title: Biological characterization of 3-(2-amino-ethyl)-5-[3-(4-butoxyl-phenyl)-propylidene]-thiazolidine-2,4-dione (K145) as a selective sphingosine kinase-2 inhibitor and anticancer agent.
abstract: In our effort to develop selective sphingosine kinase-2 (SphK2) inhibitors as pharmacological tools, a thiazolidine-2,4-dione analogue, 3-(2-amino-ethyl)-5-[3-(4-butoxyl-phenyl)-propylidene]-thiazolidine-2,4-dione (K145), was synthesized and biologically characterized. Biochemical assay results indicate that K145 is a selective SphK2 inhibitor. Molecular modeling studies also support this notion. In vitro studies using human leukemia U937 cells demonstrated that K145 accumulates in U937 cells, suppresses the S1P level, and inhibits SphK2. K145 also exhibited inhibitory effects on the growth of U937 cells as well as apoptotic effects in U937 cells, and that these effects may be through the inhibition of down-stream ERK and Akt signaling pathways. K145 also significantly inhibited the growth of U937 tumors in nude mice by both intraperitoneal and oral administration, thus demonstrating its in vivo efficacy as a potential lead anticancer agent. The antitumor activity of K145 was also confirmed in a syngeneic mouse model by implanting murine breast cancer JC cells in BALB/c mice. Collectively, these results strongly encourage further optimization of K145 as a novel lead compound for development of more potent and selective SphK2 inhibitors.
authors: Department of Medicinal Chemistry, Virginia Commonwealth University, Richmond, Virginia, USA.
authors: Kai
authors: K
authors: Liu
authors: Tai L
authors: TL
authors: Guo
authors: Nitai C
authors: NC
authors: Hait
authors: Jeremy
authors: J
authors: Allegood
authors: Hardik I
authors: HI
authors: Parikh
authors: Wenfang
authors: W
authors: Xu
authors: Glen E
authors: GE
authors: Kellogg
authors: Steven
authors: S
authors: Grant
authors: Sarah
authors: S
authors: Spiegel
authors: Shijun
authors: S
authors: Zhang
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D006801:Humans; D007938:Leukemia / Q000188:drug therapy*; D008958:Models, Molecular; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000037:antagonists & inhibitors* / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D045162:Thiazolidinediones / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D020298:U937 Cells; D023041:Xenograft Model Antitumor Assays; D000099157:Sphingosine Kinase
chemical_list: D000970:Antineoplastic Agents; D017853:Phosphotransferases (Alcohol Group Acceptor); D047428:Protein Kinase Inhibitors; D045162:Thiazolidinediones; D000099157:Sphingosine Kinase; C583313:3-(2-aminoethyl)-5-(3-(4-butoxylphenyl)propylidene)thiazolidine-2,4-dione; C500090:thiazolidine-2,4-dione