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Molecules 2013, 18(9), 10228-10241; doi:10.3390/molecules180910228
Article

A 3D QSAR Study of Betulinic Acid Derivatives as Anti-Tumor Agents Using Topomer CoMFA: Model Building Studies and Experimental Verification

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Received: 2 July 2013; in revised form: 13 August 2013 / Accepted: 13 August 2013 / Published: 22 August 2013
(This article belongs to the Section Medicinal Chemistry)
Download PDF [424 KB, uploaded 18 June 2014]
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.
Keywords: betulinic acid; betulin; 3D-QSAR; topomer CoMFA; experimental verification betulinic acid; betulin; 3D-QSAR; topomer CoMFA; experimental verification
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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MDPI and ACS Style

Ding, W.; Sun, M.; Luo, S.; Xu, T.; Cao, Y.; Yan, X.; Wang, Y. A 3D QSAR Study of Betulinic Acid Derivatives as Anti-Tumor Agents Using Topomer CoMFA: Model Building Studies and Experimental Verification. Molecules 2013, 18, 10228-10241.

AMA Style

Ding W, Sun M, Luo S, Xu T, Cao Y, Yan X, Wang Y. A 3D QSAR Study of Betulinic Acid Derivatives as Anti-Tumor Agents Using Topomer CoMFA: Model Building Studies and Experimental Verification. Molecules. 2013; 18(9):10228-10241.

Chicago/Turabian Style

Ding, Weimin; Sun, Miao; Luo, Shaman; Xu, Tao; Cao, Yibo; Yan, Xiufeng; Wang, Yang. 2013. "A 3D QSAR Study of Betulinic Acid Derivatives as Anti-Tumor Agents Using Topomer CoMFA: Model Building Studies and Experimental Verification." Molecules 18, no. 9: 10228-10241.


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