A5082256258- Asymmetric Synthesis and Catalysis
- Synthetic Organic Chemistry Methods
- Ubiquitin and proteasome pathways
- Cancer-related Molecular Pathways
- X-ray Diffraction in Crystallography
- Crystallization and Solubility Studies
- Protein Degradation and Inhibitors
- Fluorine in Organic Chemistry
- Cancer-related molecular mechanisms research
- Multiple Myeloma Research and Treatments
- Chemical Synthesis and Analysis
- Synthesis and Catalytic Reactions
- Click Chemistry and Applications
- Marine Sponges and Natural Products
- Microtubule and mitosis dynamics
- NF-κB Signaling Pathways
- RNA modifications and cancer
- Microbial Natural Products and Biosynthesis
- Traditional and Medicinal Uses of Annonaceae
- Cell death mechanisms and regulation
- Cancer Research and Treatments
- Synthesis and biological activity
- Renal Transplantation Outcomes and Treatments
- Liver Disease Diagnosis and Treatment
- MicroRNA in disease regulation
Shanghai Institute of Materia Medica
2016-2025
Nanjing University of Chinese Medicine
2021-2025
University of Chinese Academy of Sciences
2019-2025
Chinese Academy of Sciences
2016-2025
Shanxi Agricultural University
2018-2025
Shanxi Academy of Building Research
2023-2025
Third Xiangya Hospital
2015-2025
Central South University
2015-2025
Ningxia Medical University
2024-2025
Shandong Academy of Pharmaceutical Sciences
2022-2024
Background— The potential biological significance of hydrogen sulfide (H 2 S) has attracted growing interest in recent years. aim this study was to characterize a novel, water-soluble, slow-releasing H S compound [morpholin-4-ium 4 methoxyphenyl(morpholino) phosphinodithioate (GYY4137)] and evaluate its use as tool investigate the cardiovascular biology gas. Methods Results— acute vasorelaxant effect drugs assessed rat aortic rings perfused kidney vitro anesthetized vivo. chronic GYY4137 on...
The slow-releasing hydrogen sulfide (H2S) donor, GYY4137, caused concentration-dependent killing of seven different human cancer cell lines (HeLa, HCT-116, Hep G2, HL-60, MCF-7, MV4-11 and U2OS) but did not affect survival normal lung fibroblasts (IMR90, WI-38) as determined by trypan blue exclusion. Sodium hydrosulfide (NaHS) was less potent active in all lines. A structural analogue GYY4137 (ZYJ1122) lacking sulfur thence able to release H2S inactive. Similar results were obtained using a...
The bromodomain and extra-terminal (BET) family proteins, consisting of BRD2, BRD3, BRD4, testis-specific BRDT members, are epigenetic "readers" play a key role in the regulation gene transcription. BET proteins considered to be attractive therapeutic targets for cancer other human diseases. Recently, heterobifunctional small-molecule degraders have been designed based upon proteolysis targeting chimera (PROTAC) concept induce protein degradation. Herein, we present our design, synthesis,...
Abstract Blocking the oncoprotein murine double minute 2 (MDM2)–p53 protein–protein interaction has long been considered to offer a broad cancer therapeutic strategy, despite potential risks of selecting tumors harboring p53 mutations that escape MDM2 control. In this study, we report novel small-molecule inhibitor MDM2–p53 interaction, SAR405838 (MI-77301), advanced into phase I clinical trials. binds with Ki = 0.88 nmol/L and high specificity over other proteins. A cocrystal structure...
We previously reported the discovery of a class spirooxindoles as potent and selective small-molecule inhibitors MDM2–p53 interaction (MDM2 inhibitors). report herein our efforts to improve their pharmacokinetic properties in vivo antitumor activity. Our led identification 9 (MI-888) MDM2 inhibitor (Ki = 0.44 nM) with superior profile enhanced efficacy. Compound is capable achieving rapid, complete, durable tumor regression two types xenograft models human cancer oral administration...
Small-molecule inhibitors that block the MDM2-p53 protein–protein interaction (MDM2 inhibitors) are being intensely pursued as a new therapeutic strategy for cancer treatment. We previously published series of spirooxindole-containing compounds class MDM2 small-molecule inhibitors. report herein reversible ring-opening-cyclization reaction some these spirooxindoles, which affords four diastereomers from single compound. Our biochemical binding data showed stereochemistry in this has major...
Triple-negative breast cancers (TNBC) remain clinically challenging with a lack of options for targeted therapy. In this study, we report the development second-generation BET protein degrader, BETd-246, which exhibits superior selectivity, potency, and antitumor activity. human TNBC cells, BETd-246 induced degradation proteins at low nanomolar concentrations within 1 hour exposure, resulting in robust growth inhibition apoptosis. was more potent effective cells than its parental inhibitor...
Signal transducer and activator of transcription 3 (STAT3) is a factor an attractive therapeutic target for cancer other human diseases. Despite 20 years persistent research efforts, targeting STAT3 has been very challenging. We report herein the structure-based discovery potent small-molecule degraders based upon proteolysis chimera (PROTAC) concept. first designed SI-109 as potent, inhibitor SH2 domain. Employing ligands cereblon/cullin 4A E3 ligase SI-109, we obtained series PROTAC...
