【作者】 周福生；

【导师】 闻韧；

【作者基本信息】 复旦大学 ， 药物化学， 2008， 博士

【摘要】 吲哚类和四氢异喹啉类生物碱是自然界广泛存在的天然生物碱,具有抗菌、抗肿瘤和抗病毒作用等广泛的生物活性,从这两大类生物碱中已经发现了许多重要药物。本论文研究吲哚类和四氢异喹啉类衍生物,主要分为两个部分:第一部分主要研究吲哚啉-2-酮衍生物;第二部分主要研究四氢异喹啉类衍生物。论文第一章为寻找新型吲哚啉-2-酮类抗肿瘤药物的先导化合物。以2006年上市的抗肿瘤药物舒尼替尼（sutent）、天然抗肿瘤药物靛玉红和本课题组前期发现具有较好抗肿瘤作用的5-[1-[[5-[（吲哚啉-2-酮-3-烯基）甲基]-呋喃-2-基]甲基]-1,2-二氢-2-氧代-吲哚-3-烯基]甲基]-1H-吡咯甲酸乙酯类化合物作为先导化合物,设计合成了吲哚啉-2-酮类似物105个,其中新化合物81个。首先将苯甲醛和肉桂醛与5位不同取代吲哚啉-2-酮缩合得到3-取代的吲哚啉-2-酮类化合物,进一步在碳酸钾碱性条件下与氯甲基呋喃醛进行1位N烃化得到第一类化合物:3-取代的1-（5-甲酰基糠基）-吲哚啉-2-酮类化合物。其次,将3取代的1-（5-甲酰基糠基）-吲哚醌类化合物与吲哚啉-2-酮以及罗丹宁缩合,并在3-位羰基上引入西弗碱,设计合成了第二类化合物:1-（5-取代糠基）吲哚醌类化合物。最后,以3-呋喃亚甲基吲哚啉-2-酮为结构母核,在呋喃环上引入活性的哌啶环结构,得到第三类化合物:1-[5-[（1,2-二氢-2-氧代-吲哚-3-基）亚甲基]糠基]哌啶衍生物。采用稻瘟霉菌活性抑制实验对所合成的化合物进行抗肿瘤活性的初步筛选,再利用四种肿瘤细胞株模型（Caco-2结肠癌肿瘤株、SPC-A1肺癌肿瘤株、A549肺腺癌肿瘤株和HCT-116人大肠癌肿瘤株）对其体外抗肿瘤活性进行确定。结果显示所合成的化合物对于稻瘟霉菌和肿瘤株均有一定的体外抑制活性。特别是3-取代的1-（5-甲酰基糠基）-吲哚啉-2-酮类化合物普遍对Caco-2结肠癌肿瘤株具有较好的抑制活性,其IC₅₀值大多小于10μM,多数化合物的活性优于阳性药物舒尼替尼,其中有8个化合物的IC₅₀值更是低于1.0μM;而21个1-[5-[（1,2-二氢-2-氧代-吲哚-3-基）亚甲基]糠基]哌啶衍生物对A549肺腺癌肿瘤株也具有比较好的抑制活性,其中有4个化合物的抗肿瘤活性强于舒尼替尼,值得进行进一步深入研究。通过对构效关系进行初步讨论,也为寻找新型的吲哚啉-2-酮类抗肿瘤药物先导化合物打下良好基础。论文第二章为寻找新型四氢异喹啉类抗肿瘤药物的先导化合物。首先对已进入Ⅱ期临床研究的具有抗肿瘤活性的天然异喹啉生物碱noscapine的合成方法进行了较深入的研究。采用2-羟基-3-甲氧基苯甲醛为起始原料通过经氧化、烃化和甲酰化反应制得2-甲氧基-3,4-亚甲二氧基苯甲醛,然后与氨基乙醛缩二甲醇还原胺化制得[N-[2-甲氧基-3,4-（亚甲二氧基）苄基]氨基]乙醛缩二甲醇,经甲基化和环合反应制得5-羟基四氢异喹啉类化合物,再经氧化反应制得关键中间体异喹啉亚胺季铵盐。同时以2,3-二甲氧基苯甲酸为起始原料经环合和溴代反应制得另一个关键中间体3-溴-6,7-二甲氧基苯酞。最后异喹啉亚胺季铵盐与3-溴-6,7-二甲氧基苯酞经还原偶合反应得到α-noscapine。最终产物经核磁共振氢谱和碳谱、质谱确证。此方法总收率为0.5%,其中关键中间体异喹啉亚胺季铵盐的八步总收率达到20%。这也是国内对noscapine合成研究的首次报道。进一步以noscapine作为先导化合物,设计合成了noscapine类似物15个,其中新化合物8个。将cotarnine与不同取代苯酞直接缩合得到noscapine类似物,进一步将其中的氨基衍生物与各种酰氯进行酰化得到noscapine酰胺类化合物。我们还将苯酞或取代苯酞与吲哚衍生物直接进行N上烃化反应得到3-（1-吲哚基）苯酞类衍生物。采用四氮唑盐（MTT）还原法对所合成的化合物的体外抗肿瘤活性进行了初步筛选,测试它们对A549肺腺癌肿瘤株的体外抗肿瘤活性。结果显示所合成的化合物中有4个对于A549肺腺癌肿瘤株有一定的体外抑制活性。特别是含氰基和酰胺的noscapine衍生物具有较好的抑制活性,其IC₅₀值均小于10μM,均优于noscapine,值得进行进一步深入研究。本章对noscapine全合成路线的研究为制备新型的noscapine衍生物奠定了坚实的工作基础,而且本章依据此合成方法制备了15个noscapine衍生物（包括8个新化合物）,同时首次测定了这些衍生物的抗肿瘤活性,这为进一步研究noscapine的具体作用机制以及合理设计合成新型noscapine衍生物也打下了良好的基础。本章的研究结果以及对于构效关系的初步讨论为noscapine抗肿瘤活性的研究提供了新的研究方向,也为寻找新型的四氢异喹啉类抗肿瘤药物先导化合物提供了更为丰富的结构变化空间,具有较好的新颖性。更多还原

