Novel Thiazolidinone/Thiazolo[3,2-a]Benzimidazolone-Isatin Conjugates as Apoptotic Anti-proliferative Agents Towards Breast Cancer: One-Pot Synthesis and In Vitro Biological Evaluation
In connection with our research program on the development of new isatin-based anticancer candidates, herein we report the synthesis of two novel series of thiazolidinone-isatin conjugates (4a–n) and thiazolo[3,2-a]benzimidazolone-isatin conjugates (7a–d), and in vitro evaluation...
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| Format: | Article |
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MDPI AG
2018-06-01
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| Series: | Molecules |
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| Online Access: | http://www.mdpi.com/1420-3049/23/6/1420 |
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| author | Mohamed El-Naggar Wagdy M. Eldehna Hadia Almahli Amr Elgez Mohamed Fares Mahmoud M. Elaasser Hatem A. Abdel-Aziz |
| author_facet | Mohamed El-Naggar Wagdy M. Eldehna Hadia Almahli Amr Elgez Mohamed Fares Mahmoud M. Elaasser Hatem A. Abdel-Aziz |
| author_sort | Mohamed El-Naggar |
| collection | DOAJ |
| description | In connection with our research program on the development of new isatin-based anticancer candidates, herein we report the synthesis of two novel series of thiazolidinone-isatin conjugates (4a–n) and thiazolo[3,2-a]benzimidazolone-isatin conjugates (7a–d), and in vitro evaluation of their antiproliferative activity towards two breast cancer cell lines; triple negative MDA-MB-231, and MCF-7. Compounds 4m and 7b emerged as the most active congeners against MDA-MB-231 cells (IC50 = 7.6 ± 0.5 and 13.2 ± 1.1 µM, respectively). Compounds 4m and 7b were able to provoke apoptosis in MDA-MB-231 cells, evidenced by the up-regulation of Bax and down-regulation of Bcl-2, besides boosting caspase-3 levels. Hybrid 4m induced a fourfold increase in the percentage of cells at Sub-G1, with concurrent arrest in G2-M phase by 2.5-folds. Furthermore, hybrid 4m resulted in a sixfold increase in the percentage of annexin V-FITC positive apoptotic MDA-MB-231 cells as compared with the control. Moreover, the cytotoxic activities of the active conjugates were assessed towards two nontumorigenic cell lines (breast MCF-10A and lung WI-38) where both conjugates 4m and 7b displayed mean tumor selectivity index: 9.6 and 13.9, respectively. Finally, several ADME descriptors were predicted for the active conjugates via a theoretical kinetic study. |
| first_indexed | 2024-12-22T06:19:49Z |
| format | Article |
| id | doaj.art-6745a005c14045b8ace8e7c613e1f344 |
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| issn | 1420-3049 |
| language | English |
| last_indexed | 2024-12-22T06:19:49Z |
| publishDate | 2018-06-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Molecules |
| spelling | doaj.art-6745a005c14045b8ace8e7c613e1f3442022-12-21T18:36:00ZengMDPI AGMolecules1420-30492018-06-01236142010.3390/molecules23061420molecules23061420Novel Thiazolidinone/Thiazolo[3,2-a]Benzimidazolone-Isatin Conjugates as Apoptotic Anti-proliferative Agents Towards Breast Cancer: One-Pot Synthesis and In Vitro Biological EvaluationMohamed El-Naggar0Wagdy M. Eldehna1Hadia Almahli2Amr Elgez3Mohamed Fares4Mahmoud M. Elaasser5Hatem A. Abdel-Aziz6Chemistry Department, Faculty of Sciences, University of Sharjah, Sharjah 27272, UAEDepartment of Pharmaceutical Chemistry, Faculty of Pharmacy, Kafrelsheikh University, Kafrelsheikh 33516, EgyptChemistry Research Laboratory, Department of Chemistry, University of Oxford, 12 Mansfield Road, OX1 3TA Oxford, UKDepartment of Pharmacology and