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.

Figure 1

Structures of lead compounds 1 and 2 and their analogues from lead modifications.

Scheme 1. Synthesis of Analogues of Lead Compounds

Figure 2

Antiinvasion activities of selected thiazole compounds.

Figure 3

Effect of 5o and 5p on angiogenesis in chick embryo ex ovo chorioallantoic membrane (CAM) assay. Angiogenesis was scored by two scorers in a blinded fashion on a scale from 0 to 3 where 0 contained no new vessels and 3 exhibited extreme angiogenesis determined by the presence of new vessels radiating out from the plug in addition to the regular repeating pattern of the normal CAM vasculature. Dashed lines in representative images (below) indicate the top edges of the collagen and drug-containing plugs from which angiogenesis was determined. In these experiments, the thiazole analogues 5o and 5p significantly inhibited the induction of angiogenesis by bFGF and VEGF (BV) after 3 days.

Figure 4

Overexpressing fascin in MDA-MB-231 leads to enhanced migration.

Figure 5

Enhanced cell migration induced by fascin-overexpression is abrogated by thiazole analogues 5l, 5o, and 5p.

Figure 6

Effects of thiazole analogues 5o, 5p, and 8b on the F-actin structure of HeLa cells. Cells were plated on glass coverslips and incubated with vehicle (DMSO), 5o, 5p, or 8b for 24 h and were fixed and stained with Acti-stain 488 phalloidin. Cells were observed under a fluorescent microscope, a digital CCD camera, and 40× objective. Data are representative of three independent experiments.