【作者】 王涛；

【导师】 董志兵；

【作者基本信息】 武汉工程大学 ， 有机化学， 2017， 硕士

【摘要】 吲哚吡咯咔唑类生物碱由于其良好的抗菌、抗真菌、抗肿瘤等生物活性,引起广泛的研究,包括对天然来源的吲哚吡咯咔唑类生物碱的全合成研究、母核的合成研究、以及该类化合物结构修饰和构效关系研究。本文对K252c分子的C(7)位衍生物的合成及对四种癌细胞细胞毒活性进行了研究,并对K252c的合成路线进行了探索,对K252a分子的糖环结构进行了简化修饰以及C(7)位衍生的K252c咔唑氮的修饰。主要包括以下两个部分:一.以吲哚为起始物,经过草酰氯酰化、成酯、缩合反应、氧化偶联反应、加成反应、C(7)位羟基成醚反应,合成出18种C(7)位衍生的K252c,并通过卤化反应、合成出一种二溴取代的K252c衍生物。对加成反应、醚化反应以及母核的卤化反应条件进行摸索:1)尝试使用格式试剂和有机锂试剂对Arcyriaflavin A的加成反应,发现使用有机锂试剂反应的产率比用格式试剂高20%左右,并尝试用混合溶剂THF/HMPA和溶剂THF做该反应,发现产率无明显区别;2)对醚化反应条件进行摸索,在酸性条件下产物很杂未能分离得到产物;在强碱性并加热条件下,能得到产物,并且产率较高;3)尝试用NBS和NCS对加成产物做卤化反应,发现在用NBS作溴化试剂,甲醇作溶剂条件下,能够得到3,9-二溴取代的且羟基被醚化的产物,而氯代反应由于NCS的活性较NBS高,得到的产物较杂,不能得到单一的氯代产物。对合成出来的19种新的K252c衍生物做了四种癌细胞株(海拉癌细胞株Hela、人乳腺癌细胞系MCF-7、人胃癌细胞SGC-7901、人非小细胞肺癌A549)的毒活性研究,结果表明,该系列的化合物总体呈中等强度的癌细胞毒活性,并且C(7)位基团的大小,以及母核溴代等因素影响其癌细胞毒活性。二.K252c的合成是后续糖基被简化的K252a系列衍生物合成的关键,因此我们尝试了四条对吲哚吡咯咔唑母核的合成路线:1)以色胺为原料,尝试经过氨基上叔丁氧羰基保护基、氧化反应、脱保护基、与吲哚酸缩合、分子内的adol反应,但是未得到目标产物,得到一种吲哚并吡咯结构的新化合物;2)以4,5-二氯邻苯二甲酸酐为原料,经过与对甲氧基卞胺的缩合反应、氯苯的氨基化反应,最后尝试了几个以氧化偶联的反应条件合成目标产物,最终路线失败;3)基本与第二条路线类似,我们将第二步反应的底物苯胺换成邻氯苯胺,第三步用钯催化的偶联反应合成目标产物,结果得到了底物氯被脱除的产物;4)以邻碘苯胺为起始物经过十步反应合成出酰胺氮上含取代基的K252c。我们对第四条路线的反应条件进行了优化,以该条路线合成的产品(酰胺氮上含取代基的K252c)为原料,通过三步反应对其咔唑氮位进行修饰,合成出14种简化的K252a衍生物。同时,对C(7)位K252c衍生物进行进一步的氮位修饰得到了6种新的衍生物。这些化合物的合成为此类化合物的生物药学活性的构效关系研究及先导化合物的筛选奠定了物质基础。更多还原

【Abstract】 Due to the good antibacterial,antifungal,antitumor activity,indolepyrrole carbazole alkaloids are widely studied,including the total synthesis of indole carbazole pyrrole alkaloids on natural sources,synthesis of the nucleus,and the compound structural modification and structure-activity relationship research.In this work,a series of C(7)derivatives of K252 c were synthesized,the antiproliferative activities of these compounds against four cancer cell lines were tested.The synthetic route of K252 c is explored in order to simplify the sugar ring structure of K252 a.14 simplified K252 a derivatives was synthesized,and a series of 6 derivatives of K252 c which was modified at C(7)position were synthesized.This thesis mainly includes the following two parts:1.The synthetic route which utilizes indole as starting material and a sequential transformation reactions such as oxalyl chloride acylation reaction,esterification,adol condensation,oxidative coupling,and addition reaction,finally etherification,to give 18K252 c derivatives modified at C(7)position and a kind of 3,9-diromide K252 c through halogenations reaction.The addition reaction,etherification and halogenating reaction conditions were studied.1)Compared to utilizing Grignard reagent as reaction reagent,the yield of addition reaction is almost 20% higher with organic lithium reagent and The yield showed no significant differrence when component solvent THF/HMPA or THF were used.2)Etherification reaction under acidic condition results in a mess of product,while a good yield of etherification reaction can be achieved under strong basic condition at 80℃.3)Halogenation of additive product at 3,9 position and etherification of hydroxyl group can be achieved with NBS by using methanol as solvent,and chlorination with NCS causes a mess of product.The antiproliferative activities of nineteen K252 c derivatives was tested in vitro against four cell lines(human non-small-cell lung carcinoma cell line A549,henrietta lacks strain of cancer cells,human gastric carcinoma cell line SGC-7901,human breast cancer cell line MCF-7),most of the derivatives showed moderate anti-cytotoxicity activity.It also showed that the cytotoxicity of these compounds were affected by C(7)group size,the bromides at 3,9 position show positive effect on the cytotoxicity.2.Four synthetic routes designed for indole carbazole pyrrole nucleus were explored:1)we tried to use tryptamine as starting material to synthesize K252 c through a sequential transformation such as amino acylation,oxidation reaction,deprotection,and indole condensation,intramolecular adol reaction,the desired product could not be synthesized.2)we tried to use 4,5-dichlorine phthalic anhydride as starting materials,a series of condensation,amination reaction,oxidative coupling reaction were explored,but the efforts were failed.3)Almost the same with the second route,we replaced aniline with o-chloroaniline in the second step,then tried the palladium-catalyzed coupling reaction to get the target molecule in the third step,but a product with dechlorination was obtained.4)Iodoaniline as starting material was tested,2,2’-biindoles were synthesized through four steps.2,2’-Biindoles then react with the intermediate synthesized by another route to give K252 c modified at amide nitrogen atom.The reaction condition of the forth route was optimized.Fourteen derivatives of these simplified K252 a with product(K252c with a group at amide nitrogen)obtained in the forth route were synthesized in three steps,as well as 6 derivatives modified at carbazole nitrogen of C(7)derivatives of K252 c.The synthesis of these derivatives makes the material foundation for the study of structure-activity relationships and the screening of the leading compounds.更多还原