Identification of a novel 1,2 oxazine that can induce apoptosis by targeting NF-κB in hepatocellular carcinoma cells

Chaithanya Somu; Chakrabhavi Dhananjaya Mohan; Sachin Ambekar; Dukanya; Shobith Rangappa; C P Baburajeev; Alexey Sukhorukov; Srishti Mishra; Muthu K Shanmugam; Arunachalam Chinnathambi; Tahani Awad Alahmadi; Sulaiman Ali Alharbi; Basappa; Kanchugarakoppal S Rangappa

doi:10.1016/j.btre.2020.e00438

Identification of a novel 1,2 oxazine that can induce apoptosis by targeting NF-κB in hepatocellular carcinoma cells

Biotechnol Rep (Amst). 2020 Feb 19:25:e00438. doi: 10.1016/j.btre.2020.e00438. eCollection 2020 Mar.

Authors

Affiliations

¹ Department of Studies in Chemistry, University of Mysore, Manasagangotri, Mysore 570006, India.
² Department of Studies in Molecular Biology, University of Mysore, Manasagangotri, Mysore 570006, India.
³ Laboratory of Chemical Biology, Department of Chemistry, Bangalore University, Central College Campus, Palace Road, Bangalore 560001, India.
⁴ Laboratory of Chemical Biology, Department of Studies in Organic Chemistry, University of Mysore, Manasagangotri, Mysore 570006, India.
⁵ Adichunchanagiri Institute for Molecular Medicine, BG Nagara, Nagamangala Taluk, Mandya district-571448, India.
⁶ N.D. Zelinsky Institute of Organic Chemistry, Leninsky Prospect, Moscow 119991, Russia.
⁷ Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore 117600, Singapore.
⁸ Department of Botany and Microbiology, College of Science, King Saud University, Riyadh -11451, Saudi Arabia.
⁹ Department of Pediatrics, College of Medicine and King Khalid University Hospital, King Saud University Medical City, Riyadh 11461, Saudi Arabia.

Abstract

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 [e][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.

Keywords: Anticancer; DNA fragmentation; NF-κB; Oxazine.