Development of 2-oxindolin-3-ylidene-indole-3-carbohydrazide derivatives as novel apoptotic and anti-proliferative agents towards colorectal cancer cells
Mitochondrial anti-apoptotic Bcl2 and BclxL proteins, are overexpressed in multiple tumour types, and has been involved in the progression and survival of malignant cells. Therefore, inhibition of such proteins has become a validated and attractive target for anticancer drug discovery. In this manne...
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doaj-ae0ff9bf7af7424389e31b9650cd019c2021-01-15T12:46:19ZengTaylor & Francis GroupJournal of Enzyme Inhibition and Medicinal Chemistry1475-63661475-63742021-01-0136132032910.1080/14756366.2020.18621001862100Development of 2-oxindolin-3-ylidene-indole-3-carbohydrazide derivatives as novel apoptotic and anti-proliferative agents towards colorectal cancer cellsWagdy M. Eldehna0Mahmoud F. Abo-Ashour1Tarfah Al-Warhi2Sara T. Al-Rashood3Amal Alharbi4Rezk R. Ayyad5Khayal Al-Khayal6Maha Abdulla7Hatem A. Abdel-Aziz8Rehan Ahmad9Radwan El-Haggar10Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Kafrelsheikh UniversityDepartment of Pharmaceutical Chemistry, Faculty of Pharmacy, Egyptian Russian UniversityDepartment of Chemistry, College of Science, Princess Nourah bint Abdulrahman UniversityDepartment of Pharmaceutical Chemistry, College of Pharmacy, King Saud UniversityDepartment of Pharmaceutical Chemistry, College of Pharmacy, King Saud UniversityDepartment of Pharmaceutical Chemistry, Faculty of Pharmacy, Al-Azhar UniversityColorectal Research Chair, Department of Surgery, King Khalid University Hospital, King Saud University College of MedicineColorectal Research Chair, Department of Surgery, King Khalid University Hospital, King Saud University College of MedicineDepartment of Applied Organic Chemistry, National Research CenterColorectal Research Chair, Department of Surgery, King Khalid University Hospital, King Saud University College of MedicinePharmaceutical Chemistry Department, Faculty of Pharmacy, Helwan UniversityMitochondrial anti-apoptotic Bcl2 and BclxL proteins, are overexpressed in multiple tumour types, and has been involved in the progression and survival of malignant cells. Therefore, inhibition of such proteins has become a validated and attractive target for anticancer drug discovery. In this manner, the present studies developed a series of novel isatin–indole conjugates (7a-j and 9a-e) as potential anticancer Bcl2 and BclxL inhibitors. The progression of the two examined colorectal cancer cell lines was significantly inhibited by all of the prepared compounds with IC50 ranges 132–611 nM compared to IC50 = 4.6 µM for 5FU, against HT-29 and IC50 ranges 37–468 nM compared to IC50 = 1.5 µM for 5FU, against SW-620. Thereafter, compounds 7c and 7g were selected for further investigations. Interestingly, both compounds exhibited selective cytotoxicity against both cell lines with high safety to normal fibroblast (HFF-1). In addition, both compounds 7c and 7g induced apoptosis and inhibited Bcl2 and BclxL expression in a dose-dependent manner. Collectively, the high potency and selective cytotoxicity suggested that conjugates 7c and 7g could be a starting point for further optimisation to develop novel pro-apoptotic and antitumor agents towards colon cancer.http://dx.doi.org/10.1080/14756366.2020.1862100anti-proliferative indolesapoptosisisatin-indolebcl2/bclxl inhibitorscolorectal cancerwestern blotting |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Wagdy M. Eldehna Mahmoud F. Abo-Ashour Tarfah Al-Warhi Sara T. Al-Rashood Amal Alharbi Rezk R. Ayyad Khayal Al-Khayal Maha Abdulla Hatem A. Abdel-Aziz Rehan Ahmad Radwan El-Haggar |
spellingShingle |
Wagdy M. Eldehna Mahmoud F. Abo-Ashour Tarfah Al-Warhi Sara T. Al-Rashood Amal Alharbi Rezk R. Ayyad Khayal Al-Khayal Maha Abdulla Hatem A. Abdel-Aziz Rehan Ahmad Radwan El-Haggar Development of 2-oxindolin-3-ylidene-indole-3-carbohydrazide derivatives as novel apoptotic and anti-proliferative agents towards colorectal cancer cells Journal of Enzyme Inhibition and Medicinal Chemistry anti-proliferative indoles apoptosis isatin-indole bcl2/bclxl inhibitors colorectal cancer western blotting |
author_facet |
Wagdy M. Eldehna Mahmoud F. Abo-Ashour Tarfah Al-Warhi Sara T. Al-Rashood Amal Alharbi Rezk R. Ayyad Khayal Al-Khayal Maha Abdulla Hatem A. Abdel-Aziz Rehan Ahmad Radwan El-Haggar |
author_sort |
Wagdy M. Eldehna |
title |
Development of 2-oxindolin-3-ylidene-indole-3-carbohydrazide derivatives as novel apoptotic and anti-proliferative agents towards colorectal cancer cells |
title_short |
Development of 2-oxindolin-3-ylidene-indole-3-carbohydrazide derivatives as novel apoptotic and anti-proliferative agents towards colorectal cancer cells |
title_full |
Development of 2-oxindolin-3-ylidene-indole-3-carbohydrazide derivatives as novel apoptotic and anti-proliferative agents towards colorectal cancer cells |
title_fullStr |
Development of 2-oxindolin-3-ylidene-indole-3-carbohydrazide derivatives as novel apoptotic and anti-proliferative agents towards colorectal cancer cells |
title_full_unstemmed |
Development of 2-oxindolin-3-ylidene-indole-3-carbohydrazide derivatives as novel apoptotic and anti-proliferative agents towards colorectal cancer cells |
title_sort |
development of 2-oxindolin-3-ylidene-indole-3-carbohydrazide derivatives as novel apoptotic and anti-proliferative agents towards colorectal cancer cells |
publisher |
Taylor & Francis Group |
series |
Journal of Enzyme Inhibition and Medicinal Chemistry |
issn |
1475-6366 1475-6374 |
publishDate |
2021-01-01 |
description |
Mitochondrial anti-apoptotic Bcl2 and BclxL proteins, are overexpressed in multiple tumour types, and has been involved in the progression and survival of malignant cells. Therefore, inhibition of such proteins has become a validated and attractive target for anticancer drug discovery. In this manner, the present studies developed a series of novel isatin–indole conjugates (7a-j and 9a-e) as potential anticancer Bcl2 and BclxL inhibitors. The progression of the two examined colorectal cancer cell lines was significantly inhibited by all of the prepared compounds with IC50 ranges 132–611 nM compared to IC50 = 4.6 µM for 5FU, against HT-29 and IC50 ranges 37–468 nM compared to IC50 = 1.5 µM for 5FU, against SW-620. Thereafter, compounds 7c and 7g were selected for further investigations. Interestingly, both compounds exhibited selective cytotoxicity against both cell lines with high safety to normal fibroblast (HFF-1). In addition, both compounds 7c and 7g induced apoptosis and inhibited Bcl2 and BclxL expression in a dose-dependent manner. Collectively, the high potency and selective cytotoxicity suggested that conjugates 7c and 7g could be a starting point for further optimisation to develop novel pro-apoptotic and antitumor agents towards colon cancer. |
topic |
anti-proliferative indoles apoptosis isatin-indole bcl2/bclxl inhibitors colorectal cancer western blotting |
url |
http://dx.doi.org/10.1080/14756366.2020.1862100 |
work_keys_str_mv |
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