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Molecules 2014, 19(11), 18215-18231; doi:10.3390/molecules191118215

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

1
School of Chinese Pharmacy, Beijing University of Chinese Medicine, Beijing 100102, China
2
Key Laboratory for Neurodegenerative Diseases of Ministry of Education, Xuanwu Hospital of Capital Medical University, Beijing 100053, China
3
School of Basic Medicine, Beijing University of Chinese Medicine, Beijing 100029, China
*
Authors to whom correspondence should be addressed.
Received: 25 August 2014 / Revised: 27 October 2014 / Accepted: 28 October 2014 / Published: 7 November 2014
(This article belongs to the Section Medicinal Chemistry)
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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. View Full-Text
Keywords: amino acid; ligustrazine-oleanolic acid; anticancer; ClogP; low toxicity; Giemsa and DAPI staining amino acid; ligustrazine-oleanolic acid; anticancer; ClogP; low toxicity; Giemsa and DAPI staining
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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MDPI and ACS Style

Chu, F.; Xu, X.; Li, G.; Gu, S.; Xu, K.; Gong, Y.; Xu, B.; Wang, M.; Zhang, H.; Zhang, Y.; Wang, P.; Lei, H. Amino Acid Derivatives of Ligustrazine-Oleanolic Acid as New Cytotoxic Agents. Molecules 2014, 19, 18215-18231.

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