多环吲哚类杂环化合物的多样性导向合成及其抗肿瘤活性

The project is dedicated to construct simple heterocyclic ketene amines and quinines as building blocks and then synthesize 90-120 different kinds of novel polyhalogenated and highly functional polycyclic compounds which may serve as anti-tumor drugs. Specifically, polycyclic single indoles, halogenated polycyclic single indoles, polycyclic indoles and spiro oxidized indoles will be synthesized. The synthetic routes include green and environmentally benign methods such as solvent-free, microwave-assisted and one-pot multicomponents reactions, in order to efficiently synthesize aim products in parallel with molecular diversity under mild conditions. Based on the synthesis, anti-tumor drugs screening in vitro model will be established via MTT method and with CDKs as tumor target point. Upon antitumor activity screening and rescreening in vitro, 4-6 compounds showing best anti-tumor activity will be selected and subjected to screening in vivo. 1-2 new drugs or leading compounds showing better anti-tumor activity than current clinical antitumor drugs being used is expected to be found. Structure-activity relationship and mechanism of action will also be investigated.

本项目拟建立以结构简单的杂环烯酮缩胺和琨类等为砌块，以天然抗肿瘤化合物为导向，以多样性导向合成为策略，采用无溶剂合成、微波辅助合成、多组分"一锅法"等绿色环保的合成方法，在温和的条件下简洁高效、平行的设计合成分子多样化、多卤代及高功能化的90-120个结构新颖的多环单吲哚、多卤代多环单吲哚、多环双吲哚及螺环氧化吲哚类化合物。在化合物合成的基础上，建立抗肿瘤药物体外筛选模型，采用MTT法及以CDKs为靶点进行体外抗肿瘤活性初筛及复筛，优选4-6个体外抗肿瘤活性较好的化合物进行体内抗肿瘤动物模型筛选，并进行构效关系及作用机制研究，期望筛选出1-2个具有比目前临床用抗肿瘤药物更好的抗肿瘤活性化合物或先导化合物。

本项目建立了以结构简单的杂环烯酮缩胺和醌类化合物等为砌块，以天然抗肿瘤化合物为导向，以多样性导向合成为策略，采用无溶剂合成、微波辅助合成、多组分"一锅法"等绿色环保的合成方法，在温和的条件下简捷高效地设计合成了6类138个具有分子多样性、多卤代及高功能化的新颖多环吲哚类化合物。在化合物合成的基础上，建立抗肿瘤药物体外筛选模型，采用MTT法对合成的化合物进行了体外抗肿瘤活性初筛，从中优选出2个体外抗肿瘤活性较好的化合物进行长效克隆试验，结果表明2个噁二唑并吲哚酮类化合物具有较好的抗肿瘤活性，可为下一步化合物的结构设计和修饰提供结构依据。在Green Chem.; ACS Sustain. Chem. Eng.和Euro. J. Org. Chem. 等国际核心刊物上发表学术论文34篇；同时申请发明专利1项。培养了博士研究生2人（毕业1人），硕士研究生12人（毕业6人）。研究团队1人晋升教授，1人晋升副教授，形成了一支高水平的从事类天然产物药物合成研究的科研团队。