Abstract
In this study, we designed and synthesized a series of 1,4-benzothiazine and evaluated them for anticancer activity toward HT-29 human colon cancer cells using SRB assay. Before the synthesis, docking studies were performed using various molecular targets of colon cancer including IL-2, IL-6, COX-2, caspase-3, and caspase-8. The molecular dynamic (MD) simulation was also executed to examine the stability of ligand-receptor complex of more stable dock conformation. Further computational study was carried out in order to predict the pharmacokinetic profile of titled compounds. Among 34 tested compounds, compounds AR13 and AR15 were found to be active against HT-29 cells (GI50 < 10 μM). Moreover, Compounds AR5, AR22, and AR34 showed the moderate activity with GI50 < 70 μM. The binding energy was found to be > −5 kcal/mol for AR13 and AR15 with all the molecular targets and the ligand-protein complex was found stable after its formation. Again, computational analysis revealed that both molecules AR13 and AR15 had good ADMET profiling. These encouraging outcomes allowed us to conclude that both AR13 and AR15 may emerge as lead compounds against colon cancer.
Public Interest Statement
On a global scale, colon cancer is one of the fourth most common cancer in men and the third most common cancer in women. Most of the drugs available for colon cancer treatment are cost effective and with major side effects. In this project, we wanted to synthesize and explore 1,4-benzothiazine derivatives. In vitro (ADMET profiling, MD Simulation and docking) and in vitro (HT-29 cells) studies were performed to get the acceptance of these derivates for colon cancer treatment. This study may be helpful for the development of potent 1,4-benzothizine scaffold toward the colon cancer treatment.
Acknowledgments
Dr Sudipta Saha would like to express his gratitude to Advanced Centre for Treatment, Research and Education in Cancer (ACTREC), Navi Mumbai, India for undertaking anticancer screening. The authors express their sincere thanks to Delhi University, IIT Kanpur, and IIT Delhi and USIC BBAU, Lucknow for providing the spectral data.
Additional information
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Sudipta Saha
Dr Sudipta Saha obtained his PhD in Pharmaceutical Sciences from National University of Singapore, Singapore and did his Post doctorate from experimental Therapeutic Centre, Astar, Singapore. Presently he is working as assistant professor in Department of Pharmaceutical Sciences, Babasaheb Bhimrao Ambedkar University (A Central University), Lucknow, Uttar Pradesh. His research interest is mainly into organic synthesis and cancer pharmacology. He has 35 Journal articles, two book chapters and three projects up to February, 2017.