Somu Chaithanya, Mohan Chakrabhavi Dhananjaya, Ambekar Sachin, Rangappa Shobith, Baburajeev C P, Sukhorukov Alexey, Mishra Srishti, Shanmugam Muthu K, Chinnathambi Arunachalam, Awad Alahmadi Tahani, Alharbi Sulaiman Ali, Rangappa Kanchugarakoppal S
Department of Studies in Chemistry, University of Mysore, Manasagangotri, Mysore 570006, India.
Department of Studies in Molecular Biology, University of Mysore, Manasagangotri, Mysore 570006, India.
Biotechnol Rep (Amst). 2020 Feb 19;25:e00438. doi: 10.1016/j.btre.2020.e00438. eCollection 2020 Mar.
Constitutive activation of NF-κB is associated with proinflammatory diseases and suppression of the NF-κB signaling pathway has been considered as an effective therapeutic strategy in the treatment of various cancers including hepatocellular carcinoma (HCC). Herein, we report the synthesis of 1,2 oxazines and their anticancer potential. The antiproliferative studies presented 3-((4-(1H-benzo[d]imidazol-2-yl)piperidin-1-yl)methyl)-4-phenyl-4,4a,5,6,7,7a-hexahydrocyclopenta [][1,2]oxazine(3i) as a lead cytotoxic agent against HCC cells. Flow cytometric analysis showed that 3i caused a substantial increase in the subG1 cell population. Annexin-V-FITC-PI staining showed a significant increase in the percentage of apoptotic cells on treatment with 3i. Transfection with p65 siRNA significantly reduced the 3i induced DNA fragmentation indicating that 3i may primarily mediate its proapoptotic effects by abrogating the NF-κB signaling. In addition, treatment of HCC cells with 3i decreased the DNA binding ability of NF-κB and NF-κB-dependent luciferase expression. Taken together, this report introduces 1,2-oxazine that potently targets the NF-κB signaling pathway in HCC cells.
核因子κB（NF-κB）的组成性激活与促炎疾病相关，抑制NF-κB信号通路已被视为治疗包括肝细胞癌（HCC）在内的各种癌症的有效治疗策略。在此，我们报告了1,2-恶嗪的合成及其抗癌潜力。抗增殖研究表明3-((4-(1H-苯并[d]咪唑-2-基)哌啶-1-基)甲基)-4-苯基-4,4a,5,6,7,7a-六氢环戊[a][1,2]恶嗪（3i）是一种针对HCC细胞的潜在细胞毒性药物。流式细胞术分析表明3i导致亚G1期细胞群体大幅增加。膜联蛋白-V-异硫氰酸荧光素-碘化丙啶（Annexin-V-FITC-PI）染色显示用3i处理后凋亡细胞百分比显著增加。用p65小干扰RNA（siRNA）转染显著降低了3i诱导的DNA片段化，表明3i可能主要通过废除NF-κB信号传导来介导其促凋亡作用。此外，用3i处理HCC细胞降低了NF-κB的DNA结合能力和NF-κB依赖性荧光素酶表达。综上所述，本报告介绍了一种能有效靶向HCC细胞中NF-κB信号通路的1,2-恶嗪。
