Tetrazanbigen Derivatives as Peroxisome Proliferator-Activated Receptor Gamma (PPARγ) Partial Agonists: Design, Synthesis, Structure–Activity Relationship, and Anticancer Activities

Abstract

Tetrazanbigen (<b>TNBG</b>) is a novel sterol isoquinoline derivative with poor water solubility and moderate inhibitory effects on human cancer cell lines <i>via</i> lipoapoptosis induction. Herein, we developed a series of novel <b>TNBG</b> analogues with improved water solubility and antiproliferative activities. The CCK-8 assay enabled us to identify a novel compound, <b>14g</b>, which strongly inhibited HepG2 and A549 cell growth with IC₅₀ values of 0.54 and 0.47 μM, respectively. The anticancer effects might be explained by the partial activation and upregulation of PPARγ expression, as indicated by the transactivation assay and western blotting evaluation. Furthermore, the <i>in vitro</i> antiproliferative activity was verified in an <i>in vivo</i> xenograft model in which <b>14g</b> strongly reduced tumor growth at a dose of 10 mg/kg. In line with these positive observations, <b>14g</b> exhibited an excellent water solubility of 31.4 mg/mL, which was more than 1000-fold higher than that of <b>TNBG</b> (4 μg/mL). Together, these results suggest that <b>14g</b> is a promising anticancer therapeutic that deserves further investigation.