Wenhai Huang

Synthesis and biological evaluation of the pirfenidone derivatives as antifibrotic agents.

A total of 24 pirfenidone derivatives were designed, synthesized and evaluated for their inhibitory activity against the human lung fibroblast cell line MRC-5. These compounds showed the remarkable proliferation inhibition against MRC-5 compared to pirfenidone as the positive control. The possible mechanism of this kind of derivatives as antifibrotic agents was explored. The molecular docking and p38 binding affinity assays demonstrated that the antifibrotic potential of the pirfenidone derivatives was possibly through the inhibition of p38 MAPK signaling pathway. The data from this study suggested that p38 might be a potential therapeutic target for the new generation antifibrotics. All the pirfenidone derivatives are reported here for the first time.

Discovery of Novel Selective ERα/ERβ Ligands by Multi-pharmacophore Modeling and Virtual Screening

Estrogen receptor α (ERα) and estrogen receptor β (ERβ) regulate different sets of gene expression, and have different ligand responses, which make the estrogen tissue-specific. Thus, the estrogen receptor (ER) subtype-selective ligands can improve the target-site selectivity and decrease the off-target effect. In order to discover the selective ER subtype ligands with novel scaffolds, in this work three-dimensional (3D) pharmacophore models of the ERα ligands (Hypo 1) and the ERβ ligands (Hypo 2) were established (correlation coefficients were 0.959 and 0.966) and validated (R=0.936 and 0.879; enrichment factors (EFs) at 2% were 16.2 and 8.4; areas under the concentration-time curve (AUC) of the receiver operating curve (ROC) were 0.88 and 0.91) using the Discovery Studio 4.0 software package. Hypo 1 and Hypo 2 were then employed for virtual screening and ten hits were found as potential candidate leads. Based on their ERα/ERβ binding affinity results by fluorescence polarization technology, two of these leads, AH-262/34334025 (AH) and AG-670/08803023 (AG) with novel scaffolds were identified as selective ERα ligands. A molecular docking study was also performed, which provided the explanation for the ER subtype preferences for AH and AG.

An Overview on Small Molecule Inhibitors of BRD4

BRD4, an epigenetic regulator that recognizes and binds the acetylated lysine residues in histone, has been reported as a potential therapeutic target for cancers. Since the first BRD4 inhibitor JQ1 developed in 2010, numerous BRD4 inhibitors have been discovered in past five years. In this review, we have systematically summarized a series of BRD4 binding compounds, which are divided into five categories based on the similarity of their chemical structures and respectively referred as JQ1 derivatives, tetrahydroquinoline derivatives, 3,5- dimethylisoxazole derivatives, 2-thiazolidinone derivatives and others. The binding affinities for each class of compounds are also discussed.

Three new alkaloids from Veratrum grandiflorum Loes with inhibition activities on Hedgehog pathway

Three new steroidal alkaloids 1-3, together with four known compounds 4-7, were isolated from the ethanol extract of Veratrum grandiflorum Loes. Their structures were elucidated by NMR (1D and 2D NMR) and MS spectroscopic data. The inhibition activities on Hedgehog (Hh) pathway were evaluated using a cell-based bioassay system (Shh-LIGHT 2 cells). The results showed that compounds 1-3 and 5 displayed inhibitory activities obviously with the IC50 values of 0.63-3.11μM. Among them, compound 5 showed the most prominent inhibition activity (IC50=0.63±0.02μM). Thus, these active alkaloids may be potent natural compounds as Hh pathway inhibitors for the treatment of various cancers.

Synthesis and biological evaluation of novel cyclopropyl derivatives as subtype-selective ligands for estrogen receptor

Tamoxifen is the most commonly used selective estrogen receptor modulators (SERMs); however, patients often develop the acquired drug resistance on tamoxifen therapy. The aim of this study was to develop new SERMs.

Palladium-Catalyzed Dehalogenation of Benzofuran Bromides

Abstract Various benzofuran bromides were dehalogenated using the palladium catalyst and phosphine ligands in the present of 5 equiv water. This set up a new and efficient protocol for the palladium-catalyzed dehalogenation of benzofuran bromides, which could tolerate the presence of water and have selective debromination. GRAPHICAL ABSTRACT

Antifibrotic effects of a novel pirfenidone derivative in vitro and in vivo

BACKGROUND Idiopathic pulmonary fibrosis is a lethal fibrosing interstitial pneumonia characterized by progressive worsening of dyspnea and lung function with poor prognosis. Since pirfenidone was approved for IPF treatment, the search for more effective candidates has been greatly intensified. METHODS In this study, the antifibrotic effects and mechanisms of compound PBD-617, the ideal candidate discovered in our previous work, were investigated on transforming growth factor-β1 (TGF-β1)-induced human embryonic lung fibroblasts (HELF) and on bleomycin (BLM)-induced pulmonary fibrotic rats. RESULTS Oral administration with PBD-617 decreased the levels of collagen I, collagen III and matrix metalloproteinase 7, and inhibited the protein expression of α-smooth muscle actin in BLM-induced pulmonary fibrosis rats. Furthermore, PBD-617 suppressed the expression of TGF-β1, phosphorylated Smad3, phosphorylated p38 and activator protein 1 on TGF-β1-induced HELF, while the regulation could be rescued by using p38 agonist p79350. CONCLUSION PBD-617 not only inhibited TGF-β1-induced HELF proliferation, but also attenuated BLM-induced pulmonary fibrosis in rats, with efficacy to some extent higher than that of pirfenidone at the same effective dosage. PBD-617 attenuated pulmonary fibrosis effectively by suppressing activation of TGF-β1/Smad3 and p38 signaling pathways.

Design, Synthesis and Biological Evaluation of 1-Phenyl-Ethanone Derivatives for Multi-Targeted Treatment of Alzheimer's Disease

Alzheimers disease (AD) is a progressive neurodegenerative disease leading to the irreversible loss of brain neurons and cognitive abilities. Multiple factors, such as acetylcholinesterase (AChE), metal ions and amyloid-β (Aβ) have been considered play an important role in the pathogenesis of AD. In this work, AChE and metal ions, both of which are also associated with the deposition of Aβ in the brain, were selected as targets simultaneously. 22 compounds were rationally designed by hybridizing AChE inhibitor rivastigmine and metal chelator 2-hydroxyacetophenone, in a hoping that these compounds could be as a substrate and inhibitor of AChE, while the subsequent enzymatic hydrolysis products by AChE could be as a metal ion chelator. Thus these 22 compounds were synthesized and their biological activities against AD were evaluated in vitro. The results showed that compound w8 presented the best inhibitory activity of AChE (IC50=31.9 μM), and the representing enzymatic hydrolysis products 7f exhibted the metal chelating function. Furthermore, both 7f and one of the targeted compound w15 could inhibit the aggregation of Aβ.