Design, synthesis, and biological evaluation of thieno[2,3-d]pyrimidine derivatives as novel dual c-Met and VEGFR-2 kinase inhibitors

Li, Jieming; Gu, Weijie; Bi, Xinzhou; Li, Huilan; Liao, Chen; Liu, Chunxia; Huang, Wenlong; Qian, Hai

doi:10.1016/j.bmc.2017.11.010

Cited by 26 publications

(16 citation statements)

References 22 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%

“…[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. [28,29] 1.1 | Rationale and aim of the work Over the last few years, our research group members were interested in the construction and evaluation of heterocyclic molecules with expected biological activity, particularly those with anticancer 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%

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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“…Among the test compounds, compound 18 (which was found to be the most potent compound) could inhibit the kinase activities of VEGFR-2 and c-Met with IC 50 values of 0.048 ± 0.006 µM and 0.025 ± 0.003 µM, respectively. This study provided us with clear SARs, which would help design more effective VEGFR-2/c-Met inhibitors [71].…”

Section: Thienopyrimidine Derivativesmentioning

confidence: 95%

Research Progress of Small Molecule VEGFR/c-Met Inhibitors as Anticancer Agents (2016–Present)

2020

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Vascular endothelial growth factor receptor 2 (VEGFR-2) binds to VEGFR-A, VEGFR-C and VEGFR-D and participates in the formation of tumor blood vessels, mediates the proliferation of endothelial cells, enhances microvascular permeability, and blocks apoptosis. Blocking or downregulating the signal transduction of VEGFR is the main way to discover new drugs for many human angiogenesis-dependent malignancies. Mesenchymal epithelial transfer factor tyrosine kinase (c-Met) is a high affinity receptor for hepatocyte growth factor (HGF). Abnormal c-Met signaling plays an important role in the formation, invasion and metastasis of human tumors. Therefore, the HGF/c-Met signaling pathway has become a significant target for cancer treatment. Related studies have shown that the conduction of the VEGFR and c-Met signaling pathways has a synergistic effect in inducing angiogenesis and inhibiting tumor growth. In recent years, multi-target small molecule inhibitors have become a research hotspot, among which the research of VEGFR and c-Met dual-target small molecule inhibitors has become more and more extensive. In this review, we comprehensively summarize the chemical structures and biological characteristics of novel VEGFR/c-Met dual-target small-molecule inhibitors in the past five years.

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“…However, dysregulation of RTK signaling at the cellular level leads to an assortment of human diseases, most notably cancers. , The vascular endothelial growth factor 2 (VEGFR2) and c-mesenchymal epithelial transition factor (c-Met) are RTKs which are linked to the hepatocyte growth factor and endothelial cells, respectively. These RTKs activate the phosphorylation cascade of different tyrosines through the dimerization process aided by ATP to terminally induce cell growth. − The role of c-Met and VEGFR2 is complementary in the process of induction of angiogenesis of human cancer cells. , This significant role in tumorigenesis has received great attention in different research groups − for dual targeting VEGFR2 and c-Met kinases by novel antiangiogenic agents, as represented in Figure .…”

Section: Introductionmentioning

confidence: 99%

Dual Targeting of VEGFR2 and C-Met Kinases via the Design and Synthesis of Substituted 3-(Triazolo-thiadiazin-3-yl)indolin-2-one Derivatives as Angiogenesis Inhibitors

et al. 2020

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The vascular endothelial growth factor receptor 2 (VEGFR2) and c-mesenchymal epithelial transition factor (c-Met) are members of receptor tyrosine kinases which have a crucial role in the process of angiogenesis. Isatin moiety is a versatile group that is shared in many compounds targeting both c-Met and VEGFR2 kinases. In this study, we designed and synthesized different derivatives of substituted 3-(triazolo-thiadiazin-3-yl)indolin-2-one derivatives ( 6a–y ) as dual inhibitors for c-Met and VEGFR2 enzymes. Eight compounds 6a , 6b , 6e , 6l , 6n , 6r , 6v , and 6y were assessed for their anticancer activities against a panel of 58 cancer cell lines according to the US-NCI protocol. Compound 6b revealed the most effective antiproliferative potency (GI %), with broad-spectrum activity against different subpanels of the most NCI 58 tumor cell lines. An in vivo hen’s egg-chorioallantoic membrane (HET-CAM) angiogenic study was carried out for 21 compounds 6a , b , d , f , h , i , k–o , t , and 6x to check their mortality and toxicity. At 100 μM concentration, all compounds produced 100% mortality of the chick embryos. At 40 μM concentration, 13 compounds did not exhibit any detectable mortality (nontoxic) and revealed a potent antiangiogenic effect. Seven compounds 6b , 6d , 6f , 6n , 6o , 6t , and 6x significantly decreased the number of blood vessels, and compound 6b was the most effective antiangiogenic agent comparable to dexamethasone. Molecular docking studies were conducted for compound 6b to investigate its mode of interaction within the binding site of both c-Met and VEGFR2 kinases.

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Design, synthesis, and biological evaluation of thieno[2,3-d]pyrimidine derivatives as novel dual c-Met and VEGFR-2 kinase inhibitors

Cited by 26 publications

References 22 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

Research Progress of Small Molecule VEGFR/c-Met Inhibitors as Anticancer Agents (2016–Present)

Dual Targeting of VEGFR2 and C-Met Kinases via the Design and Synthesis of Substituted 3-(Triazolo-thiadiazin-3-yl)indolin-2-one Derivatives as Angiogenesis Inhibitors

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