Discovery of new 3-methylquinoxalines as potential anti-cancer agents and apoptosis inducers targeting VEGFR-2: design, synthesis, and in silico studies
There is an urgent need to design new anticancer agents that can prevent cancer cell proliferation even with minimal side effects. Accordingly, two new series of 3-methylquinoxalin-2(1H)-one and 3-methylquinoxaline-2-thiol derivatives were designed to act as VEGFR-2 inhibitors. The designed derivati...
| Main Authors: | , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Taylor & Francis Group
2021-01-01
|
| Series: | Journal of Enzyme Inhibition and Medicinal Chemistry |
| Subjects: | |
| Online Access: | http://dx.doi.org/10.1080/14756366.2021.1945591 |
| _version_ | 1828127140077371392 |
|---|---|
| author | Mohammed M. Alanazi Alaa Elwan Nawaf A. Alsaif Ahmad J. Obaidullah Hamad M. Alkahtani Abdulrahman A. Al-Mehizia Sultan M. Alsubaie Mohammed S. Taghour Ibrahim H. Eissa |
| author_facet | Mohammed M. Alanazi Alaa Elwan Nawaf A. Alsaif Ahmad J. Obaidullah Hamad M. Alkahtani Abdulrahman A. Al-Mehizia Sultan M. Alsubaie Mohammed S. Taghour Ibrahim H. Eissa |
| author_sort | Mohammed M. Alanazi |
| collection | DOAJ |
| description | There is an urgent need to design new anticancer agents that can prevent cancer cell proliferation even with minimal side effects. Accordingly, two new series of 3-methylquinoxalin-2(1H)-one and 3-methylquinoxaline-2-thiol derivatives were designed to act as VEGFR-2 inhibitors. The designed derivatives were synthesised and evaluated in vitro as cytotoxic agents against two human cancer cell lines namely, HepG-2 and MCF-7. Also, the synthesised derivatives were assessed for their VEGFR-2inhibitory effect. The most promising member 11e were further investigated to reach a valuable insight about its apoptotic effect through cell cycle and apoptosis analyses. Moreover, deep investigations were carried out for compound 11e using western-plot analyses to detect its effect against some apoptotic and apoptotic parameters including caspase-9, caspase-3, BAX, and Bcl-2. Many in silico investigations including docking, ADMET, toxicity studies were performed to predict binding affinity, pharmacokinetic, drug likeness, and toxicity of the synthesised compounds. The results revealed that compounds 11e, 11g, 12e, 12g, and 12k exhibited promising cytotoxic activities (IC50 range is 2.1 − 9.8 µM), comparing to sorafenib (IC50 = 3.4 and 2.2 µM against MCF-7 and HepG2, respectively). Moreover, 11b, 11f, 11g, 12e, 12f, 12g, and 12k showed the highest VEGFR-2 inhibitory activities (IC50 range is 2.9 − 5.4 µM), comparing to sorafenib (IC50 = 3.07 nM). Additionally, compound 11e had good potential to arrest the HepG2 cell growth at G2/M phase and to induce apoptosis by 49.14% compared to the control cells (9.71%). As well, such compound showed a significant increase in the level of caspase-3 (2.34-fold), caspase-9 (2.34-fold), and BAX (3.14-fold), and a significant decrease in Bcl-2 level (3.13-fold). For in silico studies, the synthesised compounds showed binding mode similar to that of the reference compound (sorafenib). |
| first_indexed | 2024-04-11T15:44:49Z |
| format | Article |
| id | doaj.art-7c162b46559e47c1a587919180244654 |
| institution | Directory Open Access Journal |
| issn | 1475-6366 1475-6374 |
| language | English |
| last_indexed | 2024-04-11T15:44:49Z |
| publishDate | 2021-01-01 |
| publisher | Taylor & Francis Group |
| record_format | Article |
| series | Journal of Enzyme Inhibition and Medicinal Chemistry |
| spelling | doaj.art-7c162b46559e47c1a5879191802446542022-12-22T04:15:37ZengTaylor & Francis GroupJournal of Enzyme Inhibition and Medicinal Chemistry1475-63661475-63742021-01-013611732175010.1080/14756366.2021.19455911945591Discovery of new 3-methylquinoxalines as potential anti-cancer agents and apoptosis inducers targeting VEGFR-2: design, synthesis, and in silico studiesMohammed M. Alanazi0Alaa Elwan1Nawaf A. Alsaif2Ahmad J. Obaidullah3Hamad M. Alkahtani4Abdulrahman A. Al-Mehizia5Sultan M. Alsubaie6Mohammed S. Taghour7Ibrahim H. Eissa8Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud UniversityPharmaceutical Medicinal Chemistry and Drug Design Department, Faculty of Pharmacy (Boys), Al-Azhar UniversityDepartment of Pharmaceutical Chemistry, College of Pharmacy, King Saud UniversityDepartment of Pharmaceutical Chemistry, College of Pharmacy, King Saud UniversityDepartment of Pharmaceutical Chemistry, College of Pharmacy, King Saud UniversityDepartment of Pharmaceutical Chemistry, College of Pharmacy, King Saud UniversityDepartment of Pharmaceutical Chemistry, College of Pharmacy, King Saud UniversityPharmaceutical Medicinal Chemistry and Drug Design Department, Faculty of Pharmacy (Boys), Al-Azhar UniversityPharmaceutical Medicinal Chemistry and Drug Design Department, Faculty of Pharmacy (Boys), Al-Azhar UniversityThere is an urgent need to design new anticancer agents that can prevent cancer cell proliferation even with minimal side