Tuberatolides, Potent FXR Antagonists from the Korean Marine Tunicate Botryllus tuberatus

Abstract

One isoprenoid, tuberatolide A (1), meroterpenoids tuberatolide B (2) and 2'-epi-tuberatolide B (3), and the known meroterpenoids yezoquinolide (4), (R)-sargachromenol (5), and (S)-sargachromenol (6) were isolated from the Korean marine tunicate Botryllus tuberatus. The structures of these compounds were elucidated by NMR, MS, and CD spectroscopic analyses. These terpenoids antagonized the chenodeoxycholic acid (CDCA)-activated human farnesoid X receptor (hFXR) in a cell-based co-transfection assay with IC(50) values as low as 1.5 μM without significant effect on steroid receptors. Furthermore, they released the co-activator peptide from the CDCA-bound hFXR ligand binding domain in cell-free surface plasmon resonance experiments.

Tuberatolide B Suppresses Cancer Progression by Promoting ROS-Mediated Inhibition of STAT3 Signaling

“…A combined active fraction was further subjected to a Sephadex LH-20 column saturated with 100% methanol, and then purified by reversed phase high performance liquid chromatography (HPLC) using a Waters HPLC system (Alliance 2690; Waters Corp., Milford, MA, USA) equipped with a Waters 996 photodiode array detector and C18 column (J’sphere ODS-H80, 250 × 4.6 mm, 4 μm; YMC Co., Kyoto, Japan) by stepwise elution with methanol–water gradient (UV range, 220 nm; flow rate, 1 mL/min). Finally, the purified compound was identified by comparing its 1H and 13C NMR data with literature [26]. The chemical structure of tuberatolide B is indicated in Figure 1.…”

“…Tuberatolide B (TTB, C27H34O4) is a diastereomeric meroterpenoid isolated from the Korean marine algae Sargassum macrocarpum and acts as a Farnesoid X receptor (FXR) antagonist [26]. However, the effect of TTB on various diseases, including cancer, remains unknown.…”

Meroterpenes from Marine Invertebrates: Structures, Occurrence, and Ecological Implications

“…densum [22]. Tuberatolides ( 30 and 31 ) and sargachromenols ( 32 and 33 ), isolated from Botryllus tuberatus along with their putative linear precursor yezoquinolide ( 16 ), antagonized the chenodeoxycholic acid (CDCA)-activated human farnesoid X receptor (hFXR), a ligand-dependent transcription factor in the nuclear receptor superfamily which has been recently identified as a promising drug target in the treatment of atherosclerosis [27]. Longithorol E ( 34 ), from A. longithorax , is a unique macrocyclic chromenol containing a new 14 membered carbocycle [28] (Figure 3).…”

Natural Ligands for Nuclear Receptors: Biology and Potential Therapeutic Applications

“…(6) isolated from the Korean marine tunicate Botryllus tuberatus in 2011 [236]. These terpenoids antagonized the hFXR activation by CDCA in a cell-based co-transfection assay with IC 50 values ranging from 1.5 μM to 17 μM with tuberatolide B the most active of this series.…”