Three new 3-formyl-2-arylbenzofurans from Itea yunnanensis and their anti-hepatocellular carcinoma effects.

Five 3-formyl-2-arylbenzofuran derivatives, including three new compounds (1-3) and two known analogues (4-5), were identified from the 95% EtOH extract of Itea yunnanensis. Extensive spectroscopic analyses were performed for the structure elucidation of all new benzofurans, and single-crystal X-ray diffraction analyses were further employed for the structure verification of iteafuranals C (1) and D (2). In MTT assay, iteafuranal E (3) and iteafuranal A (4) displayed significant growth inhibition effect on SK-Hep-1 cells with IC50 values of 5.365 µM and 6.013 µM, respectively. The colony formation assay of 3 and 4 further confirmed their remarkable inhibitory effect on cell growth. Preliminary mechanism study demonstrated that 3 remarkably down-regulated the phosphorylation level of ERK, which suggested 3 could inhibit cell growth and induce apoptosis of SK-Hep-1 cells by blocking RAS/RAF/MEK/ERK signaling pathway. This study highlighted the potential of 3-fomyl-2-benzofuran derivatives as novel lead compounds to treat Hepatocellular carcinoma.[Formula: see text].

Estrogen receptor ß upregulated by lncRNA-H19 to promote cancer stem-like properties in papillary thyroid carcinoma.

Estrogen receptor ß (ERß) plays critical roles in thyroid cancer progression. However, its role in thyroid cancer stem cell maintenance remains elusive. Here, we report that ERß is overexpressed in papillary thyroid cancer stem cells (PTCSCs), whereas ablation of ERß decreases stemness-related factors expression, diminishes ALDH+ cell populations, and suppresses sphere formation ability and tumor growth. Screening estrogen-responsive lncRNAs in PTC spheroid cells, we find that lncRNA-H19 is highly expressed in PTCSCs and PTC tissue specimens, which is correlated with poor overall survival. Mechanistically, estradiol (E2) significantly promotes H19 transcription via ERß and elevates H19 expression. Silencing of H19 inhibits E2-induced sphere formation ability. Furthermore, H19 acting as a competitive endogenous RNA sequesters miRNA-3126-5p to reciprocally release ERß expression. ERß depletion reverses H19-induced stem-like properties upon E2 treatment. Appropriately, ERß is upregulated in PTC tissue specimens. Notably, aspirin attenuates E2-induced cancer stem-like traits through decreasing both H19 and ERß expression. Collectively, our findings reveal that ERß-H19 positive feedback loop has a compelling role in PTCSC maintenance under E2 treatment and provides a potential therapeutic targeting strategy for PTC.

Identification of small molecule inhibitors targeting the SMARCA2 bromodomain from a high-throughput screening assay.

SMARCA2 is a critical catalytic subunit of the switch/sucrose non-fermenting (SWI/SNF) chromatin remodeling complexes. Dysregulation of SMARCA2 is associated with several diseases, including some cancers. SMARCA2 is multi-domain protein containing a bromodomain (BRD) that specifically recognizes acetylated lysine residues in histone tails, thus playing an important role in chromatin remodeling. Many potent and specific inhibitors targeting other BRDs have recently been discovered and have been widely used for cancer treatments and biological research. However, hit discovery targeting SMARCA2-BRD is particularly lacking. To date, there is a paucity of reported high-throughput screening (HTS) assays targeting the SMARCA2-BRD interface. In this study, we developed an AlphaScreen HTS system for the discovery of SMARCA2-BRD inhibitors and optimized the physicochemical conditions including pH, salt concentrations and detergent levels. Through an established AlphaScreen-based high-throughput screening assay against an in-house compound library, DCSM06 was identified as a novel SMARCA2-BRD inhibitor with an IC50 value of 39.9±3.0 µmol/L. Surface plasmon resonance demonstrated the binding between SMARCA2-BRD and DCSM06 (Kd=38.6 µmol/L). A similarity-based analog search led to identification of DCSM06-05 with an IC50 value of 9.0±1.4 µmol/L. Molecular docking was performed to predict the binding mode of DCSM06-05 and to decipher the structural basis of the infiuence of chemical modifications on inhibitor potency. DCSM06-05 may be used as a starting point for further medicinal chemistry optimization and could function as a chemical tool for SMARCA2-related functional studies.

Identification of novel 5-hydroxy-1H-indole-3-carboxylates with anti-HBV activities based on 3D QSAR studies.

Infection with hepatitis B virus (HBV) is a major cause of liver diseases such as cirrhosis and hepatocellular carcinoma. In our previous studies, we identified indole derivatives that have anti-HBV activities. In this study, we optimize a series of 5-hydroxy-1H-indole-3-carboxylates, which exhibited potent anti-HBV activities, using three-dimensional quantitative structure-activity relationship (3D QSAR) studies with comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA). The lowest energy conformation of compound 3, which exhibited the most potent anti-HBV activity, obtained from systematic search was used as the template for alignment. The best predictions were obtained with the CoMFA standard model (q (2) = 0.689, r (2) = 0.965, SEE = 0.082, F = 148.751) and with CoMSIA combined steric, electrostatic, hydrophobic and H-bond acceptor fields (q (2) = 0.578, r (2) = 0.973, SEE = 0.078, F = 100.342). Both models were validated by an external test set of six compounds giving satisfactory prediction. Based on the clues derived from CoMFA and CoMSIA models and their contour maps, another three compounds were designed and synthesized. Pharmacological assay demonstrated that the newly synthesized compounds possessed more potent anti-HBV activities than before (IC(50): compound 35a is 3.1 µmol/l, compound 3 is 4.1 µmol/l). Combining the clues derived from the 3D QSAR studies and from further validation of the 3D QSAR models, the activities of the newly synthesized indole derivatives were well accounted for. Furthermore, this showed that the CoMFA and CoMSIA models proved to have good predictive ability.

Influences of a light-dark profile and the pineal gland on the hypnotic activity of melatonin in mice and rats.

We have investigated the influences of the light-dark cycle and the pineal gland on the hypnotic activity of melatonin in rats and mice. The results showed that melatonin significantly shortened time to sleep onset and wakefulness time, increased slow wave sleep, paradoxical sleep, and total sleep time in rats during the light phase of a 12-h light:12-h dark cycle, by electroencephalogram recording. However, during the dark phase it had almost no significant sleep-promoting effect except shortened time to sleep onset. Melatonin exhibited more potent sleep-promoting effect in rats exposed to constant light compared with rats exposed to 12:12-h light:dark at 2000 h. Melatonin markedly prolonged sleeping time in the mice exposed to constant illumination. It was found that pinealectomy was an important factor that influenced the hypnotic activity of melatonin. When melatonin was administered to pinealectomized mice, the hypnotic activity of melatonin was more intense compared with sham-operated mice. These results demonstrated that the hypnotic activity of melatonin displayed a light-dependence manner. These results suggested that light exposure and the functional state of the pineal gland could substantially impact the hypnotic activity of melatonin at pharmacological dosage.