Abstract
Sphingosine-1 kinase (SphK1) is one of the important enzymes of phospholipids and its inhibition is one of the therapeutic strategies for different diseases. SphK1 over expression is observed in different types of cancer indicating its important role in tumor growth. In search of effective SphK1 inhibitors, a new series of pyrazolylbenzimidazoles was synthesized and evaluated as sphingosine kinase-1 (SphK1) inhibitors. In order to evaluate the binding affinities of all the synthesized compounds, all compounds were subjected to docking analysis and fluorescence quenching. The results indicated that there is a consistency between the docking and the fluorescence quenching results, which revealed that compounds 47 and 48 exhibited significant decrease in the fluorescence intensity of SphK1 as well as they formed stable protein–ligand complexes. In addition, enzyme inhibition assay was performed which showed effective inhibitory potential toward SphK1. Moreover, IC50 values displayed that compounds 47 and 48 were the most promising compounds. In addition, antiproliferation study for all the synthesized compounds was performed against NCI-60 cell line panel. The target compounds 47 and 48 demonstrated effective antitumor activity and growth inhibitory potential toward cancer cell lines. Most of these compounds fit well into the ATP-binding site of SphK1 and form significant hydrogen-bonding interactions with catalytically relevant residues as predicted by molecular docking. In this article, insight has been given for the importance of pyrazolylbenzimidazoles as SphK1 inhibitors and the perspectives that they hold for future research.
Highlights
Sphingolipid is a kind of phospholipid which is a major component of all cell membranes and can form lipid bilayers that maintain the fluidity of membranes [1]
The results indicated that there is a consistency between the docking and the fluorescence quenching results which revealed that compounds 47 and 48 exhibited significant decrease in the fluorescence intensity of SphK1 as well as they formed stable protein–ligand complexes
The present study aimed to synthesize new benzimidazole candidates as sphingosine kinase 1 inhibitors (Figure 3) and it was guided by molecular docking study assessing their binding energies taking into consideration that polar substitution of the benzimidazole ring at 5-position was essential for activity
Summary
Sphingolipid is a kind of phospholipid which is a major component of all cell membranes and can form lipid bilayers that maintain the fluidity of membranes [1]. Ceramide (Cer), sphingosine (Sph) and sphingosine1-phosphate (S1P) are metabolites of sphingomylein which play an important role in different diseases such as cancer [2, 3], fibrosis [4] and Alzheimer’s disease [5]. The balance between the sphingolipid metabolites which acting in two opposite ways is crucial in the determination of the cell fate [6, 7]. The two SphK isoforms (SphK1 and SphK2) are known to catalyze this transformation and regulate the sphingolipid metabolism. Studies have shown that over expression of SphK1 is observed in many tumor tissues and regulating tumorigenesis, angiogenesis, and chemotherapy resistance which play an important role in cancer progression[15,16,17,18,19,20]. Inhibition of SphK1 is considered a new therapeutic strategy in the treatment of metastatic cancer and other diseases [21, 22]
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