Identification of Novel Artemisinin Hybrids Induce Apoptosis and Ferroptosis in MCF-7 Cells.

A series of novel 1,3,4-oxadiazole-artemisinin hybrids have been designed and synthesized. An MTT assay revealed that most of tested hybrids showed more enhanced anti-proliferative activities than artemisinin, among which A8 had the superior potency with IC values ranging from 4.07 μM to 9.

Recent progress on betulinic acid and its derivatives as antitumor agents: a mini review.

Natural products are one of the important sources for the discovery of new drugs. Betulinic acid (BA), a pentacyclic triterpenoid widely distributed in the plant kingdom, exhibits powerful biological effects, including antitumor activity against various types of cancer cells. A considerable number of BA derivatives have been designed and prepared to remove their disadvantages, such as poor water solubility and low bioavailability.

Novel carbohydrate-based sulfonamide derivatives as selective carbonic anhydrase II inhibitors: Synthesis, biological and molecular docking analysis.

A series of sulfonamides containing glucosamine moieties had been prepared and investigated for the inhibition of the zinc enzyme carbonic anhydrases (CAs, EC 4.2.1.

Synthesis, Molecular Docking Analysis and Biological Evaluations of Saccharide-Modified Thiadiazole Sulfonamide Derivatives.

A series of saccharide-modified thiadiazole sulfonamide derivatives has been designed and synthesized by the "tail approach" and evaluated for inhibitory activity against carbonic anhydrases II, IX, and XII. Most of the compounds showed high topological polar surface area (TPSA) values and excellent enzyme inhibitory activity. The impacts of some compounds on the viability of HT-29, MDA-MB-231, and MG-63 human cancer cell lines were examined under both normoxic and hypoxic conditions, and they showed certain inhibitory effects on cell viability.

Synthesis and antitumor activity evaluation of oleanolic acid saponins bearing an acetylated l-arabinose moiety.

A series of oleanolic acid derivatives bearing acetyl-substituted l-arabinose moiety has been synthesized and screened in vitro for cytotoxicity against ten cancer cell lines and four normal cell lines. The antiproliferative evaluation indicated that synthetic derivatives showed excellent selectivity, as they were toxic against only A431 cell line. Among them, the compound 6 possesses the best inhibitory activity.

Recent Advances in β-Agonists for Treatment of Chronic Respiratory Diseases and Heart Failure.

β-Adrenoceptor (β-AR) agonists are widely used as bronchodilators. The emerge of ultralong acting β-agonists is an important breakthrough in pulmonary medicine. In this review, we will provide mechanistic insights into the application of β-agonists in asthma, chronic obstructive pulmonary disease (COPD), and heart failure (HF).

Molecular determinants for ligand binding at Nav1.4 and Nav1.7 channels: Experimental affinity results analyzed by molecular modeling.

Here, we focused on exploring the selectivity mechanism against Nav1.7 over Nav1.4 due to different binding modes of two selected inhibitors.

Precise design of highly isoform-selective p21-activated kinase 4 inhibitors: computational insights into the selectivity mechanism through molecular dynamics simulation and binding free energy calculation.

Understanding the selectivity mechanisms of inhibitors towards highly similar protein kinases is the first step in discovering new selective candidate for satisfactory safety profile. P21-activated kinases (PAKs) are pertain to a family of serine/threonine (Ser/Thr) protein kinases, which are the first Rho family GTPase-regulated kinases identified and served as important downstream mediators of Ras-Rac and Cdc42 function. Among PAKs, PAK4 is emerging as a promising target for cancer treatment.

Design, Synthesis and Molecular Docking Analysis of Flavonoid Derivatives as Potential Telomerase Inhibitors.

Based on the structural scaffolds of natural products, two series of flavonoid derivatives, for a total of twelve compounds, were designed and synthesized as potential human telomerase inhibitors. Using a modified TRAP-PCR assay, compound exhibited the most potent inhibitory activity against human telomerase with an IC value of less than 50 μM. In vitro, the results demonstrated that compound had potent anticancer activity against five classes of tumor cell lines.

