Synthesis of 2-alkyl benzopyran analogues of polycerasoidol as PPAR agonists or agents against triple negative breast cancer

• Autores: Ainhoa Natividad García Martín
• Directores de la Tesis: Diego M. Cortes Martínez (dir. tes.), Nuria Cabedo Escrig (codir. tes.)
• Lectura: En la Universitat de València ( España ) en 2024
• Idioma: inglés
• Número de páginas: 184
• Tribunal Calificador de la Tesis: Patrick Dallemagne (presid.), Pedro Miguel Carda Usó (secret.), Nathalie Hennuyer (voc.)
• Programa de doctorado: Programa de Doctorado en Biomedicina y Farmacia por la Universitat de València (Estudi General)
• Materias:
  • Ciencias médicas
    • Farmacología
  • Ciencias tecnológicas
    • Ingeniería y tecnología químicas
      • Síntesis química
• Enlaces
  • Tesis en acceso abierto en: webges.uv.es (pdf)
• Resumen

  • This Doctoral Thesis aims to bring novel compounds that could emerge as new hits useful in the treatment of different pathologies. For this purpose, different benzopyran derivatives containing a chromane nucleus have been synthetized and evaluated in vitro.

    Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors of the nuclear hormone receptor superfamily implicated in numerous cell functions including the control of lipid and carbohydrate metabolism and inflammation. Some benzopyrans have been demonstrated to be PPAR agonists, comprising the natural polycerasoidol, among others. Consequently, 2-prenylated benzopyran derivatives bearing some isoprenoid units or an -alkoxy-,ß-unsaturated ester moiety were synthesised via the Grignard reaction followed by the Horner-Wadsworth-Emmons reaction or the Witting olefination. The transactivation studies of the synthesized benzopyrans showed that synthetised benzopyrans were efficient as dual PPAR/ agonists or display selectivity for hPPAR or hPPAR. Moreover, 2-alkyl hydrazone derivatives were synthetised and evaluated in terms of their agonism activity and anti-inflammatory capacity. Synthetised derivatives showed partial hPPAR/ or hPPAR/ agonism activity and attenuated inflammatory markers such as IL-6 and MCP-1 in THP-1 cells via NF-kB pathway activation.

    On the other hand, breast cancer (BC) is a complex and heterogeneous disease, being the most frequent diagnosed and the leading cause of cancer-related deaths among women. Triple negative breast cancer (TNBC) is a very aggressive type of cancer and the affordable therapeutic strategy is cytotoxic chemotherapy with taxane- and tetracycline-based combination treatment and platinum-based agents, but drug resistance constitutes one of the major challenges that TNBC research faces. The discovery of new compounds that impact the survival of tumor cells in this particular subtype of breast cancer is highly significant for enhancing its treatment. Accordingly, 2-aminopropyl benzopyran derivatives were synthetised and evaluated against TNBC cells. Synthetised benzopyrans promoted apoptosis or caused cell cycle arrest in TNBC cells by downregulating apoptotic Bcl-2 or cyclins (CCNE1 and CCND2), respectively.

    Therefore, benzopyran derivatives analogues of polycerasoidol emerge as lead compounds for developing useful candidates to prevent cardiovascular diseases associate with metabolic disorders or useful agents against breast cancer.