Synthesis of benzopyran derivatives as PPARα and/or PPARγ activators
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AuthorBermejo, Almudena; Barrachina, Isabel; El Aouad, Noureddine; Franck, Xavier; Chahboune, Nadia; Andreu, Inmaculada; Figadère, Bruno; Vila, Laura; hennuyer, Nathalie; Staels, Bart; Dacquet, Catherine; Caignard, Daniel H.; Sanz, María-Jesús; Cortés, Diego; Cabedo, Nuria
Cita bibliográficaBermejo, A., Barrachina, I., El Aouad, N., Franck, X., Chahboune, N., Andreu, I., ... & Dacquet, C. (2019). Synthesis of benzopyran derivatives as PPARα and/or PPARγ activators. Bioorganic & medicinal chemistry, 27(24), 115162.
We describe the synthesis of 26 compounds, small polycerasoidol analogs, that are Lipinski’s rule-of-five compliant. In order to confirm key structural features to activate PPARα and/or PPARγ, we have adopted structural modifications in the following parts: (i) the benzopyran core (hydrophobic nucleus) by benzopyran-4-one, dihydrobenzopyran or benzopyran-4-ol; (ii) the side chain at 2-position by shortening to C3, C4 and C5-carbons versus C-9-carbons of polycerasoidol; (iii) the carboxylic group (polar head) by oxygenated groups (hydroxyl, acetoxy, epoxide, ester, aldehyde) or non-oxygenated motifs (allyl and alkyl). Benzopyran-4-ones 6, 12, 13 and 17 as well as dihydrobenzopyrans 22, 24 and 25 were able to activate hPPARα, whereas benzopyran-4-one (7) with C5-carbons in the side chain exhibited hPPARγ agonism. According to our previous docking studies, SAR confirm that the hydrophobic nucleus (benzopyran-4-one or dihydrobenzopyran) is essential to activate PPARα and/or PPARγ, and the flexible linker (side alkyl chain) should containg at least C5-carbon atoms to activate PPARγ. By contrast, the polar head (“carboxylic group”) tolerated several oxygenated groups but also non-oxygenated motifs. Taking into account these key structural features, small polycerasoidol analogs might provide potential active molecules useful in the treatment of dyslipidemia and/or type 2 diabetes.