过渡金属催化炔烃多组分反应合成杂环硒化合物

Heterocycles-containing organoselenium compounds have been extensively studied in medicinal chemistry due to their well-recognized biological activities. The traditional synthetic methods to those compounds have many drawbacks, such as tedious and expensive substrate preparation, poor functional-group tolerance or harsh reaction conditions. Multi-component reactions (MCRs) are an effective method for the construction of structurally diverse compounds due to its excellent yield and high atom economy. Based on our previous works in the preparation of heterocyclic and selenide compounds, it will be developed efficient and practical synthetic methods involving MCRs for the preparation of heterocycles-containing selenides including indole, imidazole, pyridine, quinazoline and furan skeleton from alkyne. Subsequently, these synthesis methods will be used for the rapid and effective synthesis of structurally diverse heterocycles-containing selenides libraries. It is looking forward to find organoselenium lead compounds or drug candidates with outstanding biological activities, novel structure and clear action target, through in-depth study of the biological activities screening, structure-activity relationships and mechanism of action.

杂环硒化合物因其独特的生物活性吸引药物化学工作者的广泛关注。然而，在构建杂环硒化合物时存在如方法单一、需要特定结构的原料、反应步骤多等不足，多组分反应具有高效、原子经济性好等优点，是快速大量合成结构多样性有机化合物的有效方法。本项目在前期的工作基础上，以炔为合成砌块，发展简单、高效的多组分串联反应来制备含有吲哚、咪唑、吡啶、喹唑啉和呋喃等骨架的杂环硒化合物新方法。并运用新方法合成一系列结构多样的杂环硒化合物库；同时，对合成的杂环硒化合物进行生物活性的筛选、并深入研究其构效关系和作用机制，期望从中找到生物活性突出、结构新颖、作用靶标明确的杂环硒先导化合物或候选药物。

以烯/炔为原料，获得了高效、简便地构建3-硒-螺吲哚-4-酮化合物、5-硒基-吲哚[2,1-a]异喹啉-6(5H)-酮化合物、5-羟基-3-硒基-4a,8a-二氢-2H-色满-6(5H)-酮、5-硒基-3-磺酰基-4a,8a-二氢-2H-色满-6(5H)-酮化合物、3-硒基-4H-色满-4-酮化合物、硒代喹啉衍生物、2'-硒基-4'H-螺[吲哚-3,3'-喹啉]化合物等系列有机硒化合物的新方法，构建了系列含氮杂环-硒化合物库和含氧杂环-硒化合物库；发现了13个抗肿瘤活性突出、结构新颖的有机硒化合物（IC50 <10 μM）；对部分化合物进行了作用机制研究，通过分子对接研究，发现有5个化合物能有效的对接秋水仙点，可作为秋水仙碱位点有机硒微管蛋白抑制剂的先导化合物以供后续研究。