Amino Acid Derivatives of Ligustrazine-Oleanolic Acid as New Cytotoxic Agents

• Main Authors: Fuhao Chu, Xin Xu, Guoliang Li, Shun Gu, Kuo Xu, Yan Gong, Bing Xu, Mina Wang, Huazheng Zhang, Yuzhong Zhang, Penglong Wang, Haimin Lei
• Format: Article
• Language: English
• Published: MDPI AG 2014-11-01
• Series: Molecules
• Subjects: amino acid; ligustrazine-oleanolic acid; anticancer; ClogP; low toxicity; Giemsa and DAPI staining
• Online Access: http://www.mdpi.com/1420-3049/19/11/18215

A series of novel ligustrazine-oleanolic acid (TOA) derivatives were designed, and synthesized by conjugating amino acids to the 3-hydroxy group of TOA by ester bonds. Their cytotoxicity was evaluated on four cancer cell lines (HepG2, HT-29, Hela and BGC-823) by standard MTT assays. The ClogP values were calculated by means of computer simulation, and logP values of both 3β-glycine ester olean-12-en-28-oic acid-3,5,6-trimethylpyrazin-2-methyl ester (6a) and TOA were determined using a shake flask-ultraviolet spectrophotometry method. It was found that 6a and the 3β-L-lysine ester-6g not only displayed good cytotoxicity (IC50 < 3.5 μM) but also possessed better hydrophilicity than TOA. Moreover, 6a (IC50 = 4.884 μM) had lower nephrotoxicity than both 6g (IC50 = 2.310 μM) and cisplatin (CDDP, IC50 = 3.691 μM) on MDCK cells. Combining Giemsa and DAPI staining, it was further verified that 6a could induce HepG2 apoptosis via nuclei fragmentation and had lower nephrotoxicity. In addition, the structure-activity relationships of these derivatives are briefly discussed.