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Updated: Apr 27, 2026
Facile Preparation of 4-Substituted Quinazoline Derivatives
Published on: February 15, 2016
Mechanistic studies on the anticancer activity of 2,4-disubstituted quinazoline derivative
Lijuan Su1, Huaqin Zheng1, Zeng Li1
1School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou University City, 132 Waihuan East Road, Guangzhou 510006, PR China.
Background:
Accelerated proliferation of solid tumor and hematologic cancer cells is related to accelerated transcription of ribosomal DNA by the RNA polymerase I to produce elevated level of ribosomal RNA. Therefore, down-regulation of RNA polymerase I transcription in cancer cells is an important anticancer therapeutic strategy.
Methods:
A variety of methods were used, including cloning, expression and purification of protein, electrophoretic mobility shift assay (EMSA), circular dichroic (CD) spectroscopy, CD-melting, isothermal titration calorimetry (ITC), chromatin immunoprecipitation (Ch-IP), RNA interference, RT-PCR, Western blot, and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) cell assay.
Results:
Our results showed that 2,4-disubstituted quinazoline derivative Sysu12d could down-regulate c-myc through stabilization of c-myc promoter G-quadruplex, resulting in down-regulation of nucleolin expression. Sysu12d could also disrupt nucleolin/G-quadruplex complex. Both of the above contributed to the down-regulation of ribosomal RNA synthesis, followed by activation of p53 and then cancer cell apoptosis.
Conclusions:
These mechanistic studies set up the basis for further development of Sysu12d as a new type of lead compound for cancer treatment.
General Significance:
2,4-Disubstituted quinazoline derivatives may have multi-functional effect for cancer treatment.
Insights
A novel quinazoline derivative, Sysu12d, inhibits cancer cell proliferation by stabilizing G-quadruplex structures, down-regulating ribosomal RNA synthesis, and inducing apoptosis. This compound shows promise as a new lead for cancer therapy.
Area of Science:
- Molecular Biology
- Cancer Research
- Drug Discovery
Background:
- Accelerated cancer cell proliferation correlates with increased ribosomal DNA transcription by RNA polymerase I.
- Down-regulating RNA polymerase I transcription is a key anticancer therapeutic strategy.
Purpose of the Study:
- To investigate the mechanism of action of 2,4-disubstituted quinazoline derivative Sysu12d.
- To evaluate Sysu12d's potential as a novel anticancer agent.
Main Methods:
- Protein expression and purification, electrophoretic mobility shift assay (EMSA), circular dichroic (CD) spectroscopy.
- Isothermal titration calorimetry (ITC), chromatin immunoprecipitation (Ch-IP), RNA interference, RT-PCR, Western blot, MTT assay.
Main Results:
- Sysu12d down-regulates c-myc by stabilizing its promoter G-quadruplex, reducing nucleolin expression.
- Sysu12d disrupts the nucleolin/G-quadruplex complex, inhibiting ribosomal RNA synthesis.
- This leads to p53 activation and subsequent cancer cell apoptosis.
Conclusions:
- Sysu12d demonstrates a multi-functional mechanism for cancer treatment.
- Mechanistic insights support Sysu12d's development as a lead compound for novel cancer therapies.
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