Modification and Biological Evaluation of Thiazole Derivatives as Novel Inhibitors of Metastatic Cancer Cell Migration and Invasion

Shilong Zheng, Xavier University of Louisiana
Qiu Zhong, Xavier University of Louisiana
Y. Xi, West China School of Pharmacy, Sichuan University, Chengdu, Sichuan 600041, China
M Mottamal, Xavier University of Louisiana
Richard L. Schroeder, Xavier University of Louisiana
Jayalakshmi Sridhar, Xavier University of Louisiana
L. He, West China School of Pharmacy, Sichuan University, Chengdu, Sichuan 600041, China
H. McFerrin, Xavier University of Louisiana
Guangdi Wang, Xavier University of Louisiana

DOI: 10.1021/jm500724x

PubMed ID: 25007006

Funding Statement

National Institutes of Health, United States


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.