title: Synthesis and cancer cell growth inhibitory activity of icaritin derivatives.
abstract: A series of icaritin derivatives bearing carboxylic acid or carboxylic ester groups are synthesized, and their in vitro cytotoxic activity against three cancer cell lines, MCF-7, MDA-MB-435s, and A549, are evaluated by MTT assay. Several derivatives including 2h, 2j, 5b and 5d show higher cytotoxic activity than the parent compound icaritin against these cancer cell lines. Compounds 5b and 5d are even more cytotoxic to MCF-7 cells than the clinic drug tamoxifen. Moreover, compound 5b is found to be non-toxic to normal cells (Vero) and both 5b and 5d exhibit good selectivity towards estrogen receptor positive MCF-7 breast cancer cells over estrogen receptor negative MDA-MB-435s breast cancer cells. The structure activity relationship analysis has revealed that mono-substitution at either C-3 or C-7 hydroxyl group of icaritin could improve the cytotoxicity of icaritin, and the C-3 hydroxyl group may be a preferable site for chemical modification. In addition, the length, the flexibility and the additional branching substituent group of the substitution chain(s) at both C-3 and C-7 hydroxyl groups can all affect the anti-cancer activity of these derivatives.
authors.affiliation: Key Laboratory of Plant Resources Conservation and Sustainable Utilization, South China Botanical Garden, Chinese Academy of Sciences, Xingke Road 723, Tianhe District, Guangzhou 510650, China; University of Chinese Academy of Sciences, Yuquanlu 19A, Beijing 100049, China.
authors.forename: Chen
authors.initials: C
authors.lastname: Wang
authors.affiliation: Key Laboratory of Plant Resources Conservation and Sustainable Utilization, South China Botanical Garden, Chinese Academy of Sciences, Xingke Road 723, Tianhe District, Guangzhou 510650, China.
authors.forename: Ping
authors.initials: P
authors.lastname: Wu
authors.affiliation: Key Laboratory of Plant Resources Conservation and Sustainable Utilization, South China Botanical Garden, Chinese Academy of Sciences, Xingke Road 723, Tianhe District, Guangzhou 510650, China.
authors.forename: Jing-Fang
authors.initials: JF
authors.lastname: Shi
authors.affiliation: Department of Chemistry, Lakehead University, 955 Oliver Road, Thunder Bay, Ontario P7B 5E1, Canada. Electronic address: zjiang@lakeheadu.ca.
authors.forename: Zi-Hua
authors.initials: ZH
authors.lastname: Jiang
authors.affiliation: Key Laboratory of Plant Resources Conservation and Sustainable Utilization, South China Botanical Garden, Chinese Academy of Sciences, Xingke Road 723, Tianhe District, Guangzhou 510650, China. Electronic address: wxy@scbg.ac.cn.
authors.forename: Xiao-Yi
authors.initials: XY
authors.lastname: Wei
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D005419:Flavonoids / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D061986:MCF-7 Cells; D015394:Molecular Structure; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D005419:Flavonoids; C499403:icaritin
keywords: Anti-cancer; Cytotoxic activity; Estrogen receptor; Icaritin; Selective estrogen receptor modulator; Structural modification