Tricyclic coumarin sulphonate derivatives with alkaline phosphatase inhibitory effects: in vitro and docking studies
Tissue-nonspecific alkaline phosphatase (TNAP) is an important isozyme of alkaline phosphatases, which plays different pivotal roles within the human body. Most importantly, it is responsible for maintaining the balanced ratio of phosphate and inorganic pyrophosphate, thus regulates the extracellula...
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| Format: | Article |
| Language: | English |
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Taylor & Francis Group
2018-01-01
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| Series: | Journal of Enzyme Inhibition and Medicinal Chemistry |
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| Online Access: | http://dx.doi.org/10.1080/14756366.2018.1428193 |
| _version_ | 1818538394534281216 |
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| author | Jamshed Iqbal Mohammed I. El-Gamal Syeda Abida Ejaz Joanna Lecka Jean Sévigny Chang-Hyun Oh |
| author_facet | Jamshed Iqbal Mohammed I. El-Gamal Syeda Abida Ejaz Joanna Lecka Jean Sévigny Chang-Hyun Oh |
| author_sort | Jamshed Iqbal |
| collection | DOAJ |
| description | Tissue-nonspecific alkaline phosphatase (TNAP) is an important isozyme of alkaline phosphatases, which plays different pivotal roles within the human body. Most importantly, it is responsible for maintaining the balanced ratio of phosphate and inorganic pyrophosphate, thus regulates the extracellular matrix calcification during bone formation and growth. The elevated level of TNAP has been linked to vascular calcification and end-stage renal diseases. Consequently, there is a need to search for highly potent and selective inhibitors of alkaline phosphatases (APs) for treatment of disorders associated with the over-expression of APs. Herein, a series of tricyclic coumarin sulphonate 1a-za with known antiproliferative activity, was evaluated for AP inhibition against human tissue nonspecific alkaline phosphatase (h-TNAP) and human intestinal alkaline phosphatase (h-IAP). The methylbenzenesulphonate derivative 1f (IC50 = 0.38 ± 0.01 μM) was found to be the most active h-TNAP inhibitor. Another 4-fluorobenzenesulphonate derivative 1i (IC50 = 0.45 ± 0.02 μM) was found as the strongest inhibitor of h-IAP. Some of the derivatives were also identified as highly selective inhibitors of APs. Detailed structure-activity relationship (SAR) was investigated to identify the functional groups responsible for the effective inhibition of AP isozymes. The study was also supported by the docking studies to rationalise the most possible binding site interactions of the identified inhibitors with the targeted enzymes. |
| first_indexed | 2024-12-11T21:28:25Z |
| format | Article |
| id | doaj.art-5c130c0a00fd41cb957107c9b0fe806c |
| institution | Directory Open Access Journal |
| issn | 1475-6366 1475-6374 |
| language | English |
| last_indexed | 2024-12-11T21:28:25Z |
| publishDate | 2018-01-01 |
| publisher | Taylor & Francis Group |
| record_format | Article |
| series | Journal of Enzyme Inhibition and Medicinal Chemistry |
| spelling | doaj.art-5c130c0a00fd41cb957107c9b0fe806c2022-12-22T00:50:14ZengTaylor & Francis GroupJournal of Enzyme Inhibition and Medicinal Chemistry1475-63661475-63742018-01-0133147948410.1080/14756366.2018.14281931428193Tricyclic coumarin sulphonate derivatives with alkaline phosphatase inhibitory effects: in vitro and docking studiesJamshed Iqbal0Mohammed I. El-Gamal1Syeda Abida Ejaz2Joanna Lecka3Jean Sévigny4Chang-Hyun Oh5COMSATS Institute of Information TechnologyUniversity of SharjahCOMSATS Institute of Information TechnologyUniversité LavalUniversité LavalKorea Institute of Science and TechnologyTissue-nonspecific alkaline phosphatase (TNAP) is an important isozyme of alkaline phosphatases, which plays different pivotal roles within the human body. Most importantly, it is responsible for maintaining the balanced ratio of phosphate and inorganic pyrophosphate, thus regulates the extracellular matrix calcification during bone formation and growth. The elevated level of TNAP has been linked to vascular calcification and end-stage renal diseases. Consequently, there is a need to search for highly potent and selective inhibitors of alkaline phosphatases (APs) for treatment of disorders associated with the over-expression of APs. Herein, a series of tricyclic coumarin sulphonate 1a-za with known antiproliferative activity, was evaluated for AP inhibition against human tissue nonspecific alkaline phosphatase (h-TNAP) and human intestinal alkaline phosphatase (h-IAP). The methylbenzenesulphonate derivative 1f (IC50 = 0.38 ± 0.01 μM) was found to be the most active h-TNAP inhibitor. Another 4-fluorobenzenesulphonate derivative 1i (IC50 = 0.45 ± 0.02 μM) was found as the strongest inhibitor of h-IAP. Some of the derivatives were also identified as highly selective inhibitors of APs. Detailed structure-activity relationship (SAR) was investigated to identify the functional groups responsible for the effective inhibition of AP isozymes. The study was also supported by the docking studies to rationalise the most possible binding site interactions of the identified inhibitors with the targeted enzymes.http://dx.doi.org/10.1080/14756366.2018.1428193Alkaline phosphatase inhibitorcoumarinmolecular dockingstructure-activity relationshipTricyclic coumarin sulfonate |
| spellingShingle | Jamshed Iqbal Mohammed I. El-Gamal Syeda Abida Ejaz Joanna Lecka Jean Sévigny Chang-Hyun Oh Tricyclic coumarin sulphonate derivatives with alkaline phosphatase inhibitory effects: in vitro and docking studies Journal of Enzyme Inhibition and Medicinal Chemistry Alkaline phosphatase inhibitor coumarin molecular docking structure-activity relationship Tricyclic coumarin sulfonate |
| title | Tricyclic coumarin sulphonate derivatives with alkaline phosphatase inhibitory effects: in vitro and docking studies |
| title_full | Tricyclic coumarin sulphonate derivatives with alkaline phosphatase inhibitory effects: in vitro and docking studies |
| title_fullStr | Tricyclic coumarin sulphonate derivatives with alkaline phosphatase inhibitory effects: in vitro and docking studies |
| title_full_unstemmed | Tricyclic coumarin sulphonate derivatives with alkaline phosphatase inhibitory effects: in vitro and docking studies |
| title_short | Tricyclic coumarin sulphonate derivatives with alkaline phosphatase inhibitory effects: in vitro and docking studies |
| title_sort | tricyclic coumarin sulphonate derivatives with alkaline phosphatase inhibitory effects in vitro and docking studies |
| topic | Alkaline phosphatase inhibitor coumarin molecular docking structure-activity relationship Tricyclic coumarin sulfonate |
| url | http://dx.doi.org/10.1080/14756366.2018.1428193 |
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