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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...

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Autores principales: Roy, Sonam, Mahapatra, Amarjyoti Das, Mohammad, Taj, Gupta, Preeti, Alajmi, Mohamed F., Hussain, Afzal, Rehman, Md. Tabish, Datta, Bhaskar, Hassan, Md. Imtaiyaz
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
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.
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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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