Biological evaluation of novel 5-((1H-indol-3-yl) methyl)-2-(4-chlorobenzyl)-6-phenyl-imidazo[2,1-b][13,4]thiadiazole derivatives as novel BCL-2 specific inhibitors
Antiapoptotic protein BCL2 is known to be upregulated in several cancer cells and therefore, it is an excellent target for cancer therapy. Previously, we reported a novel BCL2 inhibitor, Disarib, which inhibited BCL2 by predominantly binding to its BH1 domain and exhibited platelet-sparing ability l...
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Elsevier
2025-04-01
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| Series: | European Journal of Medicinal Chemistry Reports |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2772417425000032 |
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| author | Shivangi Sharma Sadashivamurthy Shamanth Humaira Siddiqua Laijau Goyary Kunigal S. Sagar Susmita Kumari Divya Sathees Gudapureddy Radha Bibha Choudhary Sathees C. Raghavan Kempegowda Mantelingu |
| author_facet | Shivangi Sharma Sadashivamurthy Shamanth Humaira Siddiqua Laijau Goyary Kunigal S. Sagar Susmita Kumari Divya Sathees Gudapureddy Radha Bibha Choudhary Sathees C. Raghavan Kempegowda Mantelingu |
| author_sort | Shivangi Sharma |
| collection | DOAJ |
| description | Antiapoptotic protein BCL2 is known to be upregulated in several cancer cells and therefore, it is an excellent target for cancer therapy. Previously, we reported a novel BCL2 inhibitor, Disarib, which inhibited BCL2 by predominantly binding to its BH1 domain and exhibited platelet-sparing ability like ABT199, the only FDA-approved BCL2 inhibitor. Here, we have synthesized the novel Disarib derivatives where oxindole moiety in Disarib was replaced with indole and evaluated their biological activity. We report several derivatives of Disarib and the identification of DSR 43 and 4-OCH3, as the most potent among them. Treatment of cancer cell lines with the Disarib derivatives, DSR 43 and 4-OCH3 led to the activation of the apoptotic pathway without generating any ROS or disrupting the mitochondrial membrane potential within the cells, leading to cell death. Western blot analysis in tandem with Annexin V/PI staining confirmed the activation of apoptosis. In silico studies, using derivatives suggests a promising therapeutic window with less off-target effects. Furthermore, their efficacy across different cancer cell lines highlights their broad potential as anticancer agents. Taken together, our results suggest that Disarib derivatives may have the potential to be developed as cancer therapeutic. |
| format | Article |
| id | doaj-art-b1ce7f9b665843aa999f9b985a0def8c |
| institution | Kabale University |
| issn | 2772-4174 |
| language | English |
| publishDate | 2025-04-01 |
| publisher | Elsevier |
| record_format | Article |
| series | European Journal of Medicinal Chemistry Reports |
| spelling | doaj-art-b1ce7f9b665843aa999f9b985a0def8c2025-01-30T05:15:12ZengElsevierEuropean Journal of Medicinal Chemistry Reports2772-41742025-04-0113100247Biological evaluation of novel 5-((1H-indol-3-yl) methyl)-2-(4-chlorobenzyl)-6-phenyl-imidazo[2,1-b][13,4]thiadiazole derivatives as novel BCL-2 specific inhibitorsShivangi Sharma0Sadashivamurthy Shamanth1Humaira Siddiqua2Laijau Goyary3Kunigal S. Sagar4Susmita Kumari5Divya Sathees6Gudapureddy Radha7Bibha Choudhary8Sathees C. Raghavan9Kempegowda Mantelingu10Department of Biochemistry, Indian Institute of Science, Bangalore, 560012, IndiaDepartment of Chemistry, Manasagangotri, University of Mysore, Mysuru, Karnataka, India, 570006Department of Biochemistry, Indian Institute of Science, Bangalore, 560012, IndiaDepartment of Biochemistry, Indian Institute of Science, Bangalore, 560012, IndiaDepartment of Chemistry, BMS College of Engineering, Bangalore, 560 019, IndiaDepartment of Biochemistry, Indian Institute of Science, Bangalore, 560012, IndiaDepartment of