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Updated: Feb 20, 2026
Functionalized Spirocyclic Heterocycle Synthesis and Cytotoxicity Assay
Published on: February 9, 2021
Quantitative Structure-Cytotoxicity Relationship of Newly Synthesized Piperic Acid Esters
Hiroshi Sakagami1, Yoshihiro Uesawa2, Yoshiko Masuda3,4
1Meikai University Research Institute of Odontology (M-RIO), Meikai University, School of Dentistry, Saitama, Japan sakagami@dent.meikai.ac.jp.
Background/Aim:
Eleven piperic acid esters were subjected to quantitative structure-activity relationship (QSAR) analysis based on their cytotoxicity and tumor-specificity, in order to find their new biological activities.
Materials And Methods:
Cytotoxicity against four human oral squamous cell carcinoma cell lines and three oral normal mesenchymal cells was determined by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) method. Tumor specificity (TS) was evaluated by the ratio of the mean 50% cytotoxic concentration (CC50) against normal cells to that against tumor cell lines. Potency-selectivity expression (PSE) value was calculated by dividing the TS value by CC50 against tumor cells. Apoptosis markers were detected by western blot analysis. Physicochemical, structural and quantum-chemical parameters were calculated based on the conformations optimized by force-field minimization.
Results:
One phenylmethyl ester and five phenylethyl esters showed relatively higher cytotoxicity and tumor specificity, that were significantly modified by introduction of hydroxyl and methoxy groups. On the other hand, phenylpropyl ester, phenylbutyl ester and decyl ester were essentially inactive. (2E,4E)-5-(3,4-methylenedioxyphenyl)-2,4-pentadienoic acid 2-(3,4-dihydroxyphenyl)ethyl ester [4] had the highest TS and PSE values. This compound also stimulated the cleavage of caspase-3, suggesting the induction of apoptosis. TS values were correlated with molecular size, ionization potential, molecular shape, ionization potential and electronegativity. None of the compounds had any anti-HIV activity.
Conclusion:
Chemical modification of the lead compound may be a potential choice for designing a new type of anticancer drugs.
Insights
Piperic acid esters were analyzed for anticancer potential. Certain esters, particularly those with hydroxyl and methoxy groups, showed promising cytotoxicity and tumor specificity, suggesting a basis for new anticancer drug design.
Area of Science:
- Medicinal Chemistry
- Pharmacology
- Computational Chemistry
Background:
- Piperic acid esters are investigated for novel biological activities.
- Understanding structure-activity relationships is crucial for drug discovery.
Purpose of the Study:
- To evaluate the cytotoxicity and tumor specificity of eleven piperic acid esters.
- To identify potential anticancer drug candidates through quantitative structure-activity relationship (QSAR) analysis.
Main Methods:
- Cytotoxicity was assessed using the MTT assay on oral cancer and normal cell lines.
- Tumor specificity (TS) and potency-selectivity expression (PSE) were calculated.
- Apoptosis markers were analyzed via western blot; physicochemical and quantum-chemical parameters were computed.
Main Results:
- Five phenylethyl esters and one phenylmethyl ester exhibited significant cytotoxicity and tumor specificity, influenced by hydroxyl and methoxy substitutions.
- Compound 4 demonstrated the highest TS and PSE, inducing apoptosis via caspase-3 cleavage.
- TS values correlated with molecular size, ionization potential, and electronegativity.
Conclusions:
- Piperic acid ester derivatives show potential as anticancer agents.
- Chemical modification of lead compounds offers a strategy for developing novel anticancer drugs.
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