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Updated: Nov 14, 2025
Facile Preparation of 4-Substituted Quinazoline Derivatives
Published on: February 15, 2016
Design, synthesis, biological evaluation and structure-activity relationship study of quinazolin-4(3H)-one
Peng Li1, Ying Liu1, Hua Yang1
1School of Pharmaceutical Sciences, Zhengzhou University, 100 Kexue Avenue, Zhengzhou, Henan, 450001, China.
Abstract:
Recent research has indicated that the abnormal expression of the deubiquitinase USP7 induces tumorigenesis via multiple cell pathways, and in particular, the p53-MDM2-USP7 pathway is well understood. USP7 is emerging as a promising target for cancer therapy. However, there are limited reports on USP7 inhibitors. Here we report design, synthesis and biological evaluation of novel quinazolin-4(3H)-one derivatives as potent USP7 inhibitors. Our results indicated that the compounds C9 and C19 exhibited the greatest potency against the USP7 catalytic domain, with IC50 values of 4.86 μM and 1.537 μM, respectively. Ub-AMC assays further confirmed IC50 values of 5.048 μM for C9 and 0.595 μM for C19. MTT assays indicated that gastric cancer MGC-803 cells were more sensitive to these compounds than BGC-823 cells. Flow cytometry analysis revealed that C9 restricted cancer cell growth at the G0/G1 and S phases and inhibited the proliferation and clone formation of MGC-803 cells. Further biochemical experiments indicated that C9 decreased the MDM2 protein level and increased the levels of the tumour suppressors p53 and p21 in a dose-dependent manner. Docking studies predicted that solvent exposure of the side chains of C9 and C19 would uniquely form hydrogen bonds with Met407 of USP7. Additionally, C9 exhibited a remarkable anticancer effect in a zebrafish gastric cancer MGC-803 cell model. Our results demonstrated that quinazolin-4(3H)-one derivatives were suitable as leads for the development of novel USP7 inhibitors and especially for anti-gastric cancer drugs.
Insights
Novel quinazolin-4(3H)-one derivatives show potent inhibition of USP7, a key target in cancer. Compound C19 demonstrated significant potency, and C9 effectively inhibited gastric cancer cell growth and proliferation in preclinical models.
Area of Science:
- Medicinal Chemistry
- Molecular Biology
- Cancer Research
Background:
- Abnormal expression of deubiquitinase USP7 contributes to tumorigenesis through various cell pathways, notably the p53-MDM2-USP7 axis.
- USP7 is recognized as a promising therapeutic target for cancer treatment, yet effective inhibitors are scarce.
Purpose of the Study:
- To design, synthesize, and evaluate novel quinazolin-4(3H)-one derivatives as potent USP7 inhibitors.
- To assess the anticancer efficacy of these compounds, particularly against gastric cancer cells.
Main Methods:
- Synthesis and biological evaluation of quinazolin-4(3H)-one derivatives.
- Enzyme inhibition assays (IC50 determination) and Ub-AMC assays to measure USP7 inhibition.
- Cell viability (MTT) and proliferation assays (flow cytometry, clone formation) using gastric cancer cell lines (MGC-803, BGC-823).
- Western blot analysis to assess protein level changes (MDM2, p53, p21) and molecular docking studies.
- In vivo efficacy assessment using a zebrafish gastric cancer model.
Main Results:
- Compounds C9 and C19 demonstrated potent inhibition of the USP7 catalytic domain, with IC50 values as low as 1.537 μM (C19) and 0.595 μM (C19 via Ub-AMC assay).
- Gastric cancer MGC-803 cells showed higher sensitivity to C9 and C19 compared to BGC-823 cells.
- Compound C9 inhibited MGC-803 cell proliferation, induced cell cycle arrest at G0/G1 and S phases, and reduced clone formation.
- C9 treatment led to decreased MDM2 protein levels and increased levels of tumor suppressors p53 and p21 in a dose-dependent manner.
- Docking studies suggested specific hydrogen bonding interactions between C9/C19 and Met407 of USP7.
- Compound C9 exhibited significant anticancer effects in a zebrafish model of gastric cancer.
Conclusions:
- Quinazolin-4(3H)-one derivatives are promising scaffolds for developing novel USP7 inhibitors.
- These compounds, particularly C9, show potential as anti-gastric cancer agents, warranting further investigation for therapeutic development.