effects. Accordingly, two new series of 3-methylquinoxalin-2(1H)-one and 3-methylquinoxaline-2-thiol derivatives were designed to act as VEGFR-2 inhibitors. The designed derivatives were synthesised and evaluated in vitro as cytotoxic agents against two human cancer cell lines namely, HepG-2 and MCF-7. Also, the synthesised derivatives were assessed for their VEGFR-2inhibitory effect. The most promising member 11e were further investigated to reach a valuable insight about its apoptotic effect through cell cycle and apoptosis analyses. Moreover, deep investigations were carried out for compound 11e using western-plot analyses to detect its effect against some apoptotic and apoptotic parameters including caspase-9, caspase-3, BAX, and Bcl-2. Many in silico investigations including docking, ADMET, toxicity studies were performed to predict binding affinity, pharmacokinetic, drug likeness, and toxicity of the synthesised compounds. The results revealed that compounds 11e, 11g, 12e, 12g, and 12k exhibited promising cytotoxic activities (IC50 range is 2.1 − 9.8 µM), comparing to sorafenib (IC50 = 3.4 and 2.2 µM against MCF-7 and HepG2, respectively). Moreover, 11b, 11f, 11g, 12e, 12f, 12g, and 12k showed the highest VEGFR-2 inhibitory activities (IC50 range is 2.9 − 5.4 µM), comparing to sorafenib (IC50 = 3.07 nM). Additionally, compound 11e had good potential to arrest the HepG2 cell growth at G2/M phase and to induce apoptosis by 49.14% compared to the control cells (9.71%). As well, such compound showed a significant increase in the level of caspase-3 (2.34-fold), caspase-9 (2.34-fold), and BAX (3.14-fold), and a significant decrease in Bcl-2 level (3.13-fold). For in silico studies, the synthesised compounds showed binding mode similar to that of the reference compound (sorafenib).http://dx.doi.org/10.1080/14756366.2021.1945591anticancerapoptosisin silico studies3-methylquinoxalin-2(1h)-one3-methylquinoxaline-2-thiolvegfr-2 inhibitors |
| spellingShingle | Mohammed M. Alanazi Alaa Elwan Nawaf A. Alsaif Ahmad J. Obaidullah Hamad M. Alkahtani Abdulrahman A. Al-Mehizia Sultan M. Alsubaie Mohammed S. Taghour Ibrahim H. Eissa Discovery of new 3-methylquinoxalines as potential anti-cancer agents and apoptosis inducers targeting VEGFR-2: design, synthesis, and in silico studies Journal of Enzyme Inhibition and Medicinal Chemistry anticancer apoptosis in silico studies 3-methylquinoxalin-2(1h)-one 3-methylquinoxaline-2-thiol vegfr-2 inhibitors |
| title | Discovery of new 3-methylquinoxalines as potential anti-cancer agents and apoptosis inducers targeting VEGFR-2: design, synthesis, and in silico studies |
| title_full | Discovery of new 3-methylquinoxalines as potential anti-cancer agents and apoptosis inducers targeting VEGFR-2: design, synthesis, and in silico studies |
| title_fullStr | Discovery of new 3-methylquinoxalines as potential anti-cancer agents and apoptosis inducers targeting VEGFR-2: design, synthesis, and in silico studies |
| title_full_unstemmed | Discovery of new 3-methylquinoxalines as potential anti-cancer agents and apoptosis inducers targeting VEGFR-2: design, synthesis, and in silico studies |
| title_short | Discovery of new 3-methylquinoxalines as potential anti-cancer agents and apoptosis inducers targeting VEGFR-2: design, synthesis, and in silico studies |
| title_sort | discovery of new 3 methylquinoxalines as potential anti cancer agents and apoptosis inducers targeting vegfr 2 design synthesis and in silico studies |
| topic | anticancer apoptosis in silico studies 3-methylquinoxalin-2(1h)-one 3-methylquinoxaline-2-thiol vegfr-2 inhibitors |
| url | http://dx.doi.org/10.1080/14756366.2021.1945591 |
| work_keys_str_mv | AT mohammedmalanazi discoveryofnew3methylquinoxalinesaspotentialanticanceragentsandapoptosisinducerstargetingvegfr2designsynthesisandinsilicostudies AT alaaelwan discoveryofnew3methylquinoxalinesaspotentialanticanceragentsandapoptosisinducerstargetingvegfr2designsynthesisandinsilicostudies AT nawafaalsaif discoveryofnew3methylquinoxalinesaspotentialanticanceragentsandapoptosisinducerstargetingvegfr2designsynthesisandinsilicostudies AT ahmadjobaidullah discoveryofnew3methylquinoxalinesaspotentialanticanceragentsandapoptosisinducerstargetingvegfr2designsynthesisandinsilicostudies AT hamadmalkahtani discoveryofnew3methylquinoxalinesaspotentialanticanceragentsandapoptosisinducerstargetingvegfr2designsynthesisandinsilicostudies AT abdulrahmanaalmehizia discoveryofnew3methylquinoxalinesaspotentialanticanceragentsandapoptosisinducerstargetingvegfr2designsynthesisandinsilicostudies AT sultanmalsubaie discoveryofnew3methylquinoxalinesaspotentialanticanceragentsandapoptosisinducerstargetingvegfr2designsynthesisandinsilicostudies AT mohammedstaghour discoveryofnew3methylquinoxalinesaspotentialanticanceragentsandapoptosisinducerstargetingvegfr2designsynthesisandinsilicostudies AT ibrahimheissa discoveryofnew3methylquinoxalinesaspotentialanticanceragentsandapoptosisinducerstargetingvegfr2designsynthesisandinsilicostudies |