Discovery of Harmaline as a Potent Inhibitor of Sphingosine Kinase-1: A Chemopreventive Role in Lung Cancer

Roy, Sonam; Mohammad, Taj; Gupta, Preeti; Dahiya, Rashmi; Parveen, Shabana; Luqman, Suaib; Hasan, Gulam Mustafa; Hassan, Md. Imtaiyaz

doi:10.1021/acsomega.0c02165

Cited by 46 publications

(26 citation statements)

References 105 publications

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“…In addition, it has been proved that more SphK1 inhibitors have been developed based on existing inhibitor structures or obtained from natural products. For example, jasmine B analogues based on pyrrolidine exerting anti-inflammatory activity for the treatment of RA ( Chen et al, 2021a ); therapeutic effect of SKI-349 obtained by optimizing SKI-178 structure on hematological malignancies ( Hengst et al, 2020b ); and the inhibitors derived form natural products with potential roles in the prevention of breast and lung cancer ( Jairajpuri et al, 2020 ; Khan et al, 2020 ; Roy et al, 2020 ). More compounds with inhibitory activity have been developed and researched due to the benefits of SphK1 inhibitors have been proved.…”

Section: Introductionmentioning

confidence: 99%

Therapeutic Potential of SphK1 Inhibitors Based on Abnormal Expression of SphK1 in Inflammatory Immune Related-Diseases

Hong

Deng

2021

Front. Pharmacol.

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Sphingosine kinase 1(SphK1) a key enzyme that catalyzes the conversion of sphingosine (Sph) to sphingosine 1-phosphate (S1P), so as to maintain the dynamic balance of sphingolipid-rheostat in cells and participate in cell growth and death, proliferation and migration, vasoconstriction and remodeling, inflammation and metabolism. The normal expression of SphK1 maintains the balance of physiological and pathological states, which is reflected in the regulation of inflammatory factor secretion, immune response in traditional immune cells and non-traditional immune cells, and complex signal transduction. However, abnormal SphK1 expression and activity are found in various inflammatory and immune related-diseases, such as hypertension, atherosclerosis, Alzheimer’s disease, inflammatory bowel disease and rheumatoid arthritis. In view of the therapeutic potential of regulating SphK1 and its signal, the current research is aimed at SphK1 inhibitors, such as SphK1 selective inhibitors and dual SphK1/2 inhibitor, and other compounds with inhibitory potency. This review explores the regulatory role of over-expressed SphK1 in inflammatory and immune related-diseases, and investigate the latest progress of SphK1 inhibitors and the improvement of disease or pathological state.

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Section: Introductionmentioning

confidence: 99%

Therapeutic Potential of SphK1 Inhibitors Based on Abnormal Expression of SphK1 in Inflammatory Immune Related-Diseases

Hong

Deng

2021

Front. Pharmacol.

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“…The inclusion bodies were solubilized with the help of N ‐lauroyl sarcosine and the solubilized protein was loaded on the Ni‐NTA column and subsequently purified. [ 64‐67 ] The purified SphK1 was analyzed on sodium dodecyl sulfate–polyacrylamide gel electrophoresis (SDS‐PAGE), which shows a single band of 45 kDa (Figure 3).…”

Section: Resultsmentioning

confidence: 99%

“…The absorbance value of the malachite–inorganic phosphate green complex so formed at 620 nm is converted with the help of the phosphate standard curve, as described. [ 65‐67 ] The loss in the SphK1 activity followed an inverse relationship between percentage inhibition and an increasing concentration of selected compounds (Figures 7d‐f and 8c,d), which was used for the calculation of IC 50 values (Table 2). Compound 41 efficiently inhibited SphK1 activity with a lowest IC 50 value of 3.39 ± 0.21 μM (Figure 7f).…”

Section: Resultsmentioning

confidence: 99%

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Design, synthesis, and biological evaluation of novel benzimidazole derivatives as sphingosine kinase 1 inhibitor

