Synthesis And In Vitro Anti-tumor Activity Of Betulin Fatty Acid Ester Derivatives

Betulinic acid is a triterpenoid contained in the birch bark, having unique anti-AIDS and anti-tumor activities. Betulin is a kind of hydroxyl derivative of betulinic acid.In the present study, Topomer CoMFA, a second-generation CoMFA method, was used for the3D-QSAR study on structures of different betulinic acid derivatives and their antitumor activity against HT-29colon cancer cell line based on reported data. A couple of principles for molecular design were elucidated by analyzing the contour map of Topomer’s CoMFA model. At C-3position, the smaller groups will benefit the activity more than bulky ones. When the modification is performed at the C-28side chain, the bulky electron-withdrawn group is more likely to enhance the activity.According to the above molecular design principles, betulin was selected as the parent compound, the modified molecules at C-28position of betulin are designed:hexahydro-phthalic acid28-betulin monoester, succinic acid28-betulin monoester and maleic acid28-betulin monoester, and the structures were identified by infrared spectroscopy, nuclear magnetic resonance and mass spectrometry method.In vitro anticancer activities of these new compounds were tested against pancreatic cancer cell line MPC2, colon cancer cell line HT29, prostate cancer cell line DU145, lung carcinoma cell line NCI-H520, cervical carcinoma cell line HeLa, ovarian cancer cell lines2774. with betulinic acid as the positive control. The results showed that the anti-tumor activities of hexahydro-phthalic acid28-betulin monoester, succinic acid28-betulin monoester were better than betulinic acid, and that of maleic acid28-betulin monoester was slightly lower than betulinic acid.