title: Modification and biological evaluation of thiazole derivatives as novel inhibitors of metastatic cancer cell migration and invasion.
abstract: Fascin has recently emerged as a potential therapeutic target, as its expression in cancer cells is closely associated with tumor progression and metastasis. Following the initial discovery of a series of thiazole derivatives that demonstrated potent antimigration and antiinvasion activities via possible inhibition of fascin function, we report here the design and synthesis of 63 new thiazole derivatives by further structural modifications in search of more potent fascin inhibitors. The 5 series of analogues with longer alkyl chain substitutions on the thiazole nitrogen exhibited greater antimigration activities than those with other structural motifs. The most potent analogue, 5p, inhibited 50% of cell migration at 24 nM. Moreover, the thiazole analogues showed strong antiangiogenesis activity, blocking new blood vessel formation in a chicken embryo membrane assay. Finally, a functional study was conducted to investigate the mechanism of action via interaction with the F-actin bundling protein fascin.
authors.affiliation: RCMI Cancer Research Center, ‡Department of Chemistry, and §Department of Biology, Xavier University of Louisiana , New Orleans, Louisiana 70125, United States.
authors.forename: Shilong
authors.initials: S
authors.lastname: Zheng
authors.forename: Qiu
authors.initials: Q
authors.lastname: Zhong
authors.forename: Yulan
authors.initials: Y
authors.lastname: Xi
authors.forename: Madhusoodanan
authors.initials: M
authors.lastname: Mottamal
authors.forename: Qiang
authors.initials: Q
authors.lastname: Zhang
authors.forename: Richard L
authors.initials: RL
authors.lastname: Schroeder
authors.forename: Jayalakshmi
authors.initials: J
authors.lastname: Sridhar
authors.forename: Ling
authors.initials: L
authors.lastname: He
authors.forename: Harris
authors.initials: H
authors.lastname: McFerrin
authors.forename: Guangdi
authors.initials: G
authors.lastname: Wang
mesh_terms: D008841:Actin Cytoskeleton / Q000648:ultrastructure; D020533:Angiogenesis Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D002352:Carrier Proteins / Q000037:antagonists & inhibitors / Q000235:genetics; D002461:Cell Line, Transformed; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D002642:Chick Embryo; D049033:Chorioallantoic Membrane / Q000098:blood supply / Q000187:drug effects; D003094:Collagen; D004338:Drug Combinations; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D007797:Laminin; D008840:Microfilament Proteins / Q000037:antagonists & inhibitors / Q000235:genetics; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D018919:Neovascularization, Physiologic / Q000187:drug effects; D011509:Proteoglycans; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology
chemical_list: D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D002352:Carrier Proteins; D004338:Drug Combinations; C502658:FSCN1 protein, human; D007797:Laminin; D008840:Microfilament Proteins; D011509:Proteoglycans; D013844:Thiazoles; C059485:matrigel; D003094:Collagen