基于烯/炔多组分反应构筑杂环类抗肿瘤小分子化合物研究

Multi-component reactions (MCRs) are playing a more and more important role in the field of medicinal chemistry because of its excellent yield, convergence, and high atom economy. It is the effective method for the construction of structurally diverse compound libraries. Multi-component synthesis of anti-tumor agents with small molecule compounds has been a very challenging field of research and application prospects. In this project, on the basis of some reactions founded in our laboratory, the useful synthetic methodologys involving MCRs will be developed to construct the novel heterocyclic compounds which contain some anti-tumor priviledged structures such as quinolinone, tetrahydroquinoline, indole, pyrrolizine, quinoxaline, and triazole moiety by employing alkene and alkyne as the key synthetic block. Subsequently, by means of drug combination designed and chiral control, the synthesis methods will be used for the rapid and effective synthesis of structurally diverse heterocyclic compound libraries including quinoxaline-triazoles, multiple chiral centers tetrahydroquinolines, tricyclic quinolinones, polysubstituted chiral indoles and tricyclic pyrrolizines. The new compounds in the range from 120 to 180 will be synthesized as possible alternative compounds for anti-cancer drugs. It is looking forward to find lead compounds or drug candidates in the range from 5 to 10 with outstanding anti-tumor activity, novel structure and clear action target, through in-depth study of the anti-tumor activity screening, structure-activity relationships and mechanism of action.

多组分反应具有高效、简便及原子经济性好等优点，是快速构建结构多样性化合物库的有效方法，利用多组分串联反应高效构筑抗肿瘤小分子化合物是富有挑战性和应用前景的研究工作。本项目拟在本课题组前期研究的基础上，以烯烃、炔烃化合物作为合成砌块，发展多组分串联反应构筑具有2(1H)-喹啉酮、四氢喹啉、吲哚、吡咯里嗪、喹喔啉和三唑等抗肿瘤优势结构杂环化合物的合成方法；采用药物拼合设计、手性控制等现代药物合成手段，重点构建结构类型丰富的喹喔啉-三唑、多手性中心四氢喹啉、三环喹啉酮、多取代手性吲哚和三环吡咯里嗪杂环类化合物库，作为抗肿瘤药物的备选化合物，其中包含120～180个新化合物；并通过化合物抗肿瘤活性的筛选、构效关系及作用机制的深入研究，预期从中发现5～10个抗肿瘤活性突出、结构新颖、作用靶标明确的抗肿瘤小分子先导化合物或候选药物。

以烯/炔为原料，获得了高效、简便地合成2(1H)-喹啉酮磷酸酯衍生物、含咪唑环2(1H)-喹啉酮衍生物、香豆素哌嗪衍生物、双芳基脲-6,7-二氟喹喔啉衍生物、脱氢松香氨基膦酸硫脲衍生物、脱氢松香酸二肽衍生物、三唑、烯胺酮、烯胺腈、多取代咪唑、多取代吡啶、取代苯、吡咯化合物、4-吡喃酮化合物、噁唑、苄基异喹啉生物碱、硒醇类化合物、异吲哚、5-取代异噁唑、二氢吡唑、中氮茚、3-苯乙烯基香豆素、呋喃[3,2-C]香豆素化合物、喹喔啉-三氮唑类化合物和石蒜碱类似物（三环喹啉酮）等系列化合物的新方法，构建了系列含氮杂环的化合物库，发现了21个抗肿瘤活性突出（IC50 < 10 μM）、结构新颖的抗肿瘤化合物，并明确了其中14个抗肿瘤化合物的作用机制。