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Design and Development of Novel Urea, Sulfonyltriurea, and Sulfonamide Derivatives as Potential Inhibitors of Sphingosine Kinase 1
Sphingosine kinase 1 (SphK1) is one of the well-studied drug targets for cancer and inflammatory diseases. Recently discovered small-molecule inhibitors of SphK1 have been recommended in cancer therapeutics; however, selectivity and potency of first-generation inhibitors are great challenge. In sear...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7346089/ https://www.ncbi.nlm.nih.gov/pubmed/32526899 http://dx.doi.org/10.3390/ph13060118 |
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author | Roy, Sonam Mahapatra, Amarjyoti Das Mohammad, Taj Gupta, Preeti Alajmi, Mohamed F. Hussain, Afzal Rehman, Md. Tabish Datta, Bhaskar Hassan, Md. Imtaiyaz |
author_facet | Roy, Sonam Mahapatra, Amarjyoti Das Mohammad, Taj Gupta, Preeti Alajmi, Mohamed F. Hussain, Afzal Rehman, Md. Tabish Datta, Bhaskar Hassan, Md. Imtaiyaz |
author_sort | Roy, Sonam |
collection | PubMed |
description | Sphingosine kinase 1 (SphK1) is one of the well-studied drug targets for cancer and inflammatory diseases. Recently discovered small-molecule inhibitors of SphK1 have been recommended in cancer therapeutics; however, selectivity and potency of first-generation inhibitors are great challenge. In search of effective SphK1 inhibitors, a set of small molecules have been designed and synthesized bearing urea, sulfonylurea, sulfonamide, and sulfonyltriurea groups. The binding affinity of these inhibitors was measured by fluorescence-binding assay and isothermal titration calorimetry. Compounds 1, 5, 6, and 7 showed an admirable binding affinity to the SphK1 in the sub-micromolar range and significantly inhibited SphK1 activity with admirable IC(50) values. Molecular docking studies revealed that these compounds fit well into the sphingosine binding pocket of SphK1 and formed significant number of hydrogen bonds and van der Waals interactions. These molecules may be exploited as potent and selective inhibitors of SphK1 that could be implicated in cancer therapeutics after the required in vivo validation. |
format | Online Article Text |
id | pubmed-7346089 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-73460892020-07-14 Design and Development of Novel Urea, Sulfonyltriurea, and Sulfonamide Derivatives as Potential Inhibitors of Sphingosine Kinase 1 Roy, Sonam Mahapatra, Amarjyoti Das Mohammad, Taj Gupta, Preeti Alajmi, Mohamed F. Hussain, Afzal Rehman, Md. Tabish Datta, Bhaskar Hassan, Md. Imtaiyaz Pharmaceuticals (Basel) Article Sphingosine kinase 1 (SphK1) is one of the well-studied drug targets for cancer and inflammatory diseases. Recently discovered small-molecule inhibitors of SphK1 have been recommended in cancer therapeutics; however, selectivity and potency of first-generation inhibitors are great challenge. In search of effective SphK1 inhibitors, a set of small molecules have been designed and synthesized bearing urea, sulfonylurea, sulfonamide, and sulfonyltriurea groups. The binding affinity of these inhibitors was measured by fluorescence-binding assay and isothermal titration calorimetry. Compounds 1, 5, 6, and 7 showed an admirable binding affinity to the SphK1 in the sub-micromolar range and significantly inhibited SphK1 activity with admirable IC(50) values. Molecular docking studies revealed that these compounds fit well into the sphingosine binding pocket of SphK1 and formed significant number of hydrogen bonds and van der Waals interactions. These molecules may be exploited as potent and selective inhibitors of SphK1 that could be implicated in cancer therapeutics after the required in vivo validation. MDPI 2020-06-09 /pmc/articles/PMC7346089/ /pubmed/32526899 http://dx.doi.org/10.3390/ph13060118 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Roy, Sonam Mahapatra, Amarjyoti Das Mohammad, Taj Gupta, Preeti Alajmi, Mohamed F. Hussain, Afzal Rehman, Md. Tabish Datta, Bhaskar Hassan, Md. Imtaiyaz Design and Development of Novel Urea, Sulfonyltriurea, and Sulfonamide Derivatives as Potential Inhibitors of Sphingosine Kinase 1 |
title | Design and Development of Novel Urea, Sulfonyltriurea, and Sulfonamide Derivatives as Potential Inhibitors of Sphingosine Kinase 1 |
title_full | Design and Development of Novel Urea, Sulfonyltriurea, and Sulfonamide Derivatives as Potential Inhibitors of Sphingosine Kinase 1 |
title_fullStr | Design and Development of Novel Urea, Sulfonyltriurea, and Sulfonamide Derivatives as Potential Inhibitors of Sphingosine Kinase 1 |
title_full_unstemmed | Design and Development of Novel Urea, Sulfonyltriurea, and Sulfonamide Derivatives as Potential Inhibitors of Sphingosine Kinase 1 |
title_short | Design and Development of Novel Urea, Sulfonyltriurea, and Sulfonamide Derivatives as Potential Inhibitors of Sphingosine Kinase 1 |
title_sort | design and development of novel urea, sulfonyltriurea, and sulfonamide derivatives as potential inhibitors of sphingosine kinase 1 |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7346089/ https://www.ncbi.nlm.nih.gov/pubmed/32526899 http://dx.doi.org/10.3390/ph13060118 |
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