發(fā)布時(shí)間：2018-03-30 00:32

  本文選題：2-吡啶酮衍生物　切入點(diǎn)：抗胰腺癌　出處：《南京大學(xué)》2014年碩士論文

【摘要】：胰腺癌是一種惡性程度極高的腫瘤,在全球每年導(dǎo)致超過22萬人死亡。胰腺癌缺乏特異性癥狀,早期發(fā)現(xiàn)十分困難。由于病情發(fā)展速度快,死亡率極高,胰腺癌患者的中位生存期不超過6個(gè)月,而5年以上生存率僅為3%,因此胰腺癌是整個(gè)醫(yī)學(xué)界已知的預(yù)后判斷最差的惡性腫瘤之一。目前,對于胰腺癌尚無有效的治療措施,手術(shù)切除仍然是唯一有效的治療手段,但僅15-20%的胰腺癌患者可以接受根治性切除手術(shù),并且術(shù)后容易復(fù)發(fā)和轉(zhuǎn)移。放療和化療是胰腺癌治療中重要的輔助手段,對于改善病人生存質(zhì)量、延長生存時(shí)間有一定作用。吉西他濱是用于胰腺癌化療的主要藥物,但由于胰腺癌的耐藥性,該藥的總體有效率不足20%,因此亟需找到能夠有效抑制胰腺癌的藥物。為了尋找一種具有對胰腺癌細(xì)胞選擇性抑制作用的先導(dǎo)化合物,本文采用全新的方法合成了一系列多取代2-吡啶酮類衍生物。采用MTT法,對所合成化合物在有營養(yǎng)條件和乏營養(yǎng)條件下對于胰腺癌細(xì)胞PANC-1的抑制作用進(jìn)行了評價(jià)。一、多取代2-吡啶酮類衍生物的合成前期工作中,在研究多環(huán)異戊烯化�；g苯三酚(PPAPs)類衍生物時(shí),我們發(fā)現(xiàn)雙環(huán)[3.3.1]壬酮(7a)在對甲苯磺酸存在下與正丙醇胺經(jīng)過重排反應(yīng),可以簡單高效地制備具有全新骨架結(jié)構(gòu)的多取代2-吡啶酮。在此基礎(chǔ)上進(jìn)行了條件優(yōu)化,即：以水合對甲苯磺酸作催化劑(0.3當(dāng)量),甲苯作溶劑,115℃下回流分水反應(yīng)12小時(shí),產(chǎn)率55-60%。利用該方法以1,3-環(huán)己二酮為原料,經(jīng)過7步反應(yīng)合成了含異戊烯基/香葉基的多取代2-吡啶酮母核化合物8/9,并以此為原料對4位上羥基進(jìn)行結(jié)構(gòu)修飾,設(shè)計(jì)合成了35個(gè)2-吡啶酮醚類衍生物。二、多取代2-吡啶酮類衍生物的抗胰腺癌活性研究采用MTT法,分別在有營養(yǎng)條件和乏營養(yǎng)條件下,評價(jià)了所合成的化合物對于胰腺癌細(xì)胞PANC-1的抑制率,并對該類化合物選擇性抑制作用的構(gòu)效關(guān)系進(jìn)行了初步討論。結(jié)果表明：在有營養(yǎng)條件下,絕大多數(shù)化合物對PANC-1細(xì)胞的抑制率非常低；乏營養(yǎng)條件下,異戊烯基系列化合物的取代基種類對于抑制率有較大影響,其中化合物8b的抑制率達(dá)到75%,高于陽性藥牛蒡子苷元,而香葉基系列化合物的取代基種類對于抑制率影響不大；總體上香葉基系列在乏營養(yǎng)條件下的抑制率略高于異戊烯基系列,而二者在有營養(yǎng)條件下的細(xì)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在乏營養(yǎng)條件下對PANC-1細(xì)胞的抑制率最高,分別為75.0%、73.6%、73.6%,并且在有營養(yǎng)條件下的細(xì)胞存活率都在80%以上。綜上所述,全文共合成了37個(gè)目標(biāo)產(chǎn)物,其中化合物8b、8c、9m對于胰腺癌細(xì)胞PANC-1具有很好的選擇抑制活性,可能成為潛在的具有抗胰腺癌作用的先導(dǎo)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，

本文編號：1683589