Strategy and validation of a structure-based method for the discovery of selective inhibitors of PAK isoforms and the evaluation of their anti-cancer activity.

p21 activated kinase 4 (PAK4), which belongs to the serine/threonine (Ser/Thr) protein kinase family, is a representative member of the PAK family and plays a significant role in multiple processes associated with cancer development. In this study, structure-based virtual screening was performed to discover novel and selective small molecule scaffolds, and a 6-hydroxy-2-mercapto-3-phenylpyrimidin-4(3H)-one-based compound (SPU-106, 14#) was identified as an effective PAK4 inhibitor. By combining both a molecular docking study and molecular dynamics (MD) simulation strategies, the binding mode was determined in the PAK4 site.

Identification of 10-dehydrooxyglycyuralin E as a selective human estrogen receptor alpha partial agonist.

Selective estrogen receptor modulators (SERMs) act as either agonist or antagonist of estrogen receptor (ER) in a tissue selective manner and have been used in several diseases such as breast cancer, postmenopausal syndrome, osteoporosis, and cardiovascular diseases. However, current SERMs may also increase the risk of serious side effects and trigger drug resistance. Herein, a screening program, that was designed to search for novel SERMs, resulted in the identification of a series of 2-arylbenzofuran-containing compounds that are ligands for ERα, when applying the Gaussia-luciferase reporter assay.

Targeting PAK1 with the Small Molecule Drug AK963/40708899 Suppresses Gastric Cancer Cell Proliferation and Invasion by Downregulation of PAK1 Activity and PAK1-Related Signaling Pathways.

PAK1 (p21-activated kinase 1) is a serine/threonine protein kinase which has been initially identified as downstream effector of the Rho GTPase family. In previous research, PAK1 has been involved in the regulation of diverse cellular processes, such as cell motility, cell proliferation, gene transcription, cytoskeletal rearrangement, and cell invasion. Hyper-activation of PAK1 was constantly observed in a variety of human cancer which make it a potential target of novel anti-tumor drugs.

Protein tyrosine phosphatase 1B inhibitory activities of ursane-type triterpenes from Chinese raspberry, fruits of Rubus chingii.

Protein tyrosine phosphatase 1B (PTP1B) has led to an intense interest in developing its inhibitors as anti-diabetes, anti-obesity and anti-cancer agents. The fruits of Rubus chingii (Chinese raspberry) were used as a kind of dietary traditional Chinese medicine. The methanolic extract of R.

Discovery of β-arrestin-biased β-adrenoceptor agonists from 2-amino-2-phenylethanol derivatives.

β-Arrestins are a small family of proteins important for signal transduction at G protein-coupled receptors (GPCRs). β-Arrestins are involved in the desensitization of GPCRs. Recently, biased ligands possessing different efficacies in activating the G protein- versus the β-arrestin-dependent signals downstream of a single GPCR have emerged, which can be used to selectively modulate GPCR signal transduction in such a way that desirable signals are enhanced to produce therapeutic effects while undesirable signals of the same GPCR are suppressed to avoid side effects.

Synthesis, antitumor activity evaluation and mechanistic study of novel hederacolchiside A derivatives bearing an aryl triazole moiety.

In an attempt to arrive at a more potent antitumor agent than the parent natural saponin hederacolchiside A, 23 hederacolchiside A derivatives (4a-4w) were synthesized via Cu(I)-catalyzed azide-alkyne 1,3-dipolar cycloaddition and screened in vitro for cytotoxicity against six human cancer cell lines. The structure-activity relationship of these compounds was elucidated, and the biological screening results showed that most of the compounds exhibited moderate to high levels of antitumor activities against the tested cell lines and some of them displayed more potent inhibitory activities compared with hederacolchiside A. Compound 4f showed a 2- to 7-fold more potent activity than hederacolchiside A.

Synthesis, biological evaluation and structure-activity relationship studies of hederacolchiside E and its derivatives as potential anti-Alzheimer agents.

Inspired by the previously reported neuroprotective activity of hederacolchiside E (1), we synthesized hederacolchiside E for the first time along with eleven of its derivatives. The neuroprotective effects of these compounds were further evaluated against HO- and Aβ-induced injury using cell-based assays. The derivatives showed obvious differences in activity due to structural variations, and two of them exhibited better neuroprotective effects than 1 in the Aβ-induced injury model.

LC-0882 targets PAK4 and inhibits PAK4-related signaling pathways to suppress the proliferation and invasion of gastric cancer cells.

