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A 3D QSAR study of betulinic acid derivatives as anti-tumor agents using topomer CoMFA: model building studies and
Weimin Ding1, Miao Sun, Shaman Luo
1Alkali Soil Natural Environmental Science Center, Northeast Forestry University/Key Laboratory of Saline-Alkali Vegetation Ecology Restoration in Oil Field, Ministry of Education, Harbin 150040, China.
Abstract:
Betulinic acid (BA) is a natural product that exerts its cytotoxicity against various malignant carcinomas without side effects by triggering the mitochondrial pathway to apoptosis. Betulin (BE), the 28-hydroxyl analog of BA, is present in large amounts (up to 30% dry weight) in the outer bark of birch trees, and shares the same pentacyclic triterpenoid core as BA, yet exhibits no significant cytotoxicity. Topomer CoMFA studies were performed on 37 BA and BE derivatives and their in vitro anti-cancer activity results (reported as IC₅₀ values) against HT29 human colon cancer cells in the present study. All derivatives share a common pentacyclic triterpenoid core and the molecules were split into three pieces by cutting at the C-3 and C-28 sites with a consideration toward structural diversity. The analysis gave a leave-one-out cross-validation q² value of 0.722 and a non-cross-validation r² value of 0.974, which suggested that the model has good predictive ability (q² > 0.2). The contour maps illustrated that bulky and electron-donating groups would be favorable for activity at the C-28 site, and a moderately bulky and electron-withdrawing group near the C-3 site would improve this activity. BE derivatives were designed and synthesized according to the modeling result, whereby bulky electronegative groups (maleyl, phthalyl, and hexahydrophthalyl groups) were directly introduced at the C-28 position of BE. The in vitro cytotoxicity values of the given analogs against HT29 cells were consistent with the predicted values, proving that the present topomer CoMFA model is successful and that it could potentially guide the synthesis of new betulinic acid derivatives with high anti-cancer activity. The IC₅₀ values of these three new compounds were also assayed in five other tumor cell lines. 28-O-hexahydrophthalyl BE exhibited the greatest anti-cancer activities and its IC₅₀ values were lower than those of BA in all cell lines, excluding DU145 cells.
Insights
Betulinic acid derivatives were explored for anti-cancer properties using computational modeling. New betulin derivatives synthesized based on model predictions showed enhanced cytotoxicity against cancer cells.
Area of Science:
- Medicinal Chemistry
- Computational Chemistry
- Pharmacology
Background:
- Betulinic acid (BA) exhibits cytotoxicity against cancer cells via apoptosis.
- Betulin (BE), a structural analog of BA, lacks significant anti-cancer activity.
- Understanding structure-activity relationships is crucial for developing novel anti-cancer agents.
Purpose of the Study:
- To develop a predictive computational model for betulinic acid and betulin derivatives.
- To identify key structural modifications for enhancing anti-cancer activity.
- To synthesize and evaluate novel betulin derivatives with improved efficacy.
Main Methods:
- Topomer Comparative Molecular Field Analysis (CoMFA) was employed on 37 betulinic acid and betulin derivatives.
- Quantitative Structure-Activity Relationship (QSAR) modeling was performed using in vitro anti-cancer activity data against HT29 colon cancer cells.
- New betulin derivatives were designed based on model predictions and synthesized.
Main Results:
- The Topomer CoMFA model demonstrated good predictive ability (q²=0.722, r²=0.974).
- Modeling suggested that bulky, electron-donating groups at the C-28 position and moderately bulky, electron-withdrawing groups near the C-3 position enhance activity.
- Synthesized betulin derivatives, particularly 28-O-hexahydrophthalyl BE, showed enhanced in vitro cytotoxicity, outperforming betulinic acid in most tested cell lines.
Conclusions:
- The developed Topomer CoMFA model successfully predicts anti-cancer activity of betulinic acid and betulin derivatives.
- The study validates the model's utility in guiding the synthesis of potent anti-cancer compounds.
- Novel betulin derivatives demonstrate significant therapeutic potential, warranting further investigation.
