New quinoxaline derivatives as VEGFR-2 inhibitors with anticancer and apoptotic activity: Design, molecular modeling, and synthesis

Alsaif, Nawaf A.; Dahab, Mohammed A.; Alanazi, Mohammed M.; Obaidullah, Ahmad J.; Almehizia, Abdulrahman A.; Alanazi, Manal M.; Aldawas, Saleh; Mahdy, Hazem A.; Elkady, Hazem

doi:10.1016/j.bioorg.2021.104807

Cited by 72 publications

(56 citation statements)

References 89 publications

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“…Based on facts mentioned above and in the extension of our efforts to discover novel molecules with potential anticancer activity 5,[40][41][42][43][44][45][46][47][48] , we design and synthesise a new wave of bis([1, 2, 4]triazolo)[4,3-a:3 0 ,4 0 -c]quinoxaline derivatives having the basic crucial pharmacophoric features of VEGFR-2 inhibitors.…”

Section: Rationale Of Molecular Designmentioning

confidence: 99%

Discovery of new VEGFR-2 inhibitors based on bis([1, 2, 4]triazolo)[4,3-a:3',4'-c]quinoxaline derivatives as anticancer agents and apoptosis inducers

Alsaif

Taghour

Alanazi

et al. 2021

Journal of Enzyme Inhibition and Medicinal Chemistry

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Herein, a new wave of bis([1, 2, 4]triazolo)[4,3- a :3',4'- c ]quinoxaline derivatives have been successfully designed and synthesised. The synthesised derivatives were biologically investigated for their cytotoxic activities against HepG2 and MCF-7. Also, the tested compounds were further examined in vitro for their VEGFR-2 inhibitory activity. The most promising derivative 23j was further investigated for its apoptotic behaviour in HepG2 cell lines using flow cytometric and western-plot analyses. Additional in-silico studies were performed to predict how the synthesised compounds can bind to VEGFR-2 and to determine the drug-likeness profiling of these derivatives. The results revealed that compounds 23a , 23i , 23j , 23l , and 23n displayed the highest antiproliferative activities against the two cell lines with IC 50 values ranging from 6.4 to 19.4 µM. Furthermore, compounds 23a , 23d , 23h , 23i , 23j , 23l , 23 m , and 23n showed the highest VEGFR-2 inhibitory activities with IC 50 values ranging from 3.7 to 11.8 nM, comparing to sorafenib (IC 50 = 3.12 nM). Moreover, compound 23j arrested the HepG2 cell growth at the G2/M phase and induced apoptosis by 40.12% compared to the control cells (7.07%). As well, such compound showed a significant increase in the level of caspase-3 (1.36-fold), caspase-9 (2.80-fold), and BAX (1.65-fold), and exhibited a significant decrease in Bcl-2 level (2.63-fold).

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Section: Rationale Of Molecular Designmentioning

confidence: 99%

Discovery of new VEGFR-2 inhibitors based on bis([1, 2, 4]triazolo)[4,3-a:3',4'-c]quinoxaline derivatives as anticancer agents and apoptosis inducers

Alsaif

Taghour

Alanazi

et al. 2021

Journal of Enzyme Inhibition and Medicinal Chemistry

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“…In our previous work, we developed [1,2,4]triazolo[4,3- a ]quinoxaline containing derivatives as VEGFR-2 inhibitors. Compounds 8 and 9 were the most potent candidates exhibiting an excellent VEGFR-2 inhibitory activity with a promising cytotoxic efficacy against breast and hepatocellular carcinoma 63 , 64 . In continuation of our work 63–65 aimed at synthesising new anticancer agents targeting VEGFR-2 inhibition, new quinoxaline derivatives were designed and synthesised.…”

Section: Introductionmentioning

confidence: 99%

“…Compounds 8 and 9 were the most potent candidates exhibiting an excellent VEGFR-2 inhibitory activity with a promising cytotoxic efficacy against breast and hepatocellular carcinoma 63 , 64 . In continuation of our work 63–65 aimed at synthesising new anticancer agents targeting VEGFR-2 inhibition, new quinoxaline derivatives were designed and synthesised. The synthesised compounds were evaluated for their anti-proliferative activity.…”

Section: Introductionmentioning

confidence: 99%

“…Considering compounds 7 and 8 as leading compounds 63 , 64 . The design included the replacement of [1,2,4]triazolo[4,3- a ]quinoxaline in compound 7 and/or bis([1,2,4]triazolo)[4,3- a :3′,4′- c ]quinoxaline of compound 8 by 3-methylquinoxaline scaffold.…”