Gastric cancer is the most common malignant tumor and globally the third leading cause of cancer-related deaths. Therefore, there exists an urgent need to identify new effective gastric cancer treatments. Given the important roles in tumorigenesis and progression, p21-activated kinase 4 (PAK4) has been regarded as an attractive high-value druggable target.

Design, Synthesis, Molecular Docking Analysis, and Carbonic Anhydrase IX Inhibitory Evaluations of Novel N-Substituted-β-d-Glucosamine Derivatives that Incorporate Benzenesulfonamides.

A series of novel -substituted--d-glucosamine derivatives that incorporate benzenesulfonamides were designed using a fragment-based drug design strategy. Each derivative was synthesized and evaluated in vitro for its inhibitory activity against human carbonic anhydrase (hCA) IX; several derivatives displayed desirable potency profiles against this enzyme. The molecular docking studies provided the design rationale and predicted potential binding modes for carbonic anhydrase (CA) IX and three target compounds, including the most potent inhibitor, compound (IC = 10.

Dual-tail approach to discovery of novel carbonic anhydrase IX inhibitors by simultaneously matching the hydrophobic and hydrophilic halves of the active site.

Dual-tail approach was employed to design novel Carbonic Anhydrase (CA) IX inhibitors by simultaneously matching the hydrophobic and hydrophilic halves of the active site, which also contains a zinc ion as part of the catalytic center. The classic sulfanilamide moiety was used as the zinc binding group. An amino glucosamine fragment was chosen as the hydrophilic part and a cinnamamide fragment as the hydrophobic part in order to draw favorable interactions with the corresponding halves of the active site.

[Recent advances in study of long β(2)-adrenoceptor agonist].

β2-Adrenoceptor agonists are highly effective bronchodilators and are widely used in the treatment of both chronic obstructive pulmonary disease (COPD) and asthma. In the last 15 years, there has been great interest within the pharmaceutical industry in the discovery of a long β2-adrenoceptor agonist for a mono-therapy or combination therapy. The search for new long-acting β2-adrenoreceptor agonists (LABA’s), for the treatment of asthma and COPD, has become a very active area of drug discovery.

GL-1196 Suppresses the Proliferation and Invasion of Gastric Cancer Cells via Targeting PAK4 and Inhibiting PAK4-Mediated Signaling Pathways.

Gastric cancer, which is the most common malignant gastrointestinal tumor, has jumped to the third leading cause of cancer-related mortality worldwide. It is of great importance to identify novel and potent drugs for gastric cancer treatment. P21-activated kinase 4 (PAK4) has emerged as an attractive target for the development of anticancer drugs in consideration of its vital functions in tumorigenesis and progression.

Discovery of a new series of imidazo[1,2-a]pyridine compounds as selective c-Met inhibitors.

Aim: Aberrant c-Met activation plays a critical role in cancer formation, progression and dissemination, as well as in development of resistance to anticancer drugs. Therefore, c-Met has emerged as an attractive target for cancer therapy. The aim of this study was to develop new c-Met inhibitors and elaborate the structure-activity relationships of identified inhibitors.

Design, synthesis, and biological evaluation of amide imidazole derivatives as novel metabolic enzyme CYP26A1 inhibitors.

All-trans-retinoic acid (ATRA) as a physiological metabolite of vitamin A is widely applied in the treatment of cancer, skin, neurodegenerative and autoimmune diseases. CYP26A1 enzyme, induced by ATRA in liver and target tissues, metabolizes ATRA into 4-hydroxyl-RA. Inhibition of CYP26A1 metabolic enzyme represents a promising strategy for discovery of new specific anticancer agents.

Pharmacological mechanism underlying anti-inflammatory properties of two structurally divergent coumarins through the inhibition of pro-inflammatory enzymes and cytokines.

Background: The aim of the present study is to investigate the effects of two structurally divergent coumarins, calipteryxin (1) and (3'S,4'S)-3',4'-disenecioyloxy-3',4'-dihydroseselin (2) from Seseli recinosum, in lipopolysaccharide (LPS)-stimulated murine macrophages.

Methods: The nitrite production was evaluated using Griess reagent. The protein and mRNA expression levels were investigated through Western blot and quantitative real time-PCR analyses.