title: Synthesis and tumor cell growth inhibitory activity of biotinylated annonaceous acetogenins.
abstract: Nineteen biotinylated squamocin/bullatacin derivatives have been synthesized for targeted delivery to biotin receptor overexpressed tumor cells. Most biotinylated squamocin and bullatacin derivatives show similar in vitro cytotoxicity against the biotin receptor non-overexpressed L1210 cells as squamocin and bullatacin, respectively, while against biotin receptor overexpressed 4T1 and P815 tumor cells, several derivatives show significantly higher potency and better selectivity. Among all the synthesized compounds, 15,28-di-O-(6-biotinylamidohexanoyl)squamocin (16) is the most potent, which is 10 and 26 times more active than squamocin against 4T1 and P815 cells, respectively. Compound 16 also appears to be six and fifteen times more selective than squamocin towards 4T1 and P815 cells, respectively, against L1210 cells. The structure activity relationship analysis has revealed that the preferred site for biotinylation is different for squamocin and bullatacin, and it also depends on whether a linking spacer is present.
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: Jing-Fang
authors.initials: JF
authors.lastname: Shi
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: 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: D054378:Acetogenins / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D000972:Antineoplastic Agents, Phytogenic / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D019921:Biotinylation; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D005663:Furans / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D007783:Lactones / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism; D017978:Receptors, Growth Factor / Q000378:metabolism
chemical_list: D054378:Acetogenins; D000972:Antineoplastic Agents, Phytogenic; D005663:Furans; D007783:Lactones; D017978:Receptors, Growth Factor; C052136:biotin receptor; C061022:bullatacin; C059660:squamocin
keywords: Biotinylated annonaceous acetogenins; Biotin–bullatacin conjugates; Biotin–squamocin conjugates; Cytotoxicity; Tumor-targeting drug delivery