Simultaneous generation of hydroxyl and hydrogen radicals from H/OH pairs caused by water-solid contact electrification.

Water-solid contact electrification is a common physical phenomenon involving interfacial electron and ion transfer, recently discovered to trigger unique redox reactions. Here, we demonstrate the generation of both hydroxyl and hydrogen radicals when water contacts SiO. The coexistence of hydroxyl and hydrogen radicals is confirmed by simultaneous nitrate reduction and nitrite oxidation during the contact.

HDAC8 as a target in drug discovery: Function, structure and design.

Histone deacetylases (HDACs) have emerged as prominent therapeutic targets in drug discovery. Among the members of the HDAC family, HDAC8 exhibits distinct structural and physiological features from other members of the class Ⅰ HDACs. In addition to histones, numerous non-histone substrates such as structural maintenance of chromosomes 3 (SMC3), p53, estrogen-related receptor alpha (ERRα), etc.

HDAC6 mediates tumorigenesis during mitosis and the development of targeted deactivating agents.

Epigenetics, particularly deacetylation, plays a critical role in tumorigenesis as many carcinogens are under tight control by post-translational modification. HDAC6, an important and special histone deacetylase (HDAC) family member, has been indicated to increase carcinogenesis through various functions. Recent studies demonstrated the effects of HDAC6 inhibitors in mitotic arrest, however, detailed mechanisms still remain unknown.

Recent development of selective inhibitors targeting the HDAC6 as anti-cancer drugs: Structure, function and design.

HDAC6, a member of the histone deacetylase family, mainly is a cytosolic protein and regulates cell growth by acting on non-histone substrates, such as α -tubulin, cortactin, heat shock protein HSP90, programmed death 1 (PD-1) and programmed death ligand 1 (PD-L1), that are closely related to the proliferation, invasion, immune escape and angiogenesis of cancer tissues. The approved drugs targeting the HDACs are all pan-inhibitors and have many side effects due to their lack of selectivity. Therefore, development of selective inhibitors of HDAC6 has attracted much attention in the field of cancer therapy.

Design, synthesis, and biological evaluation of novel N-Benzyl piperidine derivatives as potent HDAC/AChE inhibitors for Alzheimer's disease.

The multitarget-directed ligands approach represents a potential strategy to provide effective treatments for Alzheimer's disease (AD) given its multifactorial pathology. Herein, a series of N-benzyl piperidine derivatives were designed, synthesized, and biologically characterized for dual inhibitions of histone deacetylase (HDAC) and acetylcholinesterase (AChE). Among the compounds tested, d5 and d10 exhibited dual enzyme inhibitions (d5: HDAC = 0.

Recent advances of small molecule JNK3 inhibitors for Alzheimer's disease.

C-Jun N-terminal kinase (JNK) is a member of mitogen-activated protein kinases (MAPKs) family, with three isoforms, JNK1, JNK2 and JNK3. Alzheimer's disease (AD) is a neurological disorder and the most common type of dementia. Two well-established AD pathologies are the deposition of Aβ amyloid plaques and neurofibrillary tangles caused by Tau hyperphosphorylation.

Design, synthesis and biological evaluation of phenyl vinyl sulfone based NLRP3 inflammasome inhibitors.

As the vital component of innate immune system, the NLRP3 inflammasome is implicated in the onset and progression of a variety of inflammatory diseases and has emerged as an attractive drug target. Herein a series of novel phenyl vinyl sulfone based NLRP3 inflammasome inhibitors were designed, synthesized and biologically characterized. The most potent two hits 7a and 5b showed inhibition on the NLRP3 inflammasome with the IC of 1.

A branched small molecule-drug conjugate nanomedicine strategy for the targeted HCC chemotherapy.

Off-target toxicity is one of the main challenges faced by anticancer chemotherapeutics. For tumor targeted and precision chemotherapy, we take the advantages of the ligand directed tumor active targeting of small molecule drug conjugates (SMDCs) and the passive tumor targeting of nanoparticles via the enhanced penetration and retention (EPR) effects, put forward a branched small molecule drug conjugate (BSMDC) nanomedicine design concept. In a proof of concept, we used pentaerythritol as the branched moiety, galactosamine (GalN) as the hepatocellular carcinoma (HCC) directing ligands, PTX as a payload, and a stearoyl moiety as the amphiphilic property adjusting group, designed and synthesized BSMDC 1 and prepared its NPs.

Synthesis and biological evaluation of selective histone deacetylase 6 inhibitors as multifunctional agents against Alzheimer's disease.

Histone deacetylase 6 (HDAC6) is a potential target for Alzheimer's disease (AD). In this study, a series of novel phenothiazine-, memantine-, and 1,2,3,4-tetrahydro-γ-carboline-based HDAC6 inhibitors with a variety of linker moieties were designed and synthesized. As a hydrochloride salt, the phenothiazine-based hydroxamic acid W5 with a pyridyl-containing linker motif was identified as a high potent and selective HDAC6 inhibitor.

Design, synthesis and biological evaluation of dual-function inhibitors targeting NMDAR and HDAC for Alzheimer's disease.

Histone deacetylases (HDACs) have been indicated important roles in neurodegenerative disorders including Alzheimer's disease (AD). Herein, a series of novel compounds that contain a memantine moiety were designed to target HDACs and N-methyl-d-aspartate receptor (NMDAR) which are related to the treatment of AD. Biological characterization established that compound 9d exhibited a balanced inhibitory activity on NMDAR and HDACs.

Tacrine-hydroxamate derivatives as multitarget-directed ligands for the treatment of Alzheimer's disease: Design, synthesis, and biological evaluation.

In order to develop multitarget-directed ligands as potential treatments for Alzheimer's disease, twenty-eight new tacrine-hydroxamate derivatives were designed, synthesized, and biologically evaluated. As expected, most of the compounds exhibited inhibitory activities against cholinesterases (ChEs) and histone deacetylase (HDACs). Among the tested compounds, A10 showed not only potent and selective inhibition on AChE at sub-nanomolar potency (AChE = 0.

Development of small molecule inhibitors targeting NLRP3 inflammasome pathway for inflammatory diseases.

NLRP3