Selective VEGFR-2 inhibitors: Synthesis of pyridine derivatives, cytotoxicity and apoptosis induction profiling

AbdelHaleem, Amal; Mansour, Amira O.; AbdelKader, Marwa; Ibrahim, Tamer M.

doi:10.1016/j.bioorg.2020.104222

Cited by 24 publications

(14 citation statements)

References 30 publications

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“…The most active compound showed G1 arrest of cell cycle in MCF-7 cells (Figure 3M). [52] Two novel sets of benzene sulfonamide derivatives were developed as VEGFR-2 inhibitors. The most potent compound was obtained with inhibitory effects of 0.64 μM; also, it was found to arrest the G2/M phase and increase the expression of Bax and decrease Bcl-2.…”

Section: Progress Of Vegfr Signaling Inhibitorsmentioning

confidence: 99%

Recent Anti‐angiogenic Drug Discovery Efforts To Combat Cancer

et al. 2021

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The process of angiogenesis promotes tumor growth and metastatic spreading and angiogenesis inhibition has therapeutic efficacy in many preclinical models. The discovery of pathways mediating tumor angiogenesis, in particular VEGFs and their receptors, paved the way to the development of antiangiogenic drugs to translate into clinic as anti-cancer agents. However, dozens of anti-angiogenic drugs have been approved and routinely used under clinical practice. However, with the compelling preclinical evidence demonstrating anti-cancer activity, therapeutic benefits in patients remained modest. Recent progress in understanding the biology of tumor angiogenesis and their molecular mechanisms opened a new prospect for improving therapeutic strategies. An emergent approach to improve efficacy and avoid resistance is to hit multiple angiogenesis pathways and or administration in combination with other anticancer agents. In this review, we have highlighted some of the emerging aspects and discussed new antiangiogenic drug discovery in the past five years.

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Section: Progress Of Vegfr Signaling Inhibitorsmentioning

confidence: 99%

Recent Anti‐angiogenic Drug Discovery Efforts To Combat Cancer

et al. 2021

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“…Small‐molecule ATP‐competitive inhibitors of VEGFR‐2 (Type I inhibitors) based on a pyridine nucleus have demonstrated high activity as antitumor agents like apatinib ( III ), motesanib ( IV ), and sorafenib ( I ), as displayed in Figure 2. [ 17–21 ] In 2020, AbdelHaleem et al [ 22 ] designed a series of new pyridine scaffolds that were biologically evaluated for their inhibitory activity against VEGFR‐2. The most potent compound ( V ) (Figure 2) displayed very good anticancer activities against two prostate cancer cell lines, namely PC3 and DU145, and two breast cancer cell lines, namely MCF‐7 and MDA‐MB435, with IC 50 values of 55, 8.5, 0.5, and 96 nM, respectively.…”

Section: Introductionmentioning

confidence: 99%

“…It also inhibited VEGFR‐2 at an IC 50 value of 0.19 nM. [ 22 ] Moreover, the bioisostere pyrimidine derivative compound ( VI ) (Figure 2) displayed very good anticancer activities and potently inhibited VEGFR‐2 at an IC 50 value of 1.97 µM. [ 23 ]…”

Section: Introductionmentioning

confidence: 99%

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Pyridine‐derived VEGFR‐2 inhibitors: Rational design, synthesis, anticancer evaluations, in silico ADMET profile, and molecular docking

Saleh

Abdel‐Rahman

Omar

et al. 2021

Archiv der Pharmazie

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Novel pyridine‐derived compounds (5–19) were designed and synthesized, and their anticancer activities were evaluated against HepG2 and MCF‐7 cells, targeting the VEGFR‐2 enzyme. Compounds 10, 9, 8, and 15 were found to be the most potent derivatives against the two cancer cell lines, HepG2 and MCF‐7, respectively, with IC50 = 4.25 and 6.08 µM, 4.68 and 11.06 µM, 4.34 and 10.29 µM, and 6.37 and 12.83 µM. Compound 10 displayed higher activity against HepG2 cells than sorafenib (IC50 = 9.18 and 5.47 µM, respectively) and doxorubicin (IC50 = 7.94 and 8.07 µM, respectively). It also showed higher activity than doxorubicin against MCF‐7 cells, but lower activity than sorafenib. Compounds 9, 8, and 15 displayed higher activities than sorafenib and doxorubicin against HepG2 cells but exhibited lower activities against MCF‐7 cells. Compound 10 potently inhibited VEGFR‐2 at an IC50 value of 0.12 µM, which is nearly equipotent to sorafenib (IC50 = 0.10 µM). Compounds 8 and 9 exhibited very good activity with the same IC50 value of 0.13 µM. The six most potent derivatives, 6, 9, 8, 10, 15, and 18, were tested for their cytotoxicity against normal Vero cells. Compounds 6, 8, 9, 10, 15, and 18 are, respectively, 1.13, 3.74, 4.18, 3.64, 2.81, and 2.00 times more toxic to HepG2 and 2.06, 1.58, 1.76, 2.54, 1.40, and 2.69 times more toxic to MCF‐7 breast cancer cells than in normal Vero cells.

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“…Caspase 9 is the initiator of intrinsic apoptosis while caspase 3 plays a central role in the execution phase of apoptosis 27 . Cancer cells can avoid apoptosis by hindering caspase function, decreasing BAX expression level or increasing the gene expression level of anti-apoptotic Bcl-2 27 , 28 .…”

Section: Introductionmentioning

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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Selective VEGFR-2 inhibitors: Synthesis of pyridine derivatives, cytotoxicity and apoptosis induction profiling

Cited by 24 publications

References 30 publications

Recent Anti‐angiogenic Drug Discovery Efforts To Combat Cancer

Recent Anti‐angiogenic Drug Discovery Efforts To Combat Cancer

Pyridine‐derived VEGFR‐2 inhibitors: Rational design, synthesis, anticancer evaluations, in silico ADMET profile, and molecular docking

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

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