New bis([1,2,4]triazolo)[4,3-a:3′,4′-c]quinoxaline derivatives as VEGFR-2 inhibitors and apoptosis inducers: Design, synthesis, in silico studies, and anticancer evaluation

New bis([1,2,4]triazolo)[4,3-a:3′,4′-c]quinoxaline derivatives as VEGFR-2 inhibitors and apoptosis inducers: Design, synthesis, in silico studies, and anticancer evaluation

[Display omitted] •Sixteen bis([1,2,4]triazolo)[4,3-a:3′,4′-c]quinoxaline derivatives were designed and synthesized.•VEGFR-2 inhibitory activities and cytotoxic activities were evaluated against HepG-2 and MCF-7.•The effects on caspase-3, caspase-9, BAX, and Bcl-2 were studied.•Molecular docking stu...

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Bibliographic Details
Published in:Bioorganic chemistry 2021-07, Vol.112, p.104949-104949, Article 104949
Main Authors: Alanazi, Mohammed M., Mahdy, Hazem A., Alsaif, Nawaf A., Obaidullah, Ahmad J., Alkahtani, Hamad M., Al-Mehizia, Abdulrahman A., Alsubaie, Sultan M., Dahab, Mohammed A., Eissa, Ibrahim H.
Format: Article
Language:eng
Subjects:
Anti-proliferative
Apoptosis
Bis([1,2,4]triazolo)[4,3-a:3′,4′-c]quinoxaline
Docking studies
VEGFR-2 inhibitors
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Summary:[Display omitted] •Sixteen bis([1,2,4]triazolo)[4,3-a:3′,4′-c]quinoxaline derivatives were designed and synthesized.•VEGFR-2 inhibitory activities and cytotoxic activities were evaluated against HepG-2 and MCF-7.•The effects on caspase-3, caspase-9, BAX, and Bcl-2 were studied.•Molecular docking studies were carried out against VEGFR-2. A new series of bis([1,2,4]triazolo)[4,3-a:3′,4′-c]quinoxaline derivatives were designed and synthesized to have the main essential pharmacophoric features of VEGFR-2 inhibitors. VEGFR-2 inhibitory activities were assessed for the designed compounds. In addition, cytotoxic activity was evaluated for all derivatives against two human cancer cell lines namely, HepG-2 and MCF-7. The most cytotoxic compound 20 h was subjected to further biological investigations including cell cycle, apoptosis, caspase-3, caspase-9, BAX, and Bcl-2 analyses. Different in silico studies as docking, ADMET and toxicity were carried out. The results exhibited that compounds 20b, 20e, 20h and20mshowed promising VEGFR-2 inhibitory activities with IC50values of 5.7, 6.7, 3.2, and 3.1 µM, respectively. Moreover, these promising members exhibited the highest antiproliferative activities against the two cell lines with IC50values ranging from 3.3 to 14.2 µM, comparing to sorafenib (IC50 = 2.17 and 3.43 µM against HepG2 and MCF-7, respectively). Additionally, compound 20h induced cell cycle arrest of HepG2 cells at G2/M phase. Also, such compound increased the progress of apoptosis by 3.5-fold compared to the control. As well, compound 20h showed a significant increase in the level of caspase-3 (2.07-fold), caspase-9 (1.72-fold), and BAX (1.83-fold), and a significant decrease in Bcl-2 level (1.92-fold). The in silico studies revealed that the synthesized compounds have binding pattern like that of sorafenib.
ISSN:0045-2068
1090-2120