Section: Introductionmentioning

confidence: 99%

“…The pharmacophore (HBD/HBA) was designed to be an amide, diamide, and/or hydrazide groups. Amide pharmacophore served as hydrogen bond donor and acceptor in many reported VEGFR-2 inhibitors 61 , 63 , 64 , 66 . Finally, different, aliphatic, and un/substituted aromatic derivatives were selected to be the terminal hydrophobic moieties to occupy the allosteric hydrophobic pocket ( Figure 2) .…”

Section: Introductionmentioning

confidence: 99%

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Design, synthesis, docking, ADMET studies, and anticancer evaluation of new 3-methylquinoxaline derivatives as VEGFR-2 inhibitors and apoptosis inducers

Alanazi

Eissa

Alsaif

et al. 2021

Journal of Enzyme Inhibition and Medicinal Chemistry

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Vascular endothelial growth factor receptor-2 (VEGFR-2) plays a critical role in cancer angiogenesis. Inhibition of VEGFR-2 activity proved effective suppression of tumour propagation. Accordingly, two series of new 3-methylquinoxaline derivatives have been designed and synthesised as VEGFR-2 inhibitors. The synthesised derivatives were evaluated in vitro for their cytotoxic activities against MCF-7and HepG2 cell lines. In addition, the VEGFR-2 inhibitory activities of the target compounds were estimated to indicate the potential mechanism of their cytotoxicity. To a great extent, the results of VEGFR-2 inhibition were highly correlated with that of cytotoxicity. Compound 27a was the most potent VEGFR-2 inhibitor with IC 50 of 3.2 nM very close to positive control sorafenib (IC 50 = 3.12 nM). Such compound exhibited a strong cytotoxic effect against MCF-7 and HepG2, respectively with IC 50 of 7.7 and 4.5 µM in comparison to sorafenib (IC 50 = 3.51 and 2.17 µM). In addition, compounds 28 , 30f , 30i , and 31b exhibited excellent VEGFR-2 inhibition activities (IC 50 range from 4.2 to 6.1 nM) with promising cytotoxic activity. Cell cycle progression and apoptosis induction were investigated for the most active member 27a . Also, the effect of 27a on the level of caspase-3, caspase-9, and BAX/Bcl-2 ratio was determined. Molecular docking studies were implemented to interpret the binding mode of the target compounds with the VEGFR-2 pocket. Furthermore, toxicity and ADMET calculations were performed for the synthesised compounds to study their pharmacokinetic profiles

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Visible‐Light‐Driven Multicomponent Radical Cascade Versatile Alkylation of Quinoxalinones Enabled by Electron Donor Acceptor Complex in Water

et al. 2023

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An operationally simple aqueous phase three-component photochemical strategy for the alkylation of quinoxalin-2(1H)-ones with diethyl α-bromomalonate and unactivated alkenes in the absence of both photoredox catalysts and additive has been developed. This reaction is driven by the photochemical activity of electron donor-acceptor (EDA) complexes formed by quinoxalin-2(1H)-ones and diethyl α-bromomalonate. Irradiation with visible light triggered single-electron transfer (SET) from the quinoxalin-2(1H)-ones to the diethyl α-bromomalonate, inducing the formation of the corresponding alkyl radical and the subsequent radical tandem reaction. It provides an efficient way to construct alkylated quinoxalinones from simple small molecules.

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New quinoxaline derivatives as VEGFR-2 inhibitors with anticancer and apoptotic activity: Design, molecular modeling, and synthesis

Cited by 72 publications

References 89 publications

Discovery of new VEGFR-2 inhibitors based on bis([1, 2, 4]triazolo)[4,3-a:3',4'-c]quinoxaline derivatives as anticancer agents and apoptosis inducers

Discovery of new VEGFR-2 inhibitors based on bis([1, 2, 4]triazolo)[4,3-a:3',4'-c]quinoxaline derivatives as anticancer agents and apoptosis inducers

Design, synthesis, docking, ADMET studies, and anticancer evaluation of new 3-methylquinoxaline derivatives as VEGFR-2 inhibitors and apoptosis inducers

Visible‐Light‐Driven Multicomponent Radical Cascade Versatile Alkylation of Quinoxalinones Enabled by Electron Donor Acceptor Complex in Water

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