Design, synthesis and biological evaluation of pyrimidine-based derivatives as VEGFR-2 tyrosine kinase inhibitors

Sun, Wuji; Hu, Shengquan; Fang, Shubiao; Yan, Hong

doi:10.1016/j.bioorg.2018.04.005

Cited by 32 publications

(16 citation statements)

References 31 publications

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“…[21,22] Other pharmacophoric heterocycles have been implanted in the structures of recently reported anticancer agents with a VEGFR-2 inhibitory effect, for example, pyrazole [23,24] and pyrimidine. [25,26] The latter were reported to have spatial configurations that enable both to interact with the VEGFR-2 binding site. [26,27] Moreover, the α,β-unsaturated ketonic fragment is also present in a number of synthetic derivatives with potent VEGFR-2 inhibitory activity.…”

Section: Introductionmentioning

confidence: 99%

“…All the designed compounds retained the essential pharmacophoric features of the reported and clinically used VEGFR-2 inhibitors (Figure 2), with two additional bioisosteric modifications: (i) insertion of a new bioisosteric linker with that reported in the most recent molecular docking and molecular dynamic simulation studies. [13] The new linker was inserted in the form of pharmacophoric fragments with reported anticancer potential including an α,β-unsaturated ketonic fragment, [28,29] dihydropyrazole, [23,24] and pyrimidine [25,26] In a dose-dependent manner, VEGFR-2 was reported to be considerably upregulated in HepG2 cells with the stimulation of the hepatocyte growth factor, which is involved in the cell proliferation of hepatocellular carcinoma (HCC). [37,38] Blockade of VEGFR-2 signaling markedly inhibited the growth and metastasis of HCC.…”

Section: Introductionmentioning

confidence: 99%

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Phthalazine‐based VEGFR‐2 inhibitors: Rationale, design, synthesis, in silico, ADMET profile, docking, and anticancer evaluations

Khedr

Ibrahim

Eissa

et al. 2021

Archiv der Pharmazie

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In the designed compounds, a new linker was inserted in the form of fragments with verified VEGFR‐2 inhibitory potential, including an α,β‐unsaturated ketonic fragment, pyrazole, and pyrimidine. Also, new distal hydrophobic moieties were attached to these linkers that are expected to increase the hydrophobic interaction with VEGFR‐2 and, consequently, the affinity. These structural optimizations have led us to identify the novel dihydropyrazole derivative 6e as a promising hit molecule. All the new derivatives were evaluated to assess their anticancer activity against three human cancer cell lines, including HepG2, HCT‐116, and MCF‐7. The results of the in vitro anticancer evaluation study revealed the moderate to excellent cytotoxicity of 6c, 6e, 6g, and 7b, with IC50 values in the low micromolar range. The inhibitory activity of VEGFR‐2 was investigated for 16 of the designed compounds. The enzyme assay results of the new compounds were compared with those of sorafenib as a reference VEGFR‐2 inhibitor. The obtained results demonstrated that our derivatives are potent VEGFR‐2 inhibitors. The most potent derivatives 6c, 6e, 6g, and 7b showed IC50 values in the range of 0.11–0.22 µM. Molecular docking and pharmacokinetic studies were also conducted to rationalize the VEGFR‐2 inhibitory activity and to evaluate the ability of the most potent derivatives to be developed as good drug candidates.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Phthalazine‐based VEGFR‐2 inhibitors: Rationale, design, synthesis, in silico, ADMET profile, docking, and anticancer evaluations

Khedr

Ibrahim

Eissa

et al. 2021

Archiv der Pharmazie

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“…[53] A new set of pyrimidine based VEGFR-2 tyrosine kinase inhibitors were developed with excellent cytotoxicity on cancer cell lines and VEGFR-2 inhibitory activity (0.23 μM, Figure 3O). [54] A series of furo [2,3-d]pyrimidine and thieno [2,3-d] pyrimidine compounds were synthesized as VEGFR-2 inhibitors with inhibitory activity in nanomolar (21 nM) range. The most active compound showed inhibition of HUVEC proliferation and also showed potent anticancer activity in EAC murine model (Figure 3P).…”

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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“…Mutation of EGFR may induce the resistance of tyrosine kinase inhibitors (TKIs) [53]. Notably, in tumor angiogenesis, vascular endothelial growth factor receptor-2 (VEGFR-2) plays a key role, and inhibition of VEGFR-2 signaling pathway has become an attractive cancer treatment method [54]. The binding of VEGF to VEGFR-2 stimulates the signaling pathway (PI3K/Akt, p38MAPK) that mediates several cellular functions.…”

Section: Epidermal Growth Factor Receptor Egfrmentioning

confidence: 99%

What Are the New Challenges of the Current Cancer Biomarkers?

Chen¹,

Duan²,

Pu³

et al. 2020

Current Cancer Treatment

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Biomarkers are emerging research filed in the past decade. Even though numerous biomarkers were reported, the efficiency of cancer therapy remains low. So the question emerges as to how much can we trust the current biomarkers on cancer therapy? In this upcoming chapter, we would like to illustrate the outcomes of classical cancer therapies on advanced pancreatic cancer disclosed successful, neutral and failed in clinical trials. The analysis will be carried on the perspective interdisciplinary on the biomarkers including anatomy, physiology, pharmacology, biochemistry, history path and development of pharmacy. Particular in-depth insight may open a window for new researches and lighting the therapies.

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Design, synthesis and biological evaluation of pyrimidine-based derivatives as VEGFR-2 tyrosine kinase inhibitors

Cited by 32 publications

References 31 publications

Phthalazine‐based VEGFR‐2 inhibitors: Rationale, design, synthesis, in silico, ADMET profile, docking, and anticancer evaluations

Phthalazine‐based VEGFR‐2 inhibitors: Rationale, design, synthesis, in silico, ADMET profile, docking, and anticancer evaluations

Recent Anti‐angiogenic Drug Discovery Efforts To Combat Cancer

What Are the New Challenges of the Current Cancer Biomarkers?

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