A5014015813- Phosphodiesterase function and regulation
- Cholinesterase and Neurodegenerative Diseases
- Chemical synthesis and alkaloids
- Cancer-related gene regulation
- RNA modifications and cancer
- Synthesis and Catalytic Reactions
- RNA Research and Splicing
- Catalytic C–H Functionalization Methods
- Orthopedic Infections and Treatments
- Sulfur-Based Synthesis Techniques
- Cancer-related molecular mechanisms research
- Orthopaedic implants and arthroplasty
- Chemical Synthesis and Analysis
- Total Knee Arthroplasty Outcomes
- Catalytic Cross-Coupling Reactions
Sun Yat-sen University
2017-2025
N6-methyladenosine (m6A) modification is critical for mRNA splicing, nuclear export, stability and translation. Fat mass obesity-associated protein (FTO), the first identified m6A demethylase, cancer progression. Herein, we developed small-molecule inhibitors of FTO by virtual screening, structural optimization, bioassay. As a result, two namely 18077 18097 were identified, which can selectively inhibit demethylase activity FTO. Specifically, bound to active site then inhibited cell cycle...
Alzheimer’s disease (AD) is a widely recognized type of dementia that leads to progressive cognitive decline and memory loss, affecting significant number people their families worldwide. Given the multifactorial nature AD, multitarget-directed ligands (MTDLs) hold promise in developing effective drugs for AD. Phosphodiesterase-9 (PDE9) emerging as promising target AD therapy. In this study, by combining PDE9 inhibitor C33 with antioxidant melatonin, we designed discovered series...
N6-methyladenosine (m6A), the most abundant methylation on mRNA, plays pivotal roles in regulating mRNA biological functions, which affect cell functions. ALKBH5, an m6A demethylase, was found to be oncogene several cancer types, including triple-negative breast (TNBC). Here, we report a novel and selective ALKBH5 covalent inhibitor, W23-1006, through virtual screening structure optimization. It covalently bonds C200 residue with IC50 value of 3.848 μM, representing roughly 30- 8-fold...
Discovery of multitarget-directed ligands (MTDLs), targeting different factors simultaneously to control the complicated pathogenesis Alzheimer's disease (AD), has become an important research area in recent years. Both phosphodiesterase 9A (PDE9A) and butyrylcholinesterase (BuChE) inhibitors could participate processes AD attenuate neuronal injuries improve cognitive impairments. However, on MTDLs combining inhibition PDE9A BuChE not been reported yet. In this study, a series novel...
Our previous study demonstrated that phosphodiesterase 8 (PDE8) could work as a potential target for vascular dementia (VaD) using chemical probe 3a. However, compound 3a is chiral which was obtained by resolution on HPLC, restricting its usage in clinic. Herein, series of non-chiral 9-benzyl-2-chloro-adenine derivatives were discovered novel PDE8 inhibitors. Lead 15 exhibited potent inhibitory activity against PDE8A (IC50 = 11 nmol/L), high selectivity over other PDEs, and remarkable...
Phosphodiesterase-9 (PDE9) is a promising target for treatment of Alzheimer's disease (AD). To discover multifunctional anti-AD agents with capability PDE9 inhibition and antioxidant activity, series novel pyrazolopyrimidinone derivatives, coupling the pharmacophore antioxidants such as ferulic lipolic acids have been designed assistance molecular docking dynamics simulations. Twelve out 14 synthesised compounds inhibited PDE9A IC50 below 200 nM, showed good capacities in ORAC assay....
The pathological processes of Alzheimer's disease and type 2 diabetes mellitus have been demonstrated to be linked together. Both PDE9 inhibitors PPARγ agonists such as rosiglitazone exhibited remarkable preclinical clinical treatment effects for these two diseases. In this study, a series combining the pharmacophore were discovered. All compounds possessed affinities towards four them IC50 values <5 nmol/L. addition, showed low cell toxicity in human SH-SY5Y neuroblastoma cells. Compound...
To validate the hypothesis that Tyr748 is a crucial residue to aid discovery of highly selective phosphodiesterase 8A (PDE8A) inhibitors, we identified series 2-chloroadenine derivatives based on hit clofarabine. Structure-based design targeting in PDE8 resulted lead compound 3a (IC50 = 0.010 μM) with high selectivity reasonable druglike profile. In X-ray crystal structure, bound PDE8A different mode from 3-isobutyl-1-methylxanthine (a pan-PDE inhibitor) and gave H-bond 2.7 Å Tyr748, which...
A method for the transition-metal-free direct C–H arylation of unactivated arenes is developed with aryl bromides as substrates and 8-hydroxyquinoline an efficient promoter. variety biaryl compounds structural diversity are obtained in moderate to high yields. Mechanistic studies reveal that reaction proceeds via a homolytic aromatic substitution pathway.