Khairat

Omar

Ragab

et al. 2021

Archiv der Pharmazie

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Sphingosine kinase 1 (SphK1) has emerged as an attractive drug target for different diseases. Recently, discovered SphK1 inhibitors have been recommended in cancer therapeutics; however, selectivity and potency are great challenges. In this study, a novel series of benzimidazoles was synthesized and evaluated as SphK1 inhibitors. Our design strategy is twofold: It aimed first to study the effect of replacing the 5‐position of the benzimidazole ring with a polar carboxylic acid group on the SphK1‐inhibitory activity and cytotoxicity. Our second aim was to optimize the structures of the benzimidazoles through the elongation of the chain. The enzyme inhibition potentials against all the synthesized compounds toward SphK1 were evaluated, and the results revealed that most of the studied compounds inhibited SphK1 effectively. The binding affinity of the benzimidazole derivatives toward SphK1 was measured by fluorescence binding and molecular docking. Compounds 33, 37, 39, 41, 42, 43, and 45 showed an appreciable binding affinity. Therefore, the SphK1‐inhibitory potentials of compounds 33, 37, 39, 41, 42, 43, and 45 were studied and IC50 values were determined, to reveal high potency. The study showed that these compounds inhibited SphK1 with effective IC50 values. Among the studied compounds, compound 41 was the most effective one with the lowest IC50 value and a high cytotoxicity on a wide spectrum of cell lines. Molecular docking revealed that most of these compounds fit well into the ATP‐binding site of SphK1 and form hydrogen bond interactions with catalytically important residues. Overall, the findings suggest the therapeutic potential of benzimidazoles in the clinical management of SphK1‐associated diseases.

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“…The kinase activity of SphK1 is measured in terms of picomolar concentration of phosphate released in the reaction mixture which is represented in Figure 5 (A and B). The absorbance value of the malachite-inorganic phosphate green complex so formed at 620 nm is converted with the help of phosphate standard curve as described [57][58][59][60][61][62][63][64]. The loss in the SphK1 activity followed an inverse relationship between percentage inhibition and an increasing concentration of selected compounds as shown in Figure 5 (C and D) which was used for the calculation of IC 50 values (Table 3).…”

Section: Enzyme Inhibition Assaymentioning

confidence: 99%

Design and synthesis of new pyrazolylbenzimidazoles as sphingosine kinase-1 inhibitors

et al. 2021

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Sphingosine-1 Kinase (SphK-1) is one of the important enzymes of phospholipids and it is inhibition is one of the therapeutic strategies for different diseases. SphK1 over expression is observed in different types of cancer that indicating its important role in tumor growth. In search of effective SphK-1 inhibitors, a new series of pyrazolylbenzimidazoles was synthesized and evaluated as sphingosine1-kinase (Sphk-1) inhibitors. In order to evaluate the binding a nities of all the synthesized compounds, all compounds were subjected to docking analysis and uorescence quenching. The results indicated that there is a consistency between the docking and the uorescence quenching results which revealed that compounds 47 and 48 exhibited signi cant decrease in the uorescence intensity of SphK1 as well as they formed stable protein-ligand complexes. In addition, Enzyme inhibition assay was performed and showed effective inhibitory potential towards SphK-1. Moreover, IC 50 values was calculated and 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 inhibitory potential to the SphK-1. Most of these compounds t well into the ATP-binding site of SphK1 and form signi cant 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.

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Discovery of Harmaline as a Potent Inhibitor of Sphingosine Kinase-1: A Chemopreventive Role in Lung Cancer

Cited by 46 publications

References 105 publications

Therapeutic Potential of SphK1 Inhibitors Based on Abnormal Expression of SphK1 in Inflammatory Immune Related-Diseases

Therapeutic Potential of SphK1 Inhibitors Based on Abnormal Expression of SphK1 in Inflammatory Immune Related-Diseases

Design, synthesis, and biological evaluation of novel benzimidazole derivatives as sphingosine kinase 1 inhibitor

Design and synthesis of new pyrazolylbenzimidazoles as sphingosine kinase-1 inhibitors

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