Design, synthesis, and biological evaluation of tetrahydroisoquinoline-based diaryl urea derivatives for suppressing VEGFR-2 signaling

Two series of diaryl urea derivatives, 6a-k and 7a-n, were synthesized. All the newly synthesized compounds were tested against the NCI (US) cancer cell lines via SRB assay. The p-chloro-m-trifluoromethyl phenyl derivatives 6e-g and 7e-g showed the most potent cytotoxic activity with a GI 50 value range of 1.2-15.9 µM. Furthermore, the p-fluorobenzyloxy diaryl urea derivative 7g revealed the most potent cytotoxicity against eight cancer cell lines in the MTT assay with IC 50 values below 5 µM. Compounds 6a-k and 7a-n were tested for their vascular endothelial growth factor receptor-2 (VEGFR-2) kinase inhibitory activities. The p-chloro-mtrifluoromethyl diaryl urea benzyloxy derivatives 7e-i and the p-methoxydiaryl urea benzyloxy derivatives 7k, 7l, and 7n were found to be the most active compounds as VEGFR-2 inhibitors in the benzyloxy series 7, with an IC 50 range of 0.09-4.15 µM. In the 2-oxo-2-phenylethoxy series 6, compounds 6e-g and 6i were reported with IC 50 values of 0.94, 0.54, 2.71, and 4.81 µM, respectively. Moreover, compounds 7e and 7g induced apoptosis, causing cell cycle arrest in the G2/M phase. In addition, 7gshowed an antimigratory effect in A-375 cells and inhibited the VEGFR-2 expression in an immunohistofluorescence study. Molecular docking simulations on VEGFR-2 as well as ADME properties prediction were also performed.

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“…[ 1–3 ] Therefore, inhibition of angiogenesis has gained increasing significance in cancer chemotherapy. [ 4 ]…”

Section: Introductionmentioning

confidence: 99%

Novel 2‐oxo‐2‐phenylethoxy and benzyloxy diaryl urea hybrids as VEGFR‐2 inhibitors: Design, synthesis, and anticancer evaluation

Ghannam

Kerdawy

Mounier

et al. 2022

Archiv der Pharmazie

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Tetrahydroisoquinoline reduces angiogenesis by interacting myeloma cells with HUVECs mediated by extracellular vesicles

Kooshari,

Shahriyary,

Shahidi

et al. 2024

Med Oncol

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New 1,2,4-triazole/pyrazole hybrids linked to oxime moiety as nitric oxide donor celecoxib analogs: Synthesis, cyclooxygenase inhibition anti-inflammatory, ulcerogenicity, anti-proliferative activities, apoptosis, molecular modeling and nitric oxide release studies

Fadaly

Elshaier

Hassanein

et al. 2020

Bioorganic Chemistry

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Design, synthesis, and biological evaluation of tetrahydroisoquinoline-based diaryl urea derivatives for suppressing VEGFR-2 signaling

Cited by 3 publications

References 19 publications

Novel 2‐oxo‐2‐phenylethoxy and benzyloxy diaryl urea hybrids as VEGFR‐2 inhibitors: Design, synthesis, and anticancer evaluation

Novel 2‐oxo‐2‐phenylethoxy and benzyloxy diaryl urea hybrids as VEGFR‐2 inhibitors: Design, synthesis, and anticancer evaluation

Tetrahydroisoquinoline reduces angiogenesis by interacting myeloma cells with HUVECs mediated by extracellular vesicles

New 1,2,4-triazole/pyrazole hybrids linked to oxime moiety as nitric oxide donor celecoxib analogs: Synthesis, cyclooxygenase inhibition anti-inflammatory, ulcerogenicity, anti-proliferative activities, apoptosis, molecular modeling and nitric oxide release studies

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