Abstract
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.
Highlights
Based on the principle of chemical combination, the attempt to discover lead compounds fromTraditional Chinese Medicines (TCMs) has drawn considerable attentions [1,2,3,4,5,6]
The ClogP values were calculated by means of computer simulation. logP values of both 6a and TOA were determined using a shake flask-ultraviolet spectrophotometry method
A series of novel TOA-amino acid derivatives were synthesized by conjugating amino acids to the 3-hydroxy group of TOA by ester bonds
Summary
Based on the principle of chemical combination, the attempt to discover lead compounds from. TOA was synthesized by conjugating the effective antitumor ingredients ligustrazine (TMP) and oleanolic acid (OA) It exhibited promising anticancer effects in vitro [6] and prevented the expression of nuclear transcription factor NF-κB/p65 and COX-2 in S180 mice [7]. Twelve different amino acids were selected for conjugation to the 3-hydroxy moiety of TOA by ester bond formation. Their cytotoxicity was evaluated on four cancer cell lines, including the human hepatoma cell line HepG2, human colorectal cancer cell line HT-29, human cervical cancer cell line Hela and human gastric cancer cell lines BGC-823, by standard thiazolyl blue (MTT) assays. The structure-activity relationships of the new TOA-amino acid derivatives are briefly discussed
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