New organotin(IV) syringates as potential PPAR agonists: from chemical characterization to biological activity towards colon cancer HCT116 cells.

Abstract

As members of the nuclear receptor (NR) family of transcription factors, peroxisome proliferator-activated receptors (PPARs) regulate essential cellular processes, including lipid metabolism, glucose uptake, cell proliferation, and programmed cell death through ligand-mediated activation. Within the PPAR subfamilies, PPAR-γ (PPARG) is crucial to the development of fat cells, sensitivity to insulin, apoptosis, and metastasis.[1] PPARG is also reported to be a promising target for patients diagnosed with colorectal cancer (CRC) and it is significantly expressed in 70% of the sporadic CRC. In individuals with CRC, the precise function of PPARG remains not entirely comprehended and elucidation of the PPARG transcriptional regulation in CRC seems promising.[2] There are different ongoing works aimed at exploring the PPAR-activating capability of a wide range of natural products such as phenolic compounds. These compounds exhibit different molecular interactions with PPAR, which could be determined by their specific binding affinity to the receptor and therefore, their capacity modulating its activity.[3] Syringic acid (SA), chemically known as 4-hydroxy-3,5-dimethoxy benzoic acid, is one of the most common phenolic acids. SA has a chemical structure featuring a benzene ring bonded to a hydroxyl (-OH), a carboxylic acid (-COOH), and two methoxy (-OCH3) groups. The strategic placement of these methoxy groups at positions 3 and 5 on the aromatic ring is responsible for its beneficial therapeutic properties.[4] On the other hand, it is well known that organotin(IV) act as powerful agonists for PPARG and stimulate adipocyte differentiation via the PPARG signaling pathway.[5] With the aim of studying the modulation of antitumor efficacy and the interaction with receptor PPARG of SA, we synthesized new triorganotin(IV) syringates. Complexes structures were investigated in solid state and in solution by Fourier Transform Infrared (FT-IR), Electrospray Ionization Mass Spectroscopy (ESI-MS), Nuclear Magnetic Resonance (NMR) spectroscopies and by X-ray single crystal analysis. The interactions of SA with a series of organotin(IV) cations, namely dimethyltin(IV) (DMT), diethyltin(IV) (DET), trimethyltin(IV) (TMT), triethyltin(IV) (TET) and tripropyltin(IV) (TPT) were also investigated in KCl(aq) at I = 0.2 mol dm-3 and at T = 298.2 K, by ISE-H+ (glass electrode) potentiometric titrations. The stability constants determined enabled us to model the chemical speciation of SA / organotin(IV) systems in aqueous solution, to get further insights on the behavior of their complexes in biological fluids. Furthermore, molecular docking and dynamics revealed triorganotin(IV) syringates stably binding to PPARG interacting with Cys285, Arg288, Lys263, Ile325, Leu228 amino acids of the ligand-binding domain (LBD) of the receptor. Finally, biological studies evidenced that TBT syringate (TBT-SA) shows a significant cytotoxic activity in tumor cells, reducing the proliferation of colon cancer HCT116 cells of about 80% at 500 nM after 48 h of treatment. At the same dose, the free ligand SA was completely ineffective. The analysis of cell cycle distribution confirmed the results and demonstrated the presence of a preG0-G1 peak (from 1.86% to 23.40% in treated cells) in colon cancer cells. Taken together, our results strongly suggest that the combination of organotin(IV) moieties with natural polyphenols ligands represents a promising therapeutic strategy for colon cancer.