Design, Synthesis, and Biological Evaluation of 4-amino Substituted 2Hchromen- 2-one Derivatives as an NEDD8
Lijuan Zhu1, Peng Lu1, Lei Gong1
1School of Pharmaceutical Sciences, Nanjing Tech University, No. 5 Xinmofan Road, Nanjing 210009, China.
Background:
NEDD8 activating enzyme (NAE) plays a critical role in various cellular functions in carcinomas. The selective inhibition of NAE could mediate the rate of ubiquitination and the subsequent degradation of proteins associated with cancer so as to achieve the purpose of treatment.
Objective:
In this article, we decided to study the synthesis and screening of 4-amino substituted 2H-chromen-2-one derivatives against cancer cell lines, specifically the human pancreatic cancer cell line BxPC-3.
Methods:
After synthesis of twenty targeted compounds, we evaluated their anti-proliferative activity against six cancer cell lines, cytotoxicity against three normal cell lines through MTT assay, and hemolysis to screen out the candidate compound, which was further conducted drug-like physical property measurement, target confirmation by enzyme-based experiment, cell apoptosis, and synergistic effect research.
Results:
Starting from intermediates 4 and 5, several new 4-amino substituted 2H-chromen-2-one derivatives (9-28) were synthesized and evaluated for their cell activities using six cancer cell lines. We performed tests of cytotoxicity, hemolysis, ATP-dependent NAE inhibition in the enzyme- based system, apoptosis, and synergistic effect in BxPC-3 cells against the best candidate compound 21.
Conclusion:
Based on these results, we found that compound 21 inhibited NAE activity in an ATP-dependent manner in the enzyme-based system, induced apoptosis in BxPC-3 cells, and synergized with bortezomib on BxPC-3 cell growth inhibition. Additionally, it had low toxicity with reasonable Log P-value and water solubility.
Insights
Researchers synthesized novel 4-amino substituted 2H-chromen-2-one derivatives to target NEDD8 activating enzyme (NAE) in cancer. Compound 21 showed promising anti-cancer activity by inhibiting NAE and inducing apoptosis in pancreatic cancer cells.
Area of Science:
- Medicinal Chemistry
- Cancer Biology
- Biochemistry
Background:
- NEDD8 activating enzyme (NAE) is crucial in carcinoma cellular functions.
- Selective NAE inhibition can target ubiquitination and protein degradation in cancer treatment.
Purpose of the Study:
- Synthesize and screen 4-amino substituted 2H-chromen-2-one derivatives.
- Evaluate anti-cancer activity against human pancreatic cancer cell line BxPC-3.
Main Methods:
- Synthesized twenty novel 4-amino substituted 2H-chromen-2-one derivatives.
- Assessed anti-proliferative and cytotoxic activities using MTT assays.
- Evaluated hemolysis, drug-like properties, NAE inhibition, apoptosis, and synergistic effects.
Main Results:
- Synthesized compounds 9-28 and evaluated their activity against six cancer cell lines.
- Compound 21 demonstrated potent anti-cancer effects, including NAE inhibition and apoptosis induction.
- Compound 21 exhibited low toxicity and favorable physicochemical properties.
Conclusions:
- Compound 21 inhibits NAE activity in an ATP-dependent manner.
- Compound 21 induces apoptosis and synergizes with bortezomib in BxPC-3 cells.
- Compound 21 presents a potential therapeutic candidate with favorable drug-like properties.
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