title: Synthesis and biological evaluation of 3,5-disubstituted-4-alkynylisoxozales as a novel class of HSP90 inhibitors.
abstract: A series of 3,5-disubstitute-4-alkynylisoxazole derivatives were designed and synthesized through palladium(II)-copper(I) catalyzed Sonogashira cross-coupling reaction of an alkynyl moiety and an isoxazole scaffold as novel HSP90 inhibitors. The resultant compounds displayed moderate to potent binding affinity to HSP90 proteins, and also demonstrated good cell growth inhibitory activity against various cancer cell lines (A549, K562, MCF-7, DU145 and Hela). Some compounds (18d, 18e, 19a, 19d, 20c and 20q) show similar or better binding affinity towards HSP90α and HSP90β comparing to NVP-AUY922. In addition, compounds 18e, 19a and 20q exhibited potent inhibitory activity against various human cancer cell lines.
authors.affiliation: Chengdu University of TCM, 37 Shierqiao Road, Chengdu 610075, China.
authors.forename: Jian
authors.initials: J
authors.lastname: Sun
authors.affiliation: Guangzhou Institutes of Biomedicine and Heath, Chinese Academy of Science, 190 Kaiyuan Road, Guangzhou 510530, China.
authors.forename: Cai
authors.initials: C
authors.lastname: Lin
authors.affiliation: Guangzhou Institutes of Biomedicine and Heath, Chinese Academy of Science, 190 Kaiyuan Road, Guangzhou 510530, China.
authors.forename: Xiaochu
authors.initials: X
authors.lastname: Qin
authors.affiliation: Chengdu University of TCM, 37 Shierqiao Road, Chengdu 610075, China.
authors.forename: Xiaoping
authors.initials: X
authors.lastname: Dong
authors.affiliation: Guangzhou Institutes of Biomedicine and Heath, Chinese Academy of Science, 190 Kaiyuan Road, Guangzhou 510530, China.
authors.forename: Zhengchao
authors.initials: Z
authors.lastname: Tu
authors.affiliation: Guangzhou Institutes of Biomedicine and Heath, Chinese Academy of Science, 190 Kaiyuan Road, Guangzhou 510530, China.
authors.forename: Fei
authors.initials: F
authors.lastname: Tang
authors.affiliation: Guangzhou Institutes of Biomedicine and Heath, Chinese Academy of Science, 190 Kaiyuan Road, Guangzhou 510530, China. Electronic address: chen_chaonan@gibh.ac.cn.
authors.forename: Chaonan
authors.initials: C
authors.lastname: Chen
authors.affiliation: Guangzhou Institutes of Biomedicine and Heath, Chinese Academy of Science, 190 Kaiyuan Road, Guangzhou 510530, China; State Key Laboratory of Respiratory Disease, Guangzhou Institutes of Biomedical and Heath, Chinese Academy Of Science, 190 Kaiyuan Road, Guangzhou 510530, China. Electronic address: zhang_jiancun@gibh.ac.cn.
authors.forename: Jiancun
authors.initials: J
authors.lastname: Zhang
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D001665:Binding Sites; D002384:Catalysis; D020134:Catalytic Domain; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003300:Copper / Q000737:chemistry; D004354:Drug Screening Assays, Antitumor; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D007555:Isoxazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology / Q000633:toxicity; D062105:Molecular Docking Simulation; D010165:Palladium / Q000737:chemistry; D012118:Resorcinols / Q000633:toxicity; D013329:Structure-Activity Relationship
chemical_list: C528044:5-(2,4-dihydroxy-5-isopropylphenyl)-4-(4-morpholin-4-ylmethylphenyl)isoxazole-3-carboxylic acid ethylamide; D018841:HSP90 Heat-Shock Proteins; D007555:Isoxazoles; D012118:Resorcinols; D010165:Palladium; D003300:Copper
keywords: 3,5-Disubstitute-4-alkynylisoxazole; HSP90; HSP90 inhibitor