Showing papers by "Wannian Zhang published in 2017"
TL;DR: This review aims to highlight the recent evidence of chalcone as a privileged scaffold in medicinal chemistry and is expected to be a comprehensive, authoritative, and critical review of the chal cone template to the chemistry community.
Abstract: Privileged structures have been widely used as an effective template in medicinal chemistry for drug discovery. Chalcone is a common simple scaffold found in many naturally occurring compounds. Many chalcone derivatives have also been prepared due to their convenient synthesis. These natural products and synthetic compounds have shown numerous interesting biological activities with clinical potentials against various diseases. This review aims to highlight the recent evidence of chalcone as a privileged scaffold in medicinal chemistry. Multiple aspects of chalcone will be summarized herein, including the isolation of novel chalcone derivatives, the development of new synthetic methodologies, the evaluation of their biological properties, and the exploration of the mechanisms of action as well as target identification. This review is expected to be a comprehensive, authoritative, and critical review of the chalcone template to the chemistry community.
800 citations
TL;DR: The first small molecules that simultaneously inhibit nicotinamide phosphoribosyltransferase (NAMPT) and histone deacetylase (HDAC), two important targets of cancer metabolism and epigenetics, respectively are reported.
Abstract: Cancer metabolism and epigenetics are among the most intensely pursued research areas in anticancer drug discovery. Here we report the first small molecules that simultaneously inhibit nicotinamide phosphoribosyltransferase (NAMPT) and histone deacetylase (HDAC), two important targets of cancer metabolism and epigenetics, respectively. Through iterative structure-based drug design, chemical synthesis, and biological assays, a highly potent dual NAMPT and HDAC inhibitor was successfully identified. Compound 35 possessed excellent and balanced activities against both NAMPT (IC50 = 31 nM) and HDAC1 (IC50 = 55 nM). It could effectively induce cell apoptosis and autophagy and ultimately led to cell death. Importantly, compound 35 showed excellent in vivo antitumor efficacy in the HCT116 xenograft model. This proof-of-concept study demonstrates the feasibility of discovering an inhibitor targeting cancer metabolism and epigenetics and provides an efficient strategy for multitarget antitumor drug discovery.
72 citations
TL;DR: A target-based virtual screening was applied to discover benzothiazoles to be potent non-covalent NAE inhibitors and a preliminary structure-activity relationship (SAR) of their derivatives exhibited antitumor activities in nanomolar range.
25 citations
TL;DR: An unprecedented chiral binding pattern was observed for inhibitors of KRAS-PDEδ interactions, and fragment-based drug design was used to identify highly potent PDEδ inhibitors that can be used as promising lead compounds for target validation and antitumor drug development.
Abstract: Structural biology is a powerful tool for investigating the stereospecific interactions between a protein and its ligand. Herein, an unprecedented chiral binding pattern was observed for inhibitors of KRAS–PDEδ interactions. Virtual screening and X-ray crystallography studies revealed that two enantiomers of a racemic inhibitor could bind at different sites. Fragment-based drug design was used to identify highly potent PDEδ inhibitors that can be used as promising lead compounds for target validation and antitumor drug development.
20 citations
TL;DR: It is found that FR5 effectively inhibits proliferation and induces apoptosis of HCC cells through coordinated inhibition of YAP in the Hippo pathway and AKT in the PI3K-PTEN-mTOR pathway, and suggest FR5 as a potential therapy for HCC.
Abstract: Marsdenia tenacissimae extraction (MTE), a traditional herbal medicine, has exhibited anti-tumor effects on a variety of cancers. However, its effectiveness and the mechanism of action in Hepatocellular carcinoma (HCC) has not been fully understood. In the present study, we demonstrate that C21 steroid-enriched fraction from MTE, which contains five main C21 steroids (FR5) exhibits obvious pharmacological activities on HCC cells in vitro and in vivo. FR5 induces apoptosis and inhibits proliferation and migration of HepG2 and Bel7402 cells in a dose and time dependent manner. Furthermore, in HCC cells, we found that FR5 inhibits Hippo pathway, leading to inactivation of YAP and increase of PTEN. Enhanced PTEN results in the inhibition of PI3K/AKT signaling pathway, inhibiting cell proliferation by FR5 and FR5-induced apoptosis. Moreover, it was proved that FR5 treatment could inhibit tumor growth in a HCC xenograft mouse model, and immunohistochemistry results showed FR5 treatment resulted in down-regulation of Bcl-2 and YAP, and up-regulation of PTEN and PI3K. Taken together, we found that FR5 effectively inhibits proliferation and induces apoptosis of HCC cells through coordinated inhibition of YAP in the Hippo pathway and AKT in the PI3K-PTEN-mTOR pathway, and suggest FR5 as a potential therapy for HCC.
17 citations
TL;DR: Compound 7l was highly active against Candida albicans and Candida glabrata and showed potent in vivo antifungal efficacy in the Caenorhabditis elegans – C.Albicans infection model.
16 citations
TL;DR: Twelve analogues have been designed and synthesized with non-substituted benzyl rings or heterocycles in this work and most of the compounds showed better anticancer activities than the parent PL without apparent toxicity in normal cells.
15 citations
TL;DR: The result revealed that benzyl group on position N1 of imidazole and bromine on C4-phenyl of pyrrolidone showed higher inhibitory activities, indicating that 4,5-dihydropyrrolo[3,4-c]pyrazol-6(1H)-one moiety is a valuable scaffold for further development of p53-MDM2 inhibitors.
11 citations
TL;DR: A series of 4-substituted derivatives showed potent Top1 inhibitory activity and in vitro antiproliferative activity and were evaluated in A549, HCT-116 and ZR-75-30 human cancer cell lines.
11 citations
TL;DR: Structural-based virtual screening was performed for identifying novel scaffolds of Syk inhibitors and compound 11 (IC50=3.2μM) was active in the cellular Syk assay and could inhibit lymphocytes proliferation in a dose-dependent manner, which could be used as a good starting point for the discovery of new class of SyK inhibitors.
10 citations