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RESEARCH PRODUCT
Identification of 2-(thiophen-2-yl)acetic Acid-Based Lead Compound for mPGES-1 Inhibition.
Oliver WerzMaria C. VaccaroInes BrunoKatrin FischerGiuseppe BifulcoDafne RuggieroMarianna PotenzaStefania TerraccianoSimone Di Miccosubject
Molecular modelIn silicoanti-inflammatory drugsanti-inflammatory drugs; anticancer agents; fragment-based approach; mPGES-1 inhibitors; Suzuki-Miyaura cross-coupling01 natural sciences03 medical and health sciencesAcetic acidchemistry.chemical_compoundanticancer agentsQD1-999Suzuki-Miyaura cross-coupling030304 developmental biologyOriginal ResearchA549 cellchemistry.chemical_classification0303 health sciences010405 organic chemistryfragment-based approachmPGES-1 inhibitorsGeneral ChemistryCombinatorial chemistry0104 chemical sciencesChemistryEnzymechemistryApoptosisLead compoundMacromoleculedescription
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.
| year | journal | country | edition | language |
|---|---|---|---|---|
| 2021-05-01 | Frontiers in chemistry |