【Abstract】 Indole and tetrahydroisoquinoline alkaloids have been shown to be attractive natural products with diverse biological activities,such as antitumoral,antimicrobial and antiviral activities.In particular,a variety of indole and tetrahydroisoquinoline alkaloids have been utilized as antitumor drugs.This thesis focuses on the researches of indole and tetrahydroisoquinoline alkaloids derivatives,and can be divided into two sections,one is the studies on synthesis and biological properties of novel indole derivatives,and the other is the studies on tetrahydroisoquinoline derivatives.In the first chapter,we described the design and synthesis of a series of new indole derivatives and assessment of their antitumor activities.Taking sutent and the 1,3-disubstituted indolin-2-one found by our laboratory as lead compounds,we designed and synthesized three kinds of new indole derivatives:（1） 3-substituted 1-（5-formylfurfuryl）indolin-2-one derivatives;（2） furfurylpiperidine derivatives;（3） bis-indolin-2-one derivatives.The 81 synthesized target compounds were tested in the Pyricularia oryzae inhibition bioassay and the Caco-2,SPC-A1,A549 and HCT-116 cancer strains model in vitro.The results showed that most of the synthesized compounds possess anti Pyricularia oryzae activity and antitumor activities against Caco-2 strain in vitro.The structure-activity relationships were also discussed.Especially the 3-substituted 1-（5-formylfurfuryl）indolin-2-one derivatives possess potent antitumor activities.Among them,IC₅₀ values of eight compounds are below 1.0μM.These compounds could be studied more as antitumor lead compounds.The consents of the second part are the synthesis and antitumor evaluation of noscapine and its derivatives.Noscapine has acted as a weak anticancer agent in certain in vivo models.Recently,many researchers have performed several studies to evaluate the mechanism of action of this anticancer effect and found that noscapine can disrupt tubulin dynamics.Low cost and ready availability of noscapine allow for further exploratory medicinal chemistry of this natural product.Accordingly,our goal was to carry out the total synthesis of noscapine and then identify more potent and orally active analogues of noscapine as potential anticancer agents.The key intermediate-isoquinolinium iodide was prepared by Darkin,methylenation,Vilsmeier formylation,reductive amination,reductive N-methylation,Pomeranz-Fritsch cyclization,deoxygenation,and oxidation reaction. Finally,noscapine was obtained via zinc-promoted reductive coupling reaction of iminium salts with 3-bromo-6,7-dimethoxylphthalide.The total yield of noscapine is 0.5%and it can be prepared by large scale.Furthermore,we selected noscapine as lead compound and synthesized 15 noscapine derivatives.Among them,8 are new compounds.All of target compounds synthesized were tested in A549 cancer strain model in vitro.4 compounds exhibited significant inhibitory activities with IC₅₀ values less than 10μM.The structure-activity relationships were also discussed.更多还原