Amino acid derivatives of ligustrazine-oleanolic acid as new cytotoxic agents.
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.
School of Chinese Pharmacy, Beijing University of Chinese Medicine, Beijing 100102, China. chufhao@163.com.
Fuhao
F
Chu
School of Chinese Pharmacy, Beijing University of Chinese Medicine, Beijing 100102, China. xu.xin@vip.126.com.
Xin
X
Xu
School of Chinese Pharmacy, Beijing University of Chinese Medicine, Beijing 100102, China. liguoliangsx@163.com.
Guoliang
G
Li
Key Laboratory for Neurodegenerative Diseases of Ministry of Education, Xuanwu Hospital of Capital Medical University, Beijing 100053, China. gszy2003@163.com.
Shun
S
Gu
School of Chinese Pharmacy, Beijing University of Chinese Medicine, Beijing 100102, China. xukuoworld@126.com.
Kuo
K
Xu
School of Chinese Pharmacy, Beijing University of Chinese Medicine, Beijing 100102, China. gongyan90@163.com.
Yan
Y
Gong
School of Chinese Pharmacy, Beijing University of Chinese Medicine, Beijing 100102, China. weichenxubing@126.com.
Bing
B
Xu
School of Basic Medicine, Beijing University of Chinese Medicine, Beijing 100029, China. wangmina2013@126.com.
Mina
M
Wang
School of Basic Medicine, Beijing University of Chinese Medicine, Beijing 100029, China. zhanghuazheng1109@163.com.
Huazheng
H
Zhang
School of Basic Medicine, Beijing University of Chinese Medicine, Beijing 100029, China. zyz100102@126.com.
Yuzhong
Y
Zhang
School of Chinese Pharmacy, Beijing University of Chinese Medicine, Beijing 100102, China. wpl581@126.com.
Penglong
P
Wang
School of Chinese Pharmacy, Beijing University of Chinese Medicine, Beijing 100102, China. hm_lei@126.com.
Haimin
H
Lei
D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D003603:Cytotoxins / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D006367:HeLa Cells; D056945:Hep G2 Cells; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D009828:Oleanolic Acid / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D011719:Pyrazines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D014665:Vasodilator Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology
D000970:Antineoplastic Agents; D003603:Cytotoxins; D011719:Pyrazines; D014665:Vasodilator Agents; D009828:Oleanolic Acid; C017953:tetramethylpyrazine