A5082494084- Protein Degradation and Inhibitors
- Cancer therapeutics and mechanisms
- Peptidase Inhibition and Analysis
- Ubiquitin and proteasome pathways
- Synthesis and Biological Evaluation
- Click Chemistry and Applications
- Antifungal resistance and susceptibility
- Quinazolinone synthesis and applications
- Histone Deacetylase Inhibitors Research
- Synthesis and biological activity
- Plant Growth Enhancement Techniques
- Bioactive Compounds and Antitumor Agents
- Fungal Infections and Studies
- Multiple Myeloma Research and Treatments
- Lung Cancer Research Studies
- Sirtuins and Resveratrol in Medicine
- Cancer-related Molecular Pathways
- Microbial Natural Products and Biosynthesis
- Biochemical and Molecular Research
- Synthesis and bioactivity of alkaloids
- PARP inhibition in cancer therapy
- Phytochemical compounds biological activities
- Asymmetric Synthesis and Catalysis
- Neutropenia and Cancer Infections
- Chemical Synthesis and Analysis
Second Military Medical University
2016-2025
Guangxi University
2024
The Second Affiliated Hospital of Bengbu Medical College
2024
State Council of the People's Republic of China
2018
Institute of Medicinal Plant Development
2015
East China University of Science and Technology
2013
University of New Mexico
2013
Rigel (United States)
2004-2007
Development of proteolysis targeting chimeras (PROTACs) is emerging as a promising strategy for targeted protein degradation. However, the drug development using heterobifunctional PROTAC molecules generally limited by poor membrane permeability, low in vivo efficacy and indiscriminate distribution. Herein an aptamer-PROTAC conjugation approach was developed novel to improve tumor-specific ability antitumor potency conventional PROTACs. As proof concept, first conjugate (APC) designed...
Abstract Proteolysis‐targeting chimeras (PROTACs) have emerged as a promising strategy for targeted protein degradation and drug discovery. To overcome the inherent limitations of conventional PROTACs, an innovative drugtamer‐PROTAC conjugation approach is developed to enhance tumor targeting antitumor potency. Specifically, smart prodrug designed by conjugating “drugtamer” nicotinamide phosphoribosyltransferase (NAMPT) PROTAC using microenvironment responsible linker. The consists...
A critical question in natural product-based drug discovery is how to translate the product into drug-like molecules with optimal pharmacological properties. The generation of product-inspired scaffold diversity an effective but challenging strategy investigate broader chemical space and identify promising leads. Extending our efforts evodiamine, a diverse library containing 11 evodiamine-inspired novel scaffolds their derivatives were designed synthesized. Most them showed good excellent...
Evodiamine is a quinazolinocarboline alkaloid isolated from the fruits of traditional Chinese herb Evodiae fructus . Previously, we identified N13-substituted evodiamine derivatives as potent topoisomerase I inhibitors by structure-based virtual screening and lead optimization. Herein, library novel bearing various substitutions or modified scaffold were synthesized. Among them, number showed substantial increase antitumor activity, with GI(50) values lower than 3 nM. Moreover, these highly...
Human topoisomerase I (TopoI) is recognized as a valuable target for the development of effective antitumor agents. Structure-based virtual screening was applied to discovery structurally diverse TopoI inhibitors. From 23 compounds selected by screening, total 14 were found be Five hits (compounds 1, 14, 20, 21, and 23) also showed moderate good in vitro activity. These novel structures can considered starting points new lead compounds. Hit 20 (evodiamine) chosen preliminary...
As one of the most aggressive and lethal human malignancies with extremely poor prognosis, there is an urgent demand more effective therapy for treatment pancreatic cancer. Reported here a new, therapeutic strategy design small-molecule inhibitors that simultaneously target bromodomain extra-terminal (BET) histone deacetylase (HDAC), potentially serving as promising agents A highly potent dual inhibitor (13 a) identified to possess excellent balanced activities against BRD4 BD1 (IC50 =11 nm)...
The p53-MDM2 interaction has been proved to be a valuable target develop effective antitumor agents. Novel inhibitors bearing pyrrolidone scaffolds were successfully identified by structure-based design. nanomolar inhibitor 5 possessed good inhibitory activity (K(i) = 780 nM) due its hydrophobic and hydrogen bonding interactions with MDM2. Further hit optimization led the discovery of number highly potent derivatives improved in vitro antiproliferative potency. Compounds 41 260.0 60a 150.0...
