Synthesis and bioevaluation and doking study of 1 H -pyrrolo[2,3- b ]pyridine derivatives bearing aromatic hydrazone moiety as c-Met inhibitors

Wang, Wenhui; Xu, Shan; Duan, Yongli; Liu, Xiaobo; Li, Xiaojing; Wang, Caolin; Zhao, Bingbing; Zheng, Pengwu; Zhu, Wufu

doi:10.1016/j.ejmech.2017.12.078

Cited by 22 publications

(12 citation statements)

References 15 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…They are mainly classified into class I and class II according to their structures and their binding modes. Class II inhibitors such as Foretinib ( 1 ), 8 Cabozantinib ( 2 ), 9 and 3 ( 10 , 11 ) ( Figure 1 ) are completely embedded in c-Met kinases, and their conformations extend from the hinge region to the deep hydrophobic pockets near the C-helix region. Foretinib ( 1 ) is the first oral c-Met inhibitor that entered clinical trials.…”

Section: Introductionmentioning

confidence: 99%

“…Previous studies showed that 1 H -pyrrolo[2,3- b ]pyridine derivatives 11 (class II) exhibited good activity. Inspired by this, the structure–activity relationship of class II c-Met inhibitors has been further studied based on moieties A, B, and C. As reported, the class I c-Met inhibitors (compounds 4 and 5 ) with an active pharmacophore fragment (triazolo-pyrazine) had excellent biological activity.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Discovery of Triazolo-pyridazine/-pyrimidine Derivatives Bearing Aromatic (Heterocycle)-Coupled Azole Units as Class II c-Met Inhibitors

et al. 2020

Self Cite

View full text Add to dashboard Cite

Two series of novel triazolo-pyridazine/-pyrimidine derivatives were designed, synthesized, and evaluated for their inhibitory activity against c-Met kinase, as well as three c-Met overexpressed cancer cell lines (A549, MCF-7, and HeLa) and one normal human hepatocytes cell line LO2 in vitro . The pharmacological data indicated that most of the tested compounds showed moderate cytotoxicity, and the most promising compound 12e exhibited significant cytotoxicity against A549, MCF-7, and HeLa cell lines with IC 50 values of 1.06 ± 0.16, 1.23 ± 0.18, and 2.73 ± 0.33 μM, respectively. Moreover, the inhibitory activity of compound 12e against c-Met kinase (IC 50 = 0.090 μM) was equal to that of Foretinib (IC 50 = 0.019 μM). The result of the acridine orange (AO) single staining test demonstrated that compound 12e could remarkably induce apoptosis of A549 cells. The results of apoptosis and cycle distribution of cells showed that compound 12e could induce late apoptosis of A549 cells and stimulate A549 cells arresting in the G0/G1 phase. Structure–activity relationships (SARs), pharmacological results, and docking studies indicated that the introduction of 5-methylthiazole fragment to the five-atom moiety was beneficial for the activity. So far, the existing data indicated that compound 12e may become a potential class II c-Met inhibitor.

show abstract

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Discovery of Triazolo-pyridazine/-pyrimidine Derivatives Bearing Aromatic (Heterocycle)-Coupled Azole Units as Class II c-Met Inhibitors

et al. 2020

Self Cite

View full text Add to dashboard Cite

show abstract

“…Two compounds 8 and 9 were further profiling against c-Met kinase in vitro. An ATP mobility change assay with reference compound Foretinib (Table 4) [23].…”

Section: Pyridines Acting On Ros1 Inhibitorsmentioning

confidence: 99%

Medicinal attributes of pyridine scaffold as anticancer targeting agents

et al. 2021

View full text Add to dashboard Cite

Background The heterocyclic compounds particularly pyridine displayed clinical and biological implementation. Pyridine scaffolds have been detected in most relevant drug molecules that included pyridine provided a great possibility for treatment. Main text Pyridine-containing compounds have increasing importance for medicinal application as antiviral, anticholinesterase activities, antimalarial, antimicrobial, antidiabetic and anticancer. This has generated concern among researchers in synthesising a variety of pyridine derivatives. Conclusion This review focuses on different pyridine targets as anticancer and their pharmacophoric elements controlling its activity.

show abstract

“…The activity data showed that compounds 12 and 13 had selective inhibition on c-Met (IC 50 = 0.5 µM, and 0.9 µM) compared with FLT3 (IC 50 = 2.6 µM, and 3.8 µM), VEGFR-2 (IC 50 = 8.9 µM, and 14.4 µM) and EGFR (IC 50 > 100 µM, and IC 50 = 45.0 µM) kinases. Therefore, compounds 12 and 13 can be considered as multi-target small molecule inhibitors [67]. 4), and it showed good kinase selectivity for FLT3 (IC 50 = 0.770 µM), VEGFR-2 (IC 50 = 2.400 µM), c-Kit (IC 50 = 2.200 µM) and EGFR (IC 50 > 10.000 µM) kinases (Table 5).…”

Section: Pyrrolopyridine Derivativesmentioning

confidence: 99%

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

2020

Self Cite

View full text Add to dashboard Cite

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.

show abstract

Synthesis and bioevaluation and doking study of 1 H -pyrrolo[2,3- b ]pyridine derivatives bearing aromatic hydrazone moiety as c-Met inhibitors

Cited by 22 publications

References 15 publications

Discovery of Triazolo-pyridazine/-pyrimidine Derivatives Bearing Aromatic (Heterocycle)-Coupled Azole Units as Class II c-Met Inhibitors

Discovery of Triazolo-pyridazine/-pyrimidine Derivatives Bearing Aromatic (Heterocycle)-Coupled Azole Units as Class II c-Met Inhibitors

Medicinal attributes of pyridine scaffold as anticancer targeting agents

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

Contact Info

Product

Resources

About