A 3D QSAR Study of Betulinic Acid Derivatives as Anti-Tumor Agents Using Topomer CoMFA: Model Building Studies and Experimental Verification
Abstract
:1. Introduction
2. Results and Discussion
2.1. 3D-QSAR Model using a Topomer CoMFA Method
Comp. | Substituent | pIC50 | Res. | ||
---|---|---|---|---|---|
R1 | R2 | Experimental | Pred. | ||
Test set | |||||
1 | ―COOH | ―OH | 4.856 | 4.627 | 0.229 |
2 | ―OCOCH3 | 4.999 | 4.855 | 0.144 | |
3 | ―OCOCH3 | 5.276 | 5.244 | 0.032 | |
4 | ―OH | 5.310 | 5.150 | 0.160 | |
5 | ―OCOCH3 | 4.936 | 5.053 | −0.118 | |
6 | ―OCOCH3 | 4.921 | 4.953 | −0.032 | |
7 | ―OH | 5.229 | 4.990 | 0.239 | |
8 | ―OCOCH3 | 4.733 | 4.722 | 0.011 | |
9 | ―COOH | ―OCONHC2H5 | 4.776 | 4.806 | −0.030 |
10 | ―COOH | ―OCOC5H11 | 4.000 | 4.486 | −0.486 |
11 | ―CH2OCOCH3 | ―OCOCH3 | 4.590 | 4.782 | −0.192 |
Training set | |||||
12 | ―COOH | ―OCOCH3 | 4.792 | 4.818 | −0.026 |
13 | ―OCOCH3 | 5.611 | 5.384 | 0.227 | |
14 | ―OH | 5.051 | 5.192 | −0.141 | |
15 | ―CH2OCOCH3 | 5.009 | 4.970 | 0.039 | |
16 | ―CH2OCOCH3 | 4.997 | 4.970 | 0.026 | |
17 | ―OH | 5.056 | 5.052 | 0.004 | |
18 | ―OCOCH3 | 5.301 | 5.341 | −0.040 | |
19 | ―OCH3 | 5.328 | 5.334 | −0.006 | |
20 | ―OCOCH3 | 4.770 | 4.728 | 0.042 | |
21 | ―OCOCH3 | 4.740 | 4.775 | −0.035 | |
22 | ―OCOCH3 | 5.244 | 5.296 | −0.052 | |
23 | ―OCOCH3 | 5.292 | 5.316 | −0.024 | |
24 | ―OCOCH3 | 5.409 | 5.421 | −0.012 | |
25 | ―OCOCH3 | 4.799 | 4.825 | −0.026 | |
26 | ―OH | 4.813 | 4.711 | 0.102 | |
27 | ―OH | 4.740 | 4.711 | 0.029 | |
28 | ―OCH3 | 4.775 | 4.715 | 0.060 | |
29 | ―OCOCH3 | 4.524 | 4.527 | −0.003 | |
30 | ―COCH2COOC2H5 | ―OCOCH3 | 4.921 | 4.914 | 0.007 |
31 | ―OCOCH3 | 4.830 | 4.776 | 0.054 | |
32 | ―OCOOCH3 | ―OCONHC6H5 | 4.161 | 4.125 | 0.036 |
33 | ―CH2OCONHC2H5 | ―OCONHC2H5 | 5.208 | 5.180 | 0.028 |
34 | ―CH2OCONHC2H5 | ―OCONHC6H5 | 4.160 | 4.176 | −0.016 |
35 | ―CH2OCOCH3 | ―OCONHC6H5 | 4.117 | 4.116 | 0.001 |
36 | ―COOH | ―OCOC9H19 | 4.279 | 4.287 | −0.008 |
37 | ―CH2OCOCH2CI | ―OH | 4.559 | 4.586 | −0.027 |
2.2. Molecular Design and Experimental Verification
Compd. | IC50 (μM) | pIC50− (Exp.) | pIC50 (Pred.) |
---|---|---|---|
1 | 83.09 ± 7.53 | 4.080 | 4.925 |
2 | 35.33 ± 1.04 | 4.452 | 5.071 |
3 | 30.05 ± 1.54 | 4.522 | 5.127 |
BA | 32.66 ± 0.62 | 4.486 | 4.627 |
13.93 ± 0.46 * | 4.856 * |
Compd. | IC50 (μM) for cancer cell lines | ||||
---|---|---|---|---|---|
MPC2 (pancreatic cancer) | DU145 (prostate cancer) | NCI-H520 (lung carcinoma) | HeLa (cervical cancer) | 2774 (ovarian cancer) | |
BA | 38.58 ± 2.91 | 23.27 ± 2.20 | 19.60 ± 2.44 | 25.93 ± 1.87 | 39.54 ± 2.19 |
1 | 75.07 ± 4.96 | 92.54 ± 1.45 | 84.83 ± 2.15 | 99.62 ± 4.64 | 67.93 ± 2.00 |
2 | 31.28 ± 3.43 | 36.19 ± 2.77 | 31.24 ± 0.46 | 40.05 ± 3.37 | 27.02 ± 2.92 |
3 | 22.79 ± 0.35 | 37.99 ± 2.50 | 18.55 ± 0.38 | 17.47 ± 1.48 | 25.85 ± 1.34 |
3. Experimental
3.1. Data Sets
3.2. Topomer CoMFA Setup
3.3. Materials and Instruments
3.4. General Procedure for Synthesizing BE Esters
3.4.1. BE 28-O-Maleate 1
3.4.2. BE 28-O-Phthalate 2
3.4.3. BE 28-O-Hexahydrophthalate 3
3.5. Cell Culture and in Vitro Cytotoxicity Assay
4. Conclusions
Acknowledgments
Conflicts of Interest
References
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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. https://doi.org/10.3390/molecules180910228
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. https://doi.org/10.3390/molecules180910228
Chicago/Turabian StyleDing, Weimin, Miao Sun, Shaman Luo, Tao Xu, Yibo Cao, Xiufeng Yan, and Yang Wang. 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. https://doi.org/10.3390/molecules180910228