title: A 3D QSAR study of betulinic acid derivatives as anti-tumor agents using topomer CoMFA: model building studies and experimental verification.
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.
authors: Alkali 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.
authors: Weimin
authors: W
authors: Ding
authors: Miao
authors: M
authors: Sun
authors: Shaman
authors: S
authors: Luo
authors: Tao
authors: T
authors: Xu
authors: Yibo
authors: Y
authors: Cao
authors: Xiufeng
authors: X
authors: Yan
authors: Yang
authors: Y
authors: Wang
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D003198:Computer Simulation; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D020128:Inhibitory Concentration 50; D008956:Models, Chemical; D015394:Molecular Structure; D053978:Pentacyclic Triterpenes; D021281:Quantitative Structure-Activity Relationship; D012984:Software; D014315:Triterpenes / Q000737:chemistry* / Q000494:pharmacology; D000094062:Betulinic Acid
chemical_list: D000970:Antineoplastic Agents; D053978:Pentacyclic Triterpenes; D014315:Triterpenes; D000094062:Betulinic Acid
references: J Comput Aided Mol Des. 2012 Jul;26(7):805-19
references: 22661224
references: Invest New Drugs. 2011 Apr;29(2):266-72
references: 19957199
references: Bioorg Med Chem. 2005 May 16;13(10):3447-54
references: 15848757
references: Bioorg Med Chem. 2010 Oct 15;18(20):7252-9
references: 20846866
references: Biochem Pharmacol. 2010 Oct 15;80(8):1141-51
references: 20615390
references: Bioorg Med Chem. 2010 Feb;18(3):1344-55
references: 20034802
references: Chem Biol Interact. 2010 Apr 29;185(2):128-36
references: 20193672
references: J Med Chem. 1996 Aug 2;39(16):3060-9
references: 8759627
references: Eur J Pharm Sci. 2006 Sep;29(1):1-13
references: 16716572
references: Cancer Lett. 2002 Jan 10;175(1):17-25
references: 11734332
references: J Med Chem. 2003 Jan 30;46(3):374-88
references: 12540237
references: J Chromatogr B Analyt Technol Biomed Life Sci. 2012 Aug 15;903:81-7
references: 22824730
references: J Immunol Methods. 1983 Dec 16;65(1-2):55-63
references: 6606682
references: Bioorg Med Chem. 2010 Apr 1;18(7):2549-58
references: 20299226
references: Biopharm Drug Dispos. 1999 Nov;20(8):379-83
references: 10870094
references: Biochimie. 2011 Jun;93(6):1065-75
references: 21377507
references: Bioorg Med Chem. 2010 Jun 15;18(12):4385-96
references: 20494586
references: Int J Mol Sci. 2008 Jun;9(6):1096-107
references: 19325847
references: Bioorg Med Chem Lett. 2010 Jun 1;20(11):3409-12
references: 20451375
references: Invest New Drugs. 2008 Feb;26(1):25-34
references: 17851638
references: Eur J Med Chem. 2010 Aug;45(8):3346-53
references: 20472329
references: Nat Med. 1995 Oct;1(10):1046-51
references: 7489361