Design, Synthesis and Molecular Docking Studies of Some Tetrahydropyrimidine Derivatives as Possible Fascin Inhibitors

Abstract

Eight derivatives of tetrahydropyrimidine scaffold were designed and prepared as hybrid compounds possessing the structural features of both monastrol as an anticancer drug and nifedipine as a fascin blocking agent. All of the compounds were evaluated for their cytotoxic potency and the ability to inhibit 4T1 breast cancer cells migration. Then, they were investigated in silico for their ability to inhibit the fascin protein using molecular docking simulation. The most potent compound was 4d and the weakest one was 4a according to the in vitro cytotoxicity assay. The corresponding IC 50 values were 193.70 and 248.75 μM, respectively. The least cytotoxic compound (4a) was one of the strongest ones in binding to the fascin binding site according to the molecular docking results. 4a and 4e inhibited the 4T1 cells migration better than other compounds. They were more potent than nifedipine in inhibiting the migration process. In silico studies proved 4h to be the most potent fascin inhibitor in terms of ΔG bind although it was not inhibiting migration. The controversy between the in vitro and in silico results may cancel the theory of the involvement of the fascin inhibition in the migration inhibition. However, the considerable antimigratory effects of some of the synthesized compounds encourage performing further in vivo experiments to introduce novel tumor metastasis inhibitors.

Fascin actin-bundling protein 1 in human cancer: Promising biomarker or therapeutic target?

“…Studies are aimed at developing novel agents that can interfere with key FSCN1 functions in cancers. 8,33,[278][279][280] It is foreseeable that creative agents (siRNAs, small molecule inhibitors, nanobody, etc.) will be developed to specifically inhibit FSCN1mediated tumor metastasis.…”

Fascin-1 in Cancer Cell Metastasis: Old Target-New Insights

“…In vitro: -Fascin-1 increased formation of filopodia and increased migratory and invasive capacity -Fascin-2 was upregulated by HIF1α [41] -PDAC cell lines that were generated from primary pancreatic tumors -KRas(G12D) p53(R172H)Pdx1-Cre (KPC) mice Thiazole derivative Fascin-1 inhibitors inhibited migration and invasion in vitro in MDA-MB-231 breast cancer cells as well as angiogenesis in chick embryo ex ovo in chorioallantoic membrane (CAM) assays [46]. Similarly, the tetrahydropyrimidine derivatives inhibited 4T1 breast cancer cell migration [47]. In vivo anti-metastatic activity of these inhibitors has not yet been reported.…”

“…A phase 2A clinical trial with a particular focus on ovarian cancer is currently ongoing, at the phase of recruiting, which will test the efficacy of NP-G2-44 as a monotherapy or in combinations with anti-PD-L1 immune checkpoint Thiazole derivative Fascin-1 inhibitors inhibited migration and invasion in vitro in MDA-MB-231 breast cancer cells as well as angiogenesis in chick embryo ex ovo in chorioallantoic membrane (CAM) assays [46]. Similarly, the tetrahydropyrimidine derivatives inhibited 4T1 breast cancer cell migration [47]. In vivo anti-metastatic activity of these inhibitors has not yet been reported.…”

A nanobody inhibitor of Fascin-1 actin-bundling activity and filopodia formation

“…Fascin-1 is therefore of interest as a prognostic indicator and a therapeutic target. Small-molecule inhibitors of Fascin-1 are in development and have been used to target cancer cell invasion in vitro and in model systems [10,[21][22][23][24][25][26][27]. The first Fascin-1 inhibitor to reach clinical trials was NP-G2-044.…”