Sharjah Institute for Medical Research, University of Sharjah, P.O. Box 27272, Sharjah, UAE.
Lübeck Institute of Experimental Dermatology, University of Lübeck, Ratzeburger Allee 160 23538, Lübeck, Germany.
Nat Commun. 2018 Nov 26;9(1):4989. doi: 10.1038/s41467-018-07521-2.
Octahydroindolo[2,3-a]quinolizine ring system forms the basic framework comprised of more than 2000 distinct family members of natural products. Despite the potential applications of this privileged substructure in drug discovery, efficient, atom-economic and modular strategies for its assembly, is underdeveloped. Here we show a one-step build/couple/pair strategy that uniquely allows access to diverse octahydroindolo[2,3-a]quinolizine scaffolds with more than three contiguous chiral centers and broad distribution of molecular shapes via desymmetrization of the oxidative-dearomatization products of phenols. The cascade demonstrates excellent diastereoselectivity, and the enantioselectivity exceeded 99% when amino acids are used as chiral reagents. Furthermore, two diastereoselective reactions for the synthesis of oxocanes and piperazinones, is reported. Phenotypic screening of the octahydroindolo[2,3-a]quinolizine library identifies small molecule probes that selectively suppress mitochondrial membrane potential, ATP contents and elevate the ROS contents in hepatoma cells (Hepa1-6) without altering the immunological activation or reprogramming of T- and B-cells, a promising approach to cancer therapy.
八氢吲哚并[2,3-a]喹啉环系统构成了超过 2000 种不同天然产物家族成员的基本骨架。尽管这个特权结构在药物发现中有潜在的应用，但对于其组装的高效、原子经济性和模块化策略仍未得到充分发展。在这里，我们展示了一种一步构建/偶联/配对策略，通过酚类的氧化去芳构化产物的去对称化，独特地允许获得具有三个以上连续手性中心和广泛分子形状分布的各种八氢吲哚并[2,3-a]喹啉骨架。该级联反应表现出极好的非对映选择性，当使用氨基酸作为手性试剂时，对映选择性超过 99%。此外，还报道了两种用于合成氧杂环烷和哌嗪酮的非对映选择性反应。八氢吲哚并[2,3-a]喹啉文库的表型筛选鉴定了小分子探针，这些探针选择性地抑制肝癌细胞（Hepa1-6）中的线粒体膜电位、ATP 含量，并升高 ROS 含量，而不改变 T 和 B 细胞的免疫激活或重编程，这是一种有前途的癌症治疗方法。
