title: Michael acceptor in gambogic acid--Its role and application for potent antitumor agents.
abstract: Gambogic acid (GA), a natural product with unique structure, was reported to have broad antiproliferation activities against cancer cell lines. As a reactive Michael acceptor, the 10-position of GA is susceptible to nucleophiles, thus limiting its clinical application as an anticancer agent. Moreover, the 6-OH forms an intramolecular hydrogen bond with 8-CO, which can make the 9, 10 double bond more reactive to nucleophiles. In this essay, two strategies (A and B) were applied to solve the above-mentioned problems. Strategy A was to increase the steric hindrance of C-10 to reduce the activity of GA towards nucleophiles. Strategy B was to replace the hydroxyl of C-6 with other substituents based on the assumption that the intra-molecular hydrogen bond could increase the electrophilicity of C-10. Results showed the electrophilicity of C-10 disappeared as well as the antiproliferation activity against cancer cell lines by introducing a methyl group at C-10. Strategy B showed that the electrophilicity of C-10 was reduced dramatically while maintained the activity by replacement of the hydroxyl of C-6 with neutral or basic groups.
authors.affiliation: WuXi AppTec (Shanghai) Co., Ltd., 288 FuTe Zhong Road, Shanghai 200131, People's Republic of China.
authors.forename: Jing
authors.initials: J
authors.lastname: Wang
authors.affiliation: Jiangsu Kangyuan Pharmaceutical Co., Ltd., 58 Haichangnan Road, Lianyungang 222001, People's Republic of China.
authors.forename: Wang
authors.initials: W
authors.lastname: Shen
authors.affiliation: WuXi AppTec (Shanghai) Co., Ltd., 288 FuTe Zhong Road, Shanghai 200131, People's Republic of China.
authors.forename: Zhiliang
authors.initials: Z
authors.lastname: Yuan
authors.affiliation: WuXi AppTec (Shanghai) Co., Ltd., 288 FuTe Zhong Road, Shanghai 200131, People's Republic of China.
authors.forename: Lihong
authors.initials: L
authors.lastname: Lan
authors.affiliation: WuXi AppTec (Shanghai) Co., Ltd., 288 FuTe Zhong Road, Shanghai 200131, People's Republic of China.
authors.forename: Jiwen
authors.initials: J
authors.lastname: Xu
authors.affiliation: WuXi AppTec (Shanghai) Co., Ltd., 288 FuTe Zhong Road, Shanghai 200131, People's Republic of China.
authors.forename: Chuan
authors.initials: C
authors.lastname: Wang
authors.affiliation: WuXi AppTec (Shanghai) Co., Ltd., 288 FuTe Zhong Road, Shanghai 200131, People's Republic of China.
authors.forename: Guangming
authors.initials: G
authors.lastname: Ma
authors.affiliation: WuXi AppTec (Shanghai) Co., Ltd., 288 FuTe Zhong Road, Shanghai 200131, People's Republic of China.
authors.forename: Weihua
authors.initials: W
authors.lastname: Shi
authors.affiliation: WuXi AppTec (Shanghai) Co., Ltd., 288 FuTe Zhong Road, Shanghai 200131, People's Republic of China.
authors.forename: Lixia
authors.initials: L
authors.lastname: Han
authors.affiliation: WuXi AppTec (Shanghai) Co., Ltd., 288 FuTe Zhong Road, Shanghai 200131, People's Republic of China.
authors.forename: Zhixiang
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: WuXi AppTec (Shanghai) Co., Ltd., 288 FuTe Zhong Road, Shanghai 200131, People's Republic of China.
authors.forename: Lijuan
authors.initials: L
authors.lastname: Hou
authors.affiliation: WuXi AppTec (Shanghai) Co., Ltd., 288 FuTe Zhong Road, Shanghai 200131, People's Republic of China.
authors.forename: Liang
authors.initials: L
authors.lastname: Shen
authors.affiliation: WuXi AppTec (Shanghai) Co., Ltd., 288 FuTe Zhong Road, Shanghai 200131, People's Republic of China.
authors.forename: Zhigan
authors.initials: Z
authors.lastname: Jiang
authors.affiliation: WuXi AppTec (Shanghai) Co., Ltd., 288 FuTe Zhong Road, Shanghai 200131, People's Republic of China. Electronic address: he_haiying@wuxiapptec.com.
authors.forename: Haiying
authors.initials: H
authors.lastname: He
authors.affiliation: Jiangsu Kangyuan Pharmaceutical Co., Ltd., 58 Haichangnan Road, Lianyungang 222001, People's Republic of China.
authors.forename: Wei
authors.initials: W
authors.lastname: Xiao
authors.affiliation: Jiangsu Kangyuan Pharmaceutical Co., Ltd., 58 Haichangnan Road, Lianyungang 222001, People's Republic of China.
authors.forename: Zhenzhong
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Jiangsu Kangyuan Pharmaceutical Co., Ltd., 58 Haichangnan Road, Lianyungang 222001, People's Republic of China.
authors.forename: Qingming
authors.initials: Q
authors.lastname: Guo
authors.affiliation: WuXi AppTec (Shanghai) Co., Ltd., 288 FuTe Zhong Road, Shanghai 200131, People's Republic of China.
authors.forename: Jian
authors.initials: J
authors.lastname: Li
authors.affiliation: WuXi AppTec (Shanghai) Co., Ltd., 288 FuTe Zhong Road, Shanghai 200131, People's Republic of China.
authors.forename: Shuhui
authors.initials: S
authors.lastname: Chen
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D006207:Half-Life; D006801:Humans; D051379:Mice; D009025:Morpholines / Q000737:chemistry; D013329:Structure-Activity Relationship; D044004:Xanthones / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D009025:Morpholines; D044004:Xanthones; C037574:morpholine; C052659:gambogic acid
keywords: Gambogic acid; Intramolecular hydrogen bond; Michael acceptor