Design, synthesis, and in vitro and in vivo anti-angiogenesis study of a novel vascular endothelial growth factor receptor-2 (VEGFR-2) inhibitor based on 1,2,3-triazole scaffold

Wang, De-pu; Liu, Kai-li; Li, Xinyang; Lu, Guoqing; Xue, Wen-han; Qian, Xin-hua; O, Kamara Mohamed; Meng, Fan-hao

doi:10.1016/j.ejmech.2020.113083

Cited by 52 publications

(29 citation statements)

References 49 publications

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“…Numerous angiogenesis related factors such as VEGFR-2, Tie-2, EphB4 and tubulin have been identified as potential targets for angiogenesis inhibitors. 8–10 Tubulin, the necessary protein for the formation of the mitotic spindle and mitotic division of cell, has been an important target for the design and development of anti-cancer drugs. 11 , 12 In the past ten years, a series of tubulin colchicine site inhibitors had been found to display strong vascular disrupting and anti-angiogenesis activity.…”

Section: Introductionmentioning

confidence: 99%

Angiogenesis and anti-leukaemia activity of novel indole derivatives as potent colchicine binding site inhibitors

Yao

Huang

Wang

et al. 2022

Journal of Enzyme Inhibition and Medicinal Chemistry

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The screened compound DYT-1 from our in-house library was taken as a lead (inhibiting tubulin polymerisation: IC 50 =25.6 µM, anti-angiogenesis in Zebrafish: IC 50 =38.4 µM, anti-proliferation against K562 and Jurkat: IC 50 =6.2 and 7.9 µM, respectively). Further investigation of medicinal chemistry conditions yielded compound 29e (inhibiting tubulin polymerisation: IC 50 =4.8 µM and anti-angiogenesis in Zebrafish: IC 50 =3.6 µM) based on tubulin and zebrafish assays, which displayed noteworthily nanomolar potency against a variety of leukaemia cell lines (IC 50 = 0.09–1.22 µM), especially K562 cells where apoptosis was induced. Molecular docking, molecular dynamics (MD) simulation, radioligand binding assay and cellular microtubule networks disruption results showed that 29e stably binds to the tubulin colchicine site. 29e significantly inhibited HUVEC tube formation, migration and invasion in vitro. Anti-angiogenesis in vivo was confirmed by zebrafish xenograft. 29e also prominently blocked K562 cell proliferation and metastasis in blood vessels and surrounding tissues of the zebrafish xenograft model. Together with promising physicochemical property and metabolic stability, 29e could be considered an effective anti-angiogenesis and -leukaemia drug candidate that binds to the tubulin colchicine site.

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Section: Introductionmentioning

confidence: 99%

Angiogenesis and anti-leukaemia activity of novel indole derivatives as potent colchicine binding site inhibitors

Yao

Huang

Wang

et al. 2022

Journal of Enzyme Inhibition and Medicinal Chemistry

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“…Cpd15 was created as a new VEGFR‐2 inhibitor that is more effective and less harmful than sunitinib. Cpd15 was a superior candidate for medication development and research into novel VEGFR‐2 antagonists [88] …”

Section: Vegfr Inhibitors As Antitumor Agentsmentioning

confidence: 99%

Novel VEGFR‐2 Kinase Inhibitors as Anticancer Agents: A Review Focusing on SAR and Molecular Docking Studies (2016–2021)

Vishakha

Kajal

Mondal

et al. 2023

Chemistry & Biodiversity

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Cancer growth, annexation, and metastatic spread are all aided by the formation of new blood vessels (angiogenesis). The commencement of the VEGF pathway leads to signal transduction that enhances endothelial cell survival, relocation, and divergence from pre-existing vasculature. The ability of solid malignancies to bloom and spread depends critically on their ability to establish their independent blood circulation (tumor angiogenesis). VEGFR is a major receptor tyrosine kinase that regulates angiogenesis, cell growth, and metastasis, diminishing apoptosis, cytoskeletal function, and other biological processes VEGFR has proven to be a remarkable focus for a variety of anticancer medicines in clinical studies. This Review explores the development of anti-VEGF-based antiangiogenic therapies having different scaffolds. This review had focused on SAR and docking studies of previously reported molecules.

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“…1,2,3‐Triazole ring has attracted great interest for researchers due to its structure features including hydrogen bonding ability, reasonable dipole character, rigidity, and in vitro stability, therefore, it is considered a good scaffold for developing promising therapeutic agents (Dheer et al, 2017; Shafi et al, 2012; Wang et al, 2021; Xu, 2020; Zhang et al, 2021).…”

Section: Introductionmentioning

confidence: 99%

Click chemistry‐based synthesis of new benzenesulfonamide derivatives bearing triazole ring as selective carbonic anhydrase II inhibitors

Ewies

Sabry

Bekheit

et al. 2022

Drug Development Research

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A series of 1,2,3‐triazol‐1‐ylbenzenesulfonamide derivatives was designed, synthesized and their ability to inhibit several carbonic anhydrase isoforms was evaluated. The basis of our design is to hybridize the benzenesulfonamide moiety widely used as a zinc‐binding group, a triazole ring as spacer with a tail of different substituted aryl moieties. The synthesis of these compounds was achieved using Cu(I)‐mediated click chemistry between the azide containing the benzenesulfonamide pharmacophore and various aryl acetylenes or 1,6‐heptadiyne through copper‐catalyzed [3+2] cycloaddition reaction. The ability the new derivatives to inhibit four human carbonic anhydrase isoforms hCA I, II, IX, and XII was evaluated. All the compounds exhibited good potency and high selectivity towards isoforms hCA I and II more than isoforms hCA IX and XII, especially for the derivatives 3c and 3j that displayed Ki of 2.8 and 3.8 nM against hCA II and a high hCA II selectivity ratio ranging from 77.6 to 3571.4 over other isoforms. All the compounds were docked in the active site of the downloaded hCA II active site and their binding pattern confirmed their significant activity by interacting of the sulfonamide moiety with zinc ion in the active site, in addition to its hydrogen bond interaction with Thr199 and Thr200. All the above‐mentioned findings pointed out towards the promising activity of the synthesized series that can be presented as a new scaffold to be further optimized as selective antiglaucoma drugs.

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Design, synthesis, and in vitro and in vivo anti-angiogenesis study of a novel vascular endothelial growth factor receptor-2 (VEGFR-2) inhibitor based on 1,2,3-triazole scaffold

Cited by 52 publications

References 49 publications

Angiogenesis and anti-leukaemia activity of novel indole derivatives as potent colchicine binding site inhibitors

Angiogenesis and anti-leukaemia activity of novel indole derivatives as potent colchicine binding site inhibitors

Novel VEGFR‐2 Kinase Inhibitors as Anticancer Agents: A Review Focusing on SAR and Molecular Docking Studies (2016–2021)

Click chemistry‐based synthesis of new benzenesulfonamide derivatives bearing triazole ring as selective carbonic anhydrase II inhibitors

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