Cancer metabolism and epigenetics are among the most intensely pursued research areas in anticancer drug discovery. Here we report first small molecules that simultaneously inhibit nicotinamide phosphoribosyltransferase (NAMPT) histone deacetylase (HDAC), two important targets of cancer epigenetics, respectively. Through iterative structure-based design, chemical synthesis, biological assays, a highly potent dual NAMPT HDAC inhibitor was successfully identified. Compound 35 possessed...
Abstract Background Fulvic acid (FA) is a kind of plant growth regulator, which can promote growth, play an important role in fighting against drought, improve stress resistance, increase production and quality. However, the function FA tea plants during drought remain largely unknown. Results Here, we examined effects 0.1 g/L on genes metabolites at different periods using transcriptomics metabolomics profiles. Totally, 30,702 892 were identified. Compared with controlled groups, 604 3331...
Clinically, leukemia patients often suffer from the limited efficacy of chemotherapy and high risks infection by invasive fungal pathogens. Herein, a novel therapeutic strategy was developed in which small molecule can simultaneously treat infections (IFIs). Novel Janus kinase 2 (JAK2) histone deacetylase (HDAC) dual inhibitors were identified to possess potent anti-proliferative activity toward hematological cell lines excellent synergistic effects with fluconazole resistant Candida...
An organocatalytic enantioselective Michael–Michael cascade reaction is developed for the synthesis of chiral spirotetrahydrothiopyrans. This highly functionalized scaffold was assembled in moderate to good yield (55–74%) and excellent diastereo- enantioselectivities (>30:1 dr, ≥ 99% ee) with creation four consecutive stereogenic centers. The novel spiro-oxindole validated as a new class p53-MDM2 protein–protein interaction inhibitors antitumor activity.
Autophagosome-tethering compounds (ATTECs) are an emerging new technology in targeted protein degradation. However, effective tools and successful examples for autophagosome-tethering chimeras still rather limited. Herein, ATTEC ispinesib was identified the first time to be warhead design chimeras. As a conceptual validation study, generation of autophagic degraders nicotinamide phosphoribosyltransferase (NAMPT) were developed by connecting NAMPT inhibitor LC3-binding through flexible...
Cryptococcus neoformans is one of the most important causes life-threatening fungal infections in immunocompromised patients. Lanosterol 14 alpha-demethylase (CYP51) target azole antifungal agents. This study describes, for first time, 3-dimensional model CYP51 from (CnCYP51). The was further refined by energy minimization and molecular-dynamics simulations. active site CnCYP51 well characterized multiple-copy simultaneous-search calculations, four functional regions rational drug design...
Abstract A powerful divergent cascade strategy has been explored for the easy construction of diverse enantioenriched pyrazole‐derived scaffolds from readily available chiral fused pyrazole‐tetrahydropyran acetals. These versatile intermediates can react in various ways to give Michael–aldol, reduction–lactonization, α‐hydroxylation–acetalization–oxidation, and Wittig–aldol Wittig–oxa‐Michael reactions. Using only six simple building blocks, these processes gave five distinct molecular...
Designing multitarget drugs remains a significant challenge in current antitumor drug discovery. Because of the synergistic effect between topoisomerase and HDAC inhibitors, present study reported first-in-class triple inhibitors I/II HDAC. On basis 3-amino-10-hydroxylevodiamine SAHA, series hybrid molecules was successfully designed synthesized. In particular, compound 8c proven to be potent inhibitor with good antiproliferative apoptotic activities. This proof-of-concept also validated...
Inspired by the natural product evodiamine, a novel antitumor indolopyrazinoquinazolinone scaffold was designed hopping. Structure-activity relationship studies led to discovery of compound 15j, which shows low nanomolar inhibitory activity against HCT116 cell line. Further mechanism indicated that 15j acted dual inhibition topoisomerase 1 and tubulin induced apoptosis with G2 cell-cycle arrest. The quaternary ammonium salt (compound 15js) exhibited excellent in vivo (TGI = 66.6%) xenograft...