State Key Laboratory of Drug Research Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai, 201203, China.
School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Shenyang, Liaoning, 110016, China.
Chemistry. 2023 Sep 26;29(54):e202301553. doi: 10.1002/chem.202301553. Epub 2023 Aug 14.
Multiple-spiro/fused-heterocyclic frameworks containing indazolone are structurally unique and represent a class of potentially dominant skeletons. In this work, we successfully fulfilled Rh(III)-catalyst mediated substrate- and pH- controlled strategies to construct four novel types of complicated penta-spiro/fused-heterocyclic frameworks via C-H activation/[4+1] and [4+2] annulation cascades. This method had mild reaction conditions, a broad scope of substrates, moderate to good yields, and valuable applications, which could realize for the first time the generation of the novel di-spiro-heterocyclic and multiple fused-heterocyclic products with unique structures. More importantly, novel spiro[cyclohexane-indazolo[1,2-a]indazole] scaffold constructed by this method exhibited potent antitumor activity against a variety of refractory solid tumors and hematological malignancies in vitro. Overall, our work provided new insights into the construction of complex and diverse multiple spiro/fused-heterocyclic systems and offered novel valuable lead compounds for the discovery of antitumor drugs.
含吲唑酮的多螺/稠杂环骨架结构独特，代表了一类具有潜在优势的骨架。在这项工作中，我们成功地实现了 Rh(III)-催化的底物和 pH 控制策略，通过 C-H 活化/[4+1]和[4+2]环加成级联反应，构建了四种新型复杂的五螺/稠杂环骨架。该方法具有温和的反应条件、广泛的底物范围、中等至良好的产率以及有价值的应用，可首次实现具有独特结构的新型双螺杂环和多稠合杂环产物的生成。更重要的是，该方法构建的新型螺[环己烷-吲唑并[1,2-a]吲哚]骨架在体外对多种难治性实体瘤和血液恶性肿瘤表现出强烈的抗肿瘤活性。总的来说，我们的工作为构建复杂多样的多螺/稠杂环体系提供了新的思路，并为抗肿瘤药物的发现提供了有价值的先导化合物。
