title: 3,5-Disubstituted-thiazolidine-2,4-dione analogs as anticancer agents: design, synthesis and biological characterization.
abstract: A series of 2,5-disubstituted-thiazolidine-2,4-dione analogs based on the newly identified lead 1, a potential anticancer agent via the inhibition of the Raf/MEK/extracellular signal regulated kinase (ERK) and phosphatidylinositol 3-kinase (PI3K)/Akt signaling cascades, were synthesized and biologically characterized. A new lead structure, 15, was identified to have improved anti-proliferative activities in U937 cells, to induce apoptosis in U937, M12 and DU145 cancer cells, and to arrest U937 cells at the S-phase. Furthermore, Western blot analysis demonstrated a correlation of the anti-proliferative activity and blockade of the Raf/MEK/ERK and PI3K/Akt signaling pathways. Collectively, these results strongly encourage further optimization of 15 as a new lead with multi-target properties to develop more potent compounds as anticancer agents.
authors.affiliation: Department of Medicinal Chemistry, Virginia Commonwealth University, Richmond, VA 23298-0540, USA.
authors.forename: Kai
authors.initials: K
authors.lastname: Liu
authors.forename: Wei
authors.initials: W
authors.lastname: Rao
authors.forename: Hardik
authors.initials: H
authors.lastname: Parikh
authors.forename: Qianbin
authors.initials: Q
authors.lastname: Li
authors.forename: Tai L
authors.initials: TL
authors.lastname: Guo
authors.forename: Steven
authors.initials: S
authors.lastname: Grant
authors.forename: Glen E
authors.initials: GE
authors.lastname: Kellogg
authors.forename: Shijun
authors.initials: S
authors.lastname: Zhang
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D020134:Catalytic Domain; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004247:DNA / Q000096:biosynthesis; D015195:Drug Design; D006801:Humans; D048369:MAP Kinase Kinase 1 / Q000737:chemistry / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008958:Models, Molecular; D019869:Phosphatidylinositol 3-Kinases / Q000737:chemistry / Q000378:metabolism; D013329:Structure-Activity Relationship; D045162:Thiazolidinediones / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D045162:Thiazolidinediones; C500090:thiazolidine-2,4-dione; D004247:DNA; D019869:Phosphatidylinositol 3-Kinases; D048369:MAP Kinase Kinase 1