【作者】 洪卉；

【导师】 黄龙江；

【作者基本信息】 青岛科技大学 ， 药物化学， 2010， 硕士

【摘要】 氮杂吲哚螺环化合物是一类重要的杂螺环化合物,具有抗肿瘤、抗焦虑、消炎、解热及镇痛、降压和杀虫等生物活性,引起了药物学家和化学家的广泛关注。为探索发现新的抗肿瘤先导化合物,本课题设计合成了螺[哌啶-4,3’-吡咯[2,3.b]吡啶]-2’(1’H)-酮,并以其为母核设计合成了化合物库,并对化合物库的抗肿瘤活性进行了初步研究。通过反合成分析法设计了螺[哌啶-4,3’-吡咯[2,3_b]吡啶]-2’(1’H)-酮的合成路线。以廉价易得的烟酸为原料,经过氧化、氯化、还原得到2-氯-3-羟基吡啶;经氯化、氰基取代得到2-氯-3-氰甲基吡啶;通过双烷基化、水解、环化和脱Boc反应合成了螺[哌啶-4,3’-吡咯【2,3-b】吡啶]-2’(1,H)-酮化合物。并通过路线改进合成1’,2’-二氢螺[哌啶-4,3’-吡咯【2,3-b】吡啶化合物。通过反应条件进行优化,得到了最佳反应条件。此合成路线原料廉价易得,反应条件温和,操作简单。以烟酸为原料,经9步反应得到氮杂吲哚螺环化合物,总收率为15%。为氮杂吲哚类螺环化合物的合成提供了新的高效合成方法。根据文献中药物类似化合物的信息,设计了氮杂吲哚螺环化合物库,并选择12种具有代表性的取代基,通过还原胺化反应得到了螺[哌啶-4,3’-吡咯[2,3-b]吡啶]-2’(1’H)-酮衍生物氧化氮杂螺环化合物库,其衍生物种类多样涵盖了脂肪族、芳香族和杂环族取代基团。以合成的系列氮杂吲哚螺环化合物进行了抗肿瘤活性研究,发现氮杂吲哚螺环化合物对人肺腺癌细胞A549、人肝癌细胞BEL7402、人结肠癌细胞HcT-8均有一定的抑制作用,化合物对人肺腺癌细胞A549抗肿瘤活性明显。对人肝癌细胞BEL7402和人结肠癌细胞HCT-8也有一定的抑制活性。初步探讨了此系列化合物的构效关系,带有三氟氧基取代的苯环、呋喃基团、噻吩基团、3-氟基-4-甲基取代的苯环和环己烷基团的氧化氮杂吲哚螺环化合物能较好的抑制肿瘤细胞的增殖,这一工作为研究药物诱导癌细胞凋亡的作用机制,进一步设计合成更多结构新颖药效显著的抗肿瘤吲哚螺环类化合物打下了基础。对于发现药物前体和药物作用靶体具有重要的理论和应用意义。更多还原

【Abstract】 Spirocyclic oxazaindole is one of the most important spiro-heterocyclic compounds with a broad range of antitumor, antianxiety, antiinflammatory and antihypertensive activities. Recently, it has aroused extensive concern in pharmacy and chemistry field. In order to find new antitumor lead compounds, we designed and synthesized the spiro[piperidine-4,3’-pyrrolo[2,3-b]pyridin]- 2’(l’H)-one and its library, and studied their anti-tumor activities.The synthetic scheme of the spirocyclic oxazaindole compound named spiro[piperidine-4,3’-pyrrolo[2,3-b]pyridin]-2’(l’H)-one was derived from retrosynthesis method. Using commercial available cheap nicotinic acid as starting material, (2-chloropyridin-3-yl) methanol was obtained after successively oxidized by hydrogen peroxide, chlorinated by phosphorus oxchloride and reduced by sodium borohydride. Then, 2-(2-chloropyridin-3-yl) acetonitrile was synthetized by chlorinating with thionyl chloride and substituting with cyanide anion. After dialkylation with dichloroethylamine, hydrolysation of the cyano group to carboxylic amide and cyclization under Buchwald-Hartwig condition and finally deprotection of the protective group, the spiro[piperidine-4,3’-pyrroIo[2,3-b]pyridin] -2’(l’H)-one was obtained in 15% total yield after nine steps. With minor alternation of the synthetic route, we also synthesized another spirocyclic azazindole analogue, 7-aza-spiro [indoline-3, 4’-piperidine]. According to the literature information of similar analogues, we designed a spirocyclic oxazaindole compound library based on the synthesized compounds. The library compounds were synthesized using twelve representative substituents including aliphatic, aromatic and heterocyclic functional groups by reductive amination reaction.The antitumor activities of all the derivatives were studied against human lung cancer cell A549, human liver cancer cell BEL7402 and human colon cancer cells HCT-8. The results showed that some spirocyclic oxazaindole compounds have little inhibitory activity on human liver cancer cell BEL7402 and on human colon cancer cells HCT-8. To some extent, the derivative containing trifluoromethoxy-substituted aromatic ring may inhibit tumor cell proliferation on cancer cell. Some compounds with furyl group, thienyl group, cyclohexane group and 3 - fluoro-based - 4 -methyl-substituted benzene ring on the tumor cells also have anti-tumor activity. The antitumor activity study is still ongoing in our laboratory. A preliminary study of this compounds’ structure-activity relationship was discussed. This work is significant for designing, synthesizing novel and effective anti-tumor spirocyclic oxazaindole compounds and searching leading compounds in drug discovery.更多还原