Toxicology, Faculty of Pharmacy, Egyptian Russian University, Badr City, Cairo 11829, EgyptDepartment of Pharmaceutical Chemistry, Faculty of Pharmacy, Egyptian Russian University, Badr City, Cairo 11829, EgyptThe Regional Center for Mycology and Biotechnology, Al-Azhar University, Cairo 11759, EgyptDepartment of Applied Organic Chemistry, National Research Center, Dokki, Cairo 12622, EgyptIn connection with our research program on the development of new isatin-based anticancer candidates, herein we report the synthesis of two novel series of thiazolidinone-isatin conjugates (4a–n) and thiazolo[3,2-a]benzimidazolone-isatin conjugates (7a–d), and in vitro evaluation of their antiproliferative activity towards two breast cancer cell lines; triple negative MDA-MB-231, and MCF-7. Compounds 4m and 7b emerged as the most active congeners against MDA-MB-231 cells (IC50 = 7.6 ± 0.5 and 13.2 ± 1.1 µM, respectively). Compounds 4m and 7b were able to provoke apoptosis in MDA-MB-231 cells, evidenced by the up-regulation of Bax and down-regulation of Bcl-2, besides boosting caspase-3 levels. Hybrid 4m induced a fourfold increase in the percentage of cells at Sub-G1, with concurrent arrest in G2-M phase by 2.5-folds. Furthermore, hybrid 4m resulted in a sixfold increase in the percentage of annexin V-FITC positive apoptotic MDA-MB-231 cells as compared with the control. Moreover, the cytotoxic activities of the active conjugates were assessed towards two nontumorigenic cell lines (breast MCF-10A and lung WI-38) where both conjugates 4m and 7b displayed mean tumor selectivity index: 9.6 and 13.9, respectively. Finally, several ADME descriptors were predicted for the active conjugates via a theoretical kinetic study.http://www.mdpi.com/1420-3049/23/6/1420triple-negative breast cancerisatin-thiazolidinone hybridsanticancerapoptosisQSAR |
| spellingShingle | Mohamed El-Naggar Wagdy M. Eldehna Hadia Almahli Amr Elgez Mohamed Fares Mahmoud M. Elaasser Hatem A. Abdel-Aziz Novel Thiazolidinone/Thiazolo[3,2-a]Benzimidazolone-Isatin Conjugates as Apoptotic Anti-proliferative Agents Towards Breast Cancer: One-Pot Synthesis and In Vitro Biological Evaluation Molecules triple-negative breast cancer isatin-thiazolidinone hybrids anticancer apoptosis QSAR |
| title | Novel Thiazolidinone/Thiazolo[3,2-a]Benzimidazolone-Isatin Conjugates as Apoptotic Anti-proliferative Agents Towards Breast Cancer: One-Pot Synthesis and In Vitro Biological Evaluation |
| title_full | Novel Thiazolidinone/Thiazolo[3,2-a]Benzimidazolone-Isatin Conjugates as Apoptotic Anti-proliferative Agents Towards Breast Cancer: One-Pot Synthesis and In Vitro Biological Evaluation |
| title_fullStr | Novel Thiazolidinone/Thiazolo[3,2-a]Benzimidazolone-Isatin Conjugates as Apoptotic Anti-proliferative Agents Towards Breast Cancer: One-Pot Synthesis and In Vitro Biological Evaluation |
| title_full_unstemmed | Novel Thiazolidinone/Thiazolo[3,2-a]Benzimidazolone-Isatin Conjugates as Apoptotic Anti-proliferative Agents Towards Breast Cancer: One-Pot Synthesis and In Vitro Biological Evaluation |
| title_short | Novel Thiazolidinone/Thiazolo[3,2-a]Benzimidazolone-Isatin Conjugates as Apoptotic Anti-proliferative Agents Towards Breast Cancer: One-Pot Synthesis and In Vitro Biological Evaluation |
| title_sort | novel thiazolidinone thiazolo 3 2 a benzimidazolone isatin conjugates as apoptotic anti proliferative agents towards breast cancer one pot synthesis and in vitro biological evaluation |
| topic | triple-negative breast cancer isatin-thiazolidinone hybrids anticancer apoptosis QSAR |
| url | http://www.mdpi.com/1420-3049/23/6/1420 |
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