Synthesis and in vitro cytotoxicity of benzoxazole‐based PPARα/γ antagonists in colorectal cancer cell lines

<jats:title>Abstract</jats:title>A series of benzoxazole‐based amides and sulfonamides were synthesized and evaluated for their human peroxisome proliferator‐activated receptor (PPAR)α and PPARγ activity. All tested compounds showed a dual antagonist profile on both PPAR subtypes; based on transactivation results, seven compounds were selected to test their in vitro antiproliferative activity in a panel of eight cancer cell lines with different expression rates of PPARα and PPARγ. <jats:bold>3f</jats:bold> was identified as the most cytotoxic compound, with higher potency in the colorectal cancer cell lines HT‐29 and HCT116. Compound <jats:bold>3f</jats:bold> induced a concentration‐dependent activation of caspases and cell‐cycle arrest in both colorectal cancer models. Docking experiments were also performed to shed light on the putative binding mode of this novel class of dual PPARα/γ antagonists.