School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, 510006, PR China.
School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, 510006, PR China.
Eur J Med Chem. 2022 Mar 15;232:114200. doi: 10.1016/j.ejmech.2022.114200. Epub 2022 Feb 18.
Since more than 85% of lung cancer cases are non-small cell lung cancer (NSCLC), finding novel agents with anti-tumor activities is meaningful for NSCLC patients. Mitochondria is essential for cellular energy metabolism in cancer, and regulating mitochondrial bioenergetics is emerging as a practical approach for cancer treatment and prevention. The carbazole scaffold is an active structure showing anti-cancer biological activity, and the structural diversity has been expanded through the improvement and optimization of synthesizing methods. To find novel carbazole derivatives with great anti-tumor potential and explore structures variety, we designed and synthesized a series of 9-(pyrimidin-2-yl)-9H-carbazole derivatives based on the previously reported Cp∗Rh(III)/H tandem catalytic system. With thoroughly bioactivity exploration, we found benzo[d] [1,3]dioxol-5-yl(9-(pyrimidin-2-yl)-9H-carbazol-1-yl)methanone (compound 5n) showed notable activity in disrupting the mitochondrial homeostasis, induced cell cycle arrest and apoptosis in human adenocarcinoma cells, and finally showed anti-tumor activity in an NSCLC-xenograft mice model.
由于超过 85%的肺癌病例是非小细胞肺癌（NSCLC），因此寻找具有抗肿瘤活性的新型药物对 NSCLC 患者具有重要意义。线粒体对于癌症中的细胞能量代谢至关重要，调节线粒体生物能量学正成为癌症治疗和预防的一种实用方法。咔唑骨架是一种具有抗癌生物活性的活性结构，通过改进和优化合成方法来扩大其结构多样性。为了寻找具有巨大抗肿瘤潜力的新型咔唑衍生物并探索结构多样性，我们设计并合成了一系列基于先前报道的 Cp∗Rh(III)/H 串联催化体系的 9-(嘧啶-2-基)-9H-咔唑衍生物。通过彻底的生物活性探索，我们发现苯并[d][1,3]二恶唑-5-基(9-(嘧啶-2-基)-9H-咔唑-1-基)甲酮（化合物 5n）在破坏线粒体平衡方面表现出显著的活性，诱导人腺癌细胞的细胞周期停滞和凋亡，最终在 NSCLC 异种移植小鼠模型中表现出抗肿瘤活性。
