Identification of 2-(thiophen-2-yl)acetic Acid-Based Lead Compound for mPGES-1 Inhibition
We report the implementation of our in silico/synthesis pipeline by targeting the glutathione-dependent enzyme mPGES-1, a valuable macromolecular target in both cancer therapy and inflammation therapy. Specifically, by using a virtual fragment screening approach of aromatic bromides, straightforward...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2021-05-01
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| Series: | Frontiers in Chemistry |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fchem.2021.676631/full |
| _version_ | 1818736344146378752 |
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| author | Simone Di Micco Stefania Terracciano Dafne Ruggiero Marianna Potenza Maria C. Vaccaro Katrin Fischer Oliver Werz Ines Bruno Giuseppe Bifulco |
| author_facet | Simone Di Micco Stefania Terracciano Dafne Ruggiero Marianna Potenza Maria C. Vaccaro Katrin Fischer Oliver Werz Ines Bruno Giuseppe Bifulco |
| author_sort | Simone Di Micco |
| collection | DOAJ |
| description | We report the implementation of our in silico/synthesis pipeline by targeting the glutathione-dependent enzyme mPGES-1, a valuable macromolecular target in both cancer therapy and inflammation therapy. Specifically, by using a virtual fragment screening approach of aromatic bromides, straightforwardly modifiable by the Suzuki-Miyaura reaction, we identified 3-phenylpropanoic acid and 2-(thiophen-2-yl)acetic acid to be suitable chemical platforms to develop tighter mPGES-1 inhibitors. Among these, compounds 1c and 2c showed selective inhibitory activity against mPGES-1 in the low micromolar range in accordance with molecular modeling calculations. Moreover, 1c and 2c exhibited interesting IC50 values on A549 cell lines compared to CAY10526, selected as reference compound. The most promising compound 2c induced the cycle arrest in the G0/G1 phase at 24 h of exposure, whereas at 48 and 72 h, it caused an increase of subG0/G1 fraction, suggesting an apoptosis/necrosis effect. |
| first_indexed | 2024-12-18T00:35:39Z |
| format | Article |
| id | doaj.art-71095209381047b3a5acfad96c27ae5e |
| institution | Directory Open Access Journal |
| issn | 2296-2646 |
| language | English |
| last_indexed | 2024-12-18T00:35:39Z |
| publishDate | 2021-05-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Chemistry |
| spelling | doaj.art-71095209381047b3a5acfad96c27ae5e2022-12-21T21:27:01ZengFrontiers Media S.A.Frontiers in Chemistry2296-26462021-05-01910.3389/fchem.2021.676631676631Identification of 2-(thiophen-2-yl)acetic Acid-Based Lead Compound for mPGES-1 InhibitionSimone Di Micco0Stefania Terracciano1Dafne Ruggiero2Marianna Potenza3Maria C. Vaccaro4Katrin Fischer5Oliver Werz6Ines Bruno7Giuseppe Bifulco8European Biomedical Research Institute of Salerno (EBRIS), Salerno, ItalyDipartimento di Farmacia, University degli Studi di Salerno, Fisciano, ItalyDipartimento di Farmacia, University degli Studi di Salerno, Fisciano, ItalyDipartimento di Farmacia, University degli Studi di Salerno, Fisciano, ItalyDipartimento di Farmacia, University degli Studi di Salerno, Fisciano, ItalyInstitute of Pharmacy, Friedrich-Schiller-University Jena, Jena, GermanyInstitute of Pharmacy, Friedrich-Schiller-University Jena, Jena, GermanyDipartimento di Farmacia, University degli Studi di Salerno, Fisciano, ItalyDipartimento di Farmacia, University degli Studi di Salerno, Fisciano, ItalyWe report the implementation of our in silico/synthesis pipeline by targeting the glutathione-dependent enzyme mPGES-1, a valuable macromolecular target in both cancer therapy and inflammation therapy. Specifically, by using a virtual fragment screening approach of aromatic bromides, straightforwardly modifiable by the Suzuki-Miyaura reaction, we identified 3-phenylpropanoic acid and 2-(thiophen-2-yl)acetic acid to be suitable chemical platforms to develop tighter mPGES-1 inhibitors. Among these, compounds 1c and 2c showed selective inhibitory activity against mPGES-1 in the low micromolar range in accordance with molecular modeling calculations. Moreover, 1c and 2c exhibited interesting IC50 values on A549 cell lines compared to CAY10526, selected as reference compound. The most promising compound 2c induced the cycle arrest in the G0/G1 phase at 24 h of exposure, whereas at 48 and 72 h, it caused an increase of subG0/G1 fraction, suggesting an apoptosis/necrosis effect.https://www.frontiersin.org/articles/10.3389/fchem.2021.676631/fullfragment-based approachSuzuki-Miyaura cross-couplingmPGES-1 inhibitorsanti-inflammatory drugsanticancer agents |
| spellingShingle | Simone Di Micco Stefania Terracciano Dafne Ruggiero Marianna Potenza Maria C. Vaccaro Katrin Fischer Oliver Werz Ines Bruno Giuseppe Bifulco Identification of 2-(thiophen-2-yl)acetic Acid-Based Lead Compound for mPGES-1 Inhibition Frontiers in Chemistry fragment-based approach Suzuki-Miyaura cross-coupling mPGES-1 inhibitors anti-inflammatory drugs anticancer agents |
| title | Identification of 2-(thiophen-2-yl)acetic Acid-Based Lead Compound for mPGES-1 Inhibition |
| title_full | Identification of 2-(thiophen-2-yl)acetic Acid-Based Lead Compound for mPGES-1 Inhibition |
| title_fullStr | Identification of 2-(thiophen-2-yl)acetic Acid-Based Lead Compound for mPGES-1 Inhibition |
| title_full_unstemmed | Identification of 2-(thiophen-2-yl)acetic Acid-Based Lead Compound for mPGES-1 Inhibition |
| title_short | Identification of 2-(thiophen-2-yl)acetic Acid-Based Lead Compound for mPGES-1 Inhibition |
| title_sort | identification of 2 thiophen 2 yl acetic acid based lead compound for mpges 1 inhibition |
| topic | fragment-based approach Suzuki-Miyaura cross-coupling mPGES-1 inhibitors anti-inflammatory drugs anticancer agents |
| url | https://www.frontiersin.org/articles/10.3389/fchem.2021.676631/full |
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