薬経済学: オープンアクセス

Novel PPARα antagonists bearing Stilbene or Bioisosteres endowed with antiproliferative effects in cancer cell lines

Abstract

Alessandra Ammazzalorso

Peroxisome Proliferator-Activated Receptors (PPARs) have been widely studied in the last decades, and they attracted the attention of scientists as promising therapeutic
targets. Intensive efforts by researchers produced a wide panel of drugs targeting the three PPAR subtypes (PPARα PPARγ PPARδ) able to modulate important metabolic
functions. PPAR activation is involved in several physiologic pathways, as lipid and glucose metabolism, insulin sensitivity, energy homeostasis, and cell differentiation.
Fibrates and thiazolidinediones, respectively synthetic PPARα and PPARγ agonists, are currently used for the treatment of hyperlipidemia and hyperglycemia, in patients
affected by type 2 diabetes and metabolic syndrome.
In recent years, an increased expression of PPARα has been found in different tumors: it is well known that cancer cells present altered metabolic pathways, switching from
the glycolysis to fatty acid oxidation metabolism. In this scenario, PPARα antagonists emerged as novel potential drugs in tumors overexpressing PPARα by interfering
with cellular survival and metastasis formation.[2] In vitro anticancer effects were found for PPARα antagonists in chronic lymphocytic leukemia [3], renal cancer, colorectal
and pancreatic cancer [4], paraganglioma [5].
In this study we report on the synthesis of novel PPARα antagonists bearing stilbene or its bioisosteres, starting from the structure of a dual PPARα/γ agonist, previously
synthesized in our laboratory. We explored the cytotoxicity of the novel compounds in different cancer cell lines (colorectal, pancreatic, renal, paraganglioma) expressing PPARα.