Rose Bengal, an organic dye, was used as a visible light photocatalyst to investigate novel α-oxyamination reactions between 1,3-dicarbonyl compounds and free radical (TEMPO). Compounds that are difficult obtain such quaternary fluorinated were synthesized using this method. This photocatalytic reaction can also be performed in water.
The perfect combination: title reaction provides adducts having quaternary carbon centers bearing a fluorine atom with high ee and d.r. values (see scheme). mechanism origin of stereoselectivity were elucidated by DFT calculations. bifunctional mode the guanidine catalysis was demonstrated in transition states resulting from results.
Small-molecule inhibitors of bromodomain and extra terminal proteins (BET), including BRD2, BRD3, BRD4 have therapeutic potential for the treatment human cancers other diseases conditions. In this paper, we report design, synthesis, evaluation γ-carboline-containing compounds as a new class small-molecule BET inhibitors. The most potent inhibitor (compound 18, RX-37) obtained from study binds to (BRD2, BRD4) with Ki values 3.2-24.7 nM demonstrates high selectivity over non-BET...
Abstract Nonalcoholic steatohepatitis (NASH) is a key step in the progression of nonalcoholic fatty liver (NAFL) to cirrhosis. However, molecular mechanisms NAFL-to-NASH transition are largely unknown. Here, we identify methyltransferase like 3 (METTL3) as negative regulator NASH pathogenesis. Hepatocyte-specific deletion Mettl3 drives by increasing CD36-mediated hepatic free acid uptake and CCL2-induced inflammation, which due increased chromatin accessibility promoter region Cd36 Ccl2 ....
Abstract A chiral bicyclic guanidine was developed as a versatile Brønsted base catalyst for the enantioselective Michael reactions of dithiomalonates and β‐keto thioesters using range acceptors including maleimides, cyclic enones, furanone acyclic 1,4‐dicarbonylbutenes.
Useful degradation: A highly enantio- and diastereoselective guanidine-catalyzed Mannich reaction was developed with α-fluoro-β-keto acyloxazolidinone as the fluorocarbon nucleophile (see scheme). α-Fluoro-β-amino ester α-fluoro-β-amino ketones chiral fluorinated carbon were obtained by selective deacylation decarboxylation reactions, respectively. Detailed facts of importance to specialist readers are published "Supporting Information". Such documents peer-reviewed, but not copy-edited or...
Abstract As a result of the low reactivity simple esters, use them as nucleophiles in direct asymmetric transformations is long‐standing challenge synthetic organic chemistry. Nature approaches this difficulty through decarboxylative mechanism, which used for polyketide synthesis. Inspired by nature, we report guanidine‐catalyzed biomimetic CC and CN bond‐formation reactions. These highly enantioselective Mannich amination reactions utilized malonic acid half thioesters ester surrogates....
Inactivation of the function tumor suppressor p53 is common in human cancers. In approximately half cancers, inactivated by deletion or mutation TP53, gene encoding protein. remaining 50% can be effectively inhibited oncoprotein MDM2 its homolog MDMX. Since inhibition MDMX protein mediated their direct interaction with p53, small-molecule inhibitors designed to block MDM2-p53 MDMX-p53 protein-protein (MDM2 inhibitors) activate cells retaining wild-type p53. last few years, several classes...
Potent and selective chemical probes are valuable tools for discovery of novel treatments human diseases. NF-κβ-inducing kinase (NIK) is a key trigger in the development liver injury fibrosis. Whether inhibition NIK activity by ameliorates inflammation largely unknown. In this study, small-molecule inhibitor NIK, B022, was found to be potent probe injury. B022 inhibited signaling pathway, including NIK-induced p100-to-p52 processing inflammatory gene expression, both vitro vivo. Furthermore,...
This paper describes highly efficient catalytic enantioselective cationic polyene cyclization and intramolecular carbonyl-ene reaction in good to high yields with enantioselectivities. The intimate relationship mechanistic differences between the two reactions were studied detail. In addition, products are versatile useful building blocks for natural pharmaceuticals syntheses.
Highly enantioselective Mannich and α-amination reactions have been successfully developed using α-fluorinated aromatic ketones as fluorocarbon nucleophiles in the presence of a bicyclic chiral guanidine (see scheme; Ms=methanesulfonyl). This method is simple efficient approach to construction fluorinated quaternary stereogenic centers.
Two clinical-stage anticancer drugs, the Bcl-2 inhibitor ABT-263, and MDM2 SAR405838 achieve complete tumor regression in animal models of leukemia but also induce acquired resistance. Elucidation resistance mechanisms development strategies to overcome are critical for their successful clinical development.We employed RS4;11 MV4;11 cell lines, two acute models, investigate both drugs vitro vivo evaluated several treatment regimens xenograft mouse improve long-term, regression.Resistance...