Yongzhou Hu

Design and synthesis of a highly selective fluorescent turn-on probe for thiol bioimaging in living cells

A new fluorescent turn-on probe for the rapid optical sensing of thiols has been designed and synthesized. The probe displays high on/off signal ratios and high selectivity towards thiols. The potential of the probe as a biosensor for thiols was demonstrated by imaging of thiols in living cells.

Recent Development and SAR Analysis of Colchicine Binding Site Inhibitors

Microtubules are cytoskeletal components that play important roles in a number of cellular processes. Colchicine binding site inhibitors (CSIs) is one major class of tubulin polymerization inhibitors, inhibiting microtubule polymerization and blocking cell proliferation at metaphase during mitosis. Many CSIs were discovered or designed and synthesized as anticancer agents in the past several years and great progress had been made. Here, we discuss the insights gained so far relevant to the mechanism of CSIs and their common pharmacophore. The recent development of CSIs with their biological activity and structure-activity relationship (SAR) are also reviewed.

An ICT-based fluorescent switch-on probe for hydrogen sulfide in living cells

An ICT-based fluorescent turn-on probe for hydrogen sulfide with high selectivity has been designed and synthesized. It exhibits up to 62-fold switch-on response toward H2S at given concentrations and can detect H2S in living cells with high sensitivity.

Progress in the Development of Nonpeptidomimetic BACE 1 Inhibitors for Alzheimers Disease

It is believed that the production and accumulation of beta-amyloid (Abeta) peptide is a critical step to the pathogenesis of Alzheimers disease (AD). BACE 1 (beta-site APP-cleaving enzyme 1 or beta-secretase), the key enzyme required for generating Abeta from the beta-amyloid precursor protein (APP), is regarded as an ideal target for AD therapeutic drug design. Due to low oral bioavailability, metabolic instability and poor ability to penetrate the central nervous system (CNS) of the existing peptidomimetic inhibitors, researchers have paid more attention to the development of nonpeptidomimetic inhibitors in recent years. A number of drug screening approaches and technologies have been used to identify novel nonpeptidomimetic BACE 1 inhibitors. This review mainly focuses on the recent developments in structure-based design and synthesis of the nonpeptidomimetic BACE 1 inhibitors.

Design, synthesis and evaluation of galanthamine derivatives as acetylcholinesterase inhibitors.

A new series of galanthamine derivatives have been designed, synthesized and evaluated as acetylcholinesterase inhibitors. All of the new compounds prepared showed high AChE inhibitory activities, with compound 3e that has an N-hexyl-benzyl piperidine substituent on the nitrogen atom reaching the best inhibitory activity for AChE (IC(50)=5.62 nM). The docking study performed with AutoDock demonstrated that 3e was nicely accommodated by AChE.

Abrogation of Akt signaling by Isobavachalcone contributes to its anti-proliferative effects towards human cancer cells

Akt signaling pathway has attracted much attention as a promising target for cancer therapeutics. Herein, we report that Isobavachalcone (IBC), a natural chalcone, potently abrogates Akt signaling and exerts anti-proliferative effects on several human cancer cell lines. Modeling results from the Sybyl/FlexiDock program suggest that IBC potentially binds to the ATP-binding pocket of Akt, which is confirmed by the observations that IBC inhibits Akt1 kinase in vitro. Further studies reveal that IBC significantly abates Akt phosphorylation at Ser-473 and Akt kinase activity in cells, which subsequently leads to inhibition of Akt downstream substrates and evokes significant levels of apoptosis associated with mitochondria pathway.

Alkenyl/Thiol-Derived Metal-Organic Frameworks (MOFs) by Means of Postsynthetic Modification for Effective Mercury Adsorption

The synthesis of new functionally diverse alkenyl-derived Cr-MIL-101s (MIL=material of Institute Lavoisier) was realized by a novel and convenient postsynthetic modification (PSM) protocol by means of the carbon-carbon bond-forming Mizoroki-Heck reaction. The new PSM protocol demonstrates a broad scope of substrates with excellent tolerance of functionality under mild reaction conditions. Moreover, a new metal-organic framework (MOF) that bears both alkenyl and thiol side chains prepared by means of the tandem PSM method has shown excellent adsorbent ability in removing mercury ions from water.

Synthesis and biological evaluation of imidazol-2-one derivatives as potential antitumor agents

A new series of aryl substituted imidazol-2-one derivatives structurally related to combretastatin A-4 (CA-4) were synthesized and evaluated for their cytotoxic activities in vitro against various human cancer cell lines including MDR cell line. The cytotoxic effects of compounds 7b and 7i proved to be similar to or greater than that of docetaxel. The highly active compound 7b also exhibited excellent inhibitory activity on tumor growth in vivo.

Synergistic Antitumor Activity of Gemcitabine and ABT-737 In Vitro and In Vivo through Disrupting the Interaction of USP9X and Mcl-1

The Bcl-2 antagonist ABT-737 targets Bcl-2/Bcl-xL, but not Mcl-1, which may confer resistance to this agent in various cancers with high levels of Mcl-1. Here, we showed that the combination of gemcitabine and ABT-737 exhibited synergistic cytotoxicity and induced significant apoptosis in multiple cancer types, including lung, renal, bladder, and prostate cancers. The enhanced apoptosis induced by gemcitabine plus ABT-737 was accompanied by the greater extent of mitochondrial depolarization, caspases-3 activation, and PARP cleavage in 95-D and 5637 cell lines. Importantly, in ABT-737–resistant cancer cells, the interaction between USP9X and Mcl-1, which was increased by ABT-737 treatment, could be disrupted by gemcitabine, thus resulting in enhanced ubiquitination and the subsequent degradation of Mcl-1 and ultimately in the synergism of these two drugs. Moreover, the increased anticancer efficacy of gemcitabine combined with ABT-737 was further validated in a human lung cancer 95-D xenograft model in nude mice. Taken together, our data first showed the synergistic anticancer capabilities achieved by combining gemcitabine and ABT-737 and, second, opened new opportunities to use antiapoptotic Bcl-2 family members, which drive tumor cell resistance in current anticancer therapies, therapeutically. Mol Cancer Ther; 10(7); 1264–75. ©2011 AACR.

Searching for the Multi-Target-Directed Ligands against Alzheimer’s disease: Discovery of quinoxaline-based hybrid compounds with AChE, H3R and BACE 1 inhibitory activities

A novel series of quinoxaline derivatives, as Multi-Target-Directed Ligands (MTDLs) for AD treatment, were designed by lending the core structural elements required for H(3)R antagonists and hybridizing BACE 1 inhibitor 1 with AChE inhibitor BYYT-25. A virtual database consisting of quinoxaline derivatives was first screened on a pharmacophore model of BACE 1 inhibitors, and then filtered by a molecular docking model of AChE. Seventeen quinoxaline derivatives with high score values were picked out, synthesized and evaluated for their biological activities. Compound 11a, the most effective MTDL, showed the potent activity to H(3)R/AChE/BACE 1 (H(3)R antagonism, IC(50)=280.0 ± 98.0 nM; H(3)R inverse agonism, IC(50)=189.3 ± 95.7 nM; AChE, IC(50)=483 ± 5 nM; BACE 1, 46.64±2.55% inhibitory rate at 20 μM) and high selectivity over H(1)R/H(2)R/H(4)R. Furthermore, the protein binding patterns between 11a and AChE/BACE 1 showed that it makes several essential interactions with the enzymes.