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Synthesis of benzopyran derivatives as PPAR alpha and/or PPAR gamma activators

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Autores de INCLIVA

Participantes ajenos a INCLIVA

  • Bermejo, A
  • Barrachina, I
  • El Aouad, N
  • Franck, X
  • Chahboune, N
  • Andreu, I
  • Figadere, B
  • Hennuyer, N
  • Staels, B
  • Dacquet, C
  • Caignard, DH
  • Cortes, D

Grupos y Plataformas de I+D+i

Abstract

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 PPAR alpha and/or PPAR gamma, we have adopted structural modifications in the following parts: (i) the benzopyran core (hydrophobic nucleus) by benzopyran-4-one, di-hydrobenzopyran 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 hPPAR alpha, whereas benzopyran-4-one (7) with C5-carbons in the side chain exhibited hPPAR gamma agonism. According to our previous docking studies, SAR confirm that the hydrophobic nucleus (benzopyran-4-one or dihydrobenzopyran) is essential to activate PPAR alpha and/or PPAR gamma, and the flexible linker (side alkyl chain) should containg at least C5-carbon atoms to activate PPAR gamma. 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.

© 2019 Elsevier Ltd. All rights reserved.

Datos de la publicación

ISSN/ISSNe:
0968-0896, 1464-3391

BIOORGANIC & MEDICINAL CHEMISTRY  PERGAMON-ELSEVIER SCIENCE LTD

Tipo:
Article
Páginas:
115162-115162
PubMed:
31703893

Citas Recibidas en Web of Science: 11

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Keywords

  • Benzopyrans; Polycerasoidol; PPAR alpha agonism; PPAR gamma agonism

Financiación

INSTITUTO SALUD CARLOS III (CP15/00150)
INSTITUTO SALUD CARLOS III (PI18/00150)
INSTITUTO SALUD CARLOS III (PI18/01450)
MINISTERIO ECONOMIA Y COMPETITIVIDAD (SAF2014-57845-R)
MINISTERIO ECONOMIA Y COMPETITIVIDAD (SAF2017-89714-R)

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