C-H键官能化新技术用于活性生物碱结构修饰或全合成的新策略和新方法

Natural products, especially alkaloids, represent a unique and highly prolific source of bioactive lead compounds for drug discovery. The structural decoration or modification of natural products thus provides an important shortcut for drug development. However, due to the structural or chemical constraints, the modification or synthesis of the majority of natural products is still a big challenge in organic synthesis. Over the past few years, metal-catalyzed direct C–H functionalization has been demonstrated to be effective for various C–C and C–X bond formation reactions. Given the great experience in C-H activation reactions, the applicant proposes a new strategy on applying C-H functionalization in late-stage modification or total synthesis of biologically active alkaloids. G-quadruplex DNA is new but promising target for anti-cancer drug design. The research team the applicant affiliated has previously discovered that alkaloids cryptolepine and berberine derivatives show good and selective binding affinities with G-quadruplex DNA. However, the attempt to find more active and selective ligands derived from cryptolepine and berberine was hampered by the lack of efficient synthetic methods for their modifications or synthesis. To tackle these problems, we propose to carry out researches on: 1) the late-stage modification of cryptolepine using C-H functionalization technology; 2) the total synthesis of berberine and its derivatives using C-H functionalization as the key step; 3) the construction of small molecule library derived from cryptolepine and berberine; and 4) biological evaluation and discovery of potential drug candidate targeting G-quadruplex DNA. The fulfillment of this project will maintain abundant high-quality small molecules for anti-cancer drug discovery targeting G-quadruplex DNA. Besides, the novel strategies applied in the current project will offer great inspiration for other alkaloids modification or synthesis. Some exciting preparatory results have been achieved.

天然产物，特别是生物碱具有广泛的生物活性。对天然产物的结构修饰与改造是新药发现的重要和有效途径。由于结构的局限性，很难对天然产物进行定向修饰。C-H键官能化是最新发展的由C-H键直接引入各种官能团的合成方法。申请人在前期研究基础上，提出了将C–H键官能化用于生物碱的结构修饰和全合成的新策略。G-四链体是抗癌药物设计的新靶点。申请人所依托团队前期发现了白叶藤碱及小檗碱是G-四链体的优良配体，但对它们的结构改造遇到瓶颈。对此，本项目的研究内容为：1）基于C–H键官能化的白叶藤碱的后阶段结构修饰；2）基于C–H键官能化的小檗碱及基衍生物的全合成；3）构建基于白叶藤碱和小檗碱的化合物库；4）筛选和发现具开发前景的小分子G-四链体配体。本项目将为以G-四链体为靶点的抗癌药物研究提供丰富的小分子实体。同时，所采用的创新合成策略将对其它生物碱的合成和修饰起到很好的借鉴作用。前期探索已经取得了满意的结果。

药物研发创新最重要的是化合物实体的创新。C-H键活化是近年来发展起来的以C-H键而不是C-X (X = Cl, Br, I, OTf, etc.)键作为反应官能团,在过渡金属M (M常为 Pd，Rh，Ru，Cu，Fe) 催化下，通过形成C-M达到进一步官能化目的的一类新型化学反应类型，具有原子经济、步骤经济、环境友好等诸多优点。C-H 键活化技术为生物活性分子的合成，结构修饰或改造提供了简单高效的途径。本项目利用C-H键活化技术和融合C-H键活化的串联反应，实现了多种活性杂环骨架的快速构建和结构修饰。利用这些方法，完成了生物活性分子TNFa抑制剂，NOS抑制剂合成；实现了药物托烷司琼，雌酮，丙磺舒，喜树碱，美金刚的后阶段结构修饰；实现了小檗碱类似物，马兜铃内酰胺BII，GanocinB和C，herniarin, xanthyletin, seselin的全合成。组建了基于药物活性骨架约800个小分子的化合物库。通过活性筛选，发现了若干个具有抗肿瘤活性的小分子（IC50达到亚纳摩尔级别），部分化合物表现出良好的抗菌活性。项目按照原计划书进行，进展顺利。在该基金的资助下，取得了一系列研究成果。

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