title: Synthesis and anticancer mechanism investigation of dual Hsp27 and tubulin inhibitors.
abstract: Heat shock protein 27 (Hsp27) is a chaperone protein, and its expression is increased in response to various stress stimuli including anticancer chemotherapy, which allows the cells to survive and causes drug resistance. We previously identified lead compounds that bound to Hsp27 and tubulin via proteomic approaches. Systematic ligand based optimization in the current study significantly increased the cell growth inhibition and apoptosis inducing activities of the compounds. Compared to the lead compounds, one of the new derivatives exhibited much better potency to inhibit tubulin polymerization but a decreased activity to inhibit Hsp27 chaperone function, suggesting that the structural modification dissected the dual targeting effects of the compound. The most potent compounds 20 and 22 exhibited strong cell proliferation inhibitory activities at subnanomolar concentration against 60 human cancer cell lines conducted by Developmental Therapeutic Program at the National Cancer Institute and represented promising candidates for anticancer drug development.
authors.affiliation: Department of Chemistry, College of Sciences and Health Professions, Cleveland State University , 2121 Euclid Avenue, Cleveland, Ohio 44115, United States.
authors.forename: Bo
authors.initials: B
authors.lastname: Zhong
authors.forename: Snigdha
authors.initials: S
authors.lastname: Chennamaneni
authors.forename: Rati
authors.initials: R
authors.lastname: Lama
authors.forename: Xin
authors.initials: X
authors.lastname: Yi
authors.forename: Werner J
authors.initials: WJ
authors.lastname: Geldenhuys
authors.forename: John J
authors.initials: JJ
authors.lastname: Pink
authors.forename: Afshin
authors.initials: A
authors.lastname: Dowlati
authors.forename: Yan
authors.initials: Y
authors.lastname: Xu
authors.forename: Aimin
authors.initials: A
authors.lastname: Zhou
authors.forename: Bin
authors.initials: B
authors.lastname: Su
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D015153:Blotting, Western; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D045325:HCT116 Cells; D055551:HSP27 Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D019073:HT29 Cells; D006801:Humans; D020014:K562 Cells; D061986:MCF-7 Cells; D008956:Models, Chemical; D018832:Molecular Chaperones / Q000037:antagonists & inhibitors / Q000378:metabolism; D015394:Molecular Structure; D058105:Polymerization / Q000187:drug effects; D013329:Structure-Activity Relationship; D014404:Tubulin / Q000378:metabolism*; D050257:Tubulin Modulators / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D055551:HSP27 Heat-Shock Proteins; D018832:Molecular Chaperones; D014404:Tubulin; D050257:Tubulin Modulators