Biochemistry, Indian Institute of Science, Bangalore, 560012, India; St Joseph's University, Bangalore, 560027, IndiaDepartment of Biochemistry, Indian Institute of Science, Bangalore, 560012, IndiaInstitute of Bioinformatics and Applied Biotechnology, Biotech Park, Electronic City Phase I, Bangalore, 560100, IndiaDepartment of Biochemistry, Indian Institute of Science, Bangalore, 560012, India; Corresponding author. Department of Biochemistry, Indian Institute of Science, Bangalore, 560012, India.Department of Chemistry, Manasagangotri, University of Mysore, Mysuru, Karnataka, India, 570006; Corresponding author. Department of Chemistry, Manasagangotri, University of Mysore, Mysuru, 570006, India.Antiapoptotic protein BCL2 is known to be upregulated in several cancer cells and therefore, it is an excellent target for cancer therapy. Previously, we reported a novel BCL2 inhibitor, Disarib, which inhibited BCL2 by predominantly binding to its BH1 domain and exhibited platelet-sparing ability like ABT199, the only FDA-approved BCL2 inhibitor. Here, we have synthesized the novel Disarib derivatives where oxindole moiety in Disarib was replaced with indole and evaluated their biological activity. We report several derivatives of Disarib and the identification of DSR 43 and 4-OCH3, as the most potent among them. Treatment of cancer cell lines with the Disarib derivatives, DSR 43 and 4-OCH3 led to the activation of the apoptotic pathway without generating any ROS or disrupting the mitochondrial membrane potential within the cells, leading to cell death. Western blot analysis in tandem with Annexin V/PI staining confirmed the activation of apoptosis. In silico studies, using derivatives suggests a promising therapeutic window with less off-target effects. Furthermore, their efficacy across different cancer cell lines highlights their broad potential as anticancer agents. Taken together, our results suggest that Disarib derivatives may have the potential to be developed as cancer therapeutic.http://www.sciencedirect.com/science/article/pii/S2772417425000032Cancer therapyBCL2DisaribABT199ApoptosisAnticancer drug |
| spellingShingle | Shivangi Sharma Sadashivamurthy Shamanth Humaira Siddiqua Laijau Goyary Kunigal S. Sagar Susmita Kumari Divya Sathees Gudapureddy Radha Bibha Choudhary Sathees C. Raghavan Kempegowda Mantelingu Biological evaluation of novel 5-((1H-indol-3-yl) methyl)-2-(4-chlorobenzyl)-6-phenyl-imidazo[2,1-b][13,4]thiadiazole derivatives as novel BCL-2 specific inhibitors European Journal of Medicinal Chemistry Reports Cancer therapy BCL2 Disarib ABT199 Apoptosis Anticancer drug |
| title | Biological evaluation of novel 5-((1H-indol-3-yl) methyl)-2-(4-chlorobenzyl)-6-phenyl-imidazo[2,1-b][13,4]thiadiazole derivatives as novel BCL-2 specific inhibitors |
| title_full | Biological evaluation of novel 5-((1H-indol-3-yl) methyl)-2-(4-chlorobenzyl)-6-phenyl-imidazo[2,1-b][13,4]thiadiazole derivatives as novel BCL-2 specific inhibitors |
| title_fullStr | Biological evaluation of novel 5-((1H-indol-3-yl) methyl)-2-(4-chlorobenzyl)-6-phenyl-imidazo[2,1-b][13,4]thiadiazole derivatives as novel BCL-2 specific inhibitors |
| title_full_unstemmed | Biological evaluation of novel 5-((1H-indol-3-yl) methyl)-2-(4-chlorobenzyl)-6-phenyl-imidazo[2,1-b][13,4]thiadiazole derivatives as novel BCL-2 specific inhibitors |
| title_short | Biological evaluation of novel 5-((1H-indol-3-yl) methyl)-2-(4-chlorobenzyl)-6-phenyl-imidazo[2,1-b][13,4]thiadiazole derivatives as novel BCL-2 specific inhibitors |
| title_sort | biological evaluation of novel 5 1h indol 3 yl methyl 2 4 chlorobenzyl 6 phenyl imidazo 2 1 b 13 4 thiadiazole derivatives as novel bcl 2 specific inhibitors |
| topic | Cancer therapy BCL2 Disarib ABT199 Apoptosis Anticancer drug |
| url | http://www.sciencedirect.com/science/article/pii/S2772417425000032 |
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