(PPAPs)类衍生物时,我们发现双环[3.3.1]壬酮(7a)在对甲苯磺酸存在下与正丙醇胺经过重排反应,可以简单高效地制备具有全新骨架结构的多取代2-吡啶酮。在此基础上进行了条件优化,即：以水合对甲苯磺酸作催化剂(0.3当量),甲苯作溶剂,115℃下回流分水反应12小时,产率55-60%。利用该方法以1,3-环己二酮为原料,经过7步反应合成了含异戊烯基/香叶基的多取代2-吡啶酮母核化合物8/9,并以此为原料对4位上羟基进行结构修饰,设计合成了35个2-吡啶酮醚类衍生物。二、多取代2-吡啶酮类衍生物的抗胰腺癌活性研究采用MTT法,分别在有营养条件和乏营养条件下,评价了所合成的化合物对于胰腺癌细胞PANC-1的抑制率,并对该类化合物选择性抑制作用的构效关系进行了初步讨论。结果表明：在有营养条件下,绝大多数化合物对PANC-1细胞的抑制率非常低；乏营养条件下,异戊烯基系列化合物的取代基种类对于抑制率有较大影响,其中化合物8b的抑制率达到75%,高于阳性药牛蒡子苷元,而香叶基系列化合物的取代基种类对于抑制率影响不大；总体上香叶基系列在乏营养条件下的抑制率略高于异戊烯基系列,而二者在有营养条件下的细胞的存活率接近。在所有的2-吡啶酮衍生物中,化合物8b、8c、9m在乏营养条件下对PANC-1细胞的抑制率最高,分别为75.0%、73.6%、73.6%,并且在有营养条件下的细胞存活率都在80%以上。综上所述,全文共合成了37个目标产物,其中化合物8b、8c、9m对于胰腺癌细胞PANC-1具有很好的选择抑制活性,可能成为潜在的具有抗胰腺癌作用的先导化合物。
[Abstract]:Pancreatic cancer is a highly malignant tumor that kills more than 220000 people a year worldwide. It lacks specific symptoms and is difficult to detect early. The median survival time of patients with pancreatic cancer is less than 6 months, and the 5-year survival rate is only 3 percent, so pancreatic cancer is one of the worst known malignancies in the medical profession. At present, there is no effective treatment for pancreatic cancer. Surgical resection is still the only effective treatment, but only 15-20% of patients with pancreatic cancer can undergo radical resection and are prone to recurrence and metastasis. Radiotherapy and chemotherapy are important auxiliary methods in the treatment of pancreatic cancer. Gemcitabine is the main drug used in chemotherapy of pancreatic cancer, but because of the drug resistance of pancreatic cancer, The overall effective rate of the drug is less than 20 percent, so there is an urgent need to find a drug that can effectively inhibit pancreatic cancer. In this paper, a series of polysubstituted 2-pyridinone derivatives were synthesized by a new method. The inhibitory effects of the synthesized compounds on PANC-1 of pancreatic cancer cells were evaluated by MTT method. In the early stage of synthesis of polysubstituted 2-pyridinone derivatives, we found that in the presence of p-toluenesulfonic acid, Bicyclic [3.3.1] nonone has been rearranged with n-propanolamine in the presence of p-toluenesulfonic acid in the study of polycyclic isopentenoylated phloroglucinol (PPAPs) derivatives. The polysubstituted 2-pyridinone with a new skeleton structure can be prepared simply and efficiently. On the basis of this, the conditions are optimized, that is, the hydrated p-toluenesulfonic acid is used as the catalyst and the toluene is used as the solvent for reflux and water separation for 12 hours at 115 鈩，

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