A 3D-QSAR Study on Betulinic Acid Derivatives as Anti-Tumor Agents and the Synthesis of Novel Derivatives for Modeling Validation.

Background: Betulinic acid is a lupane-type triterpene firstly extracted from the bark of white birch. It has displayed anti-inflammatory, antioxidant, anti-HIV and selective cytotoxicity. Objective: To understand the structure-anti-tumor activity relationship of betulinic acid and betulin derivatives and to synthesize novel anti-tumor derivatives of betulinic acid and betulin. Method: The 3D-QSAR methods including CoMFA and CoMSIA methods were performed to study the structure-antitumor activity relationship of betulinic acid (BA) and betulin (BE) derivatives. Results: According to the models, near the C-3 site, non-bulky, negatively charged electron-donating, hydrophobic, non-hydrogen-bond-donating and hydrogen-bond-accepting groups are favored to the activity. Around the C-28 site, the bulky, positively charged electron-withdrawing and hydrophobic groups are favored, whereas hydrophilic groups may be introduced at the terminal of the side chain. Based on the models, BA and BE were esterified with substituted amino acid derivatives achieving novel derivatives for the modeling validation. Conclusion: The experimental results verified the modeling rules, and showed when different rules may apply to the new structures, the steric effects might be more important. The synthesized derivatives were showed promising cytotoxicity against tested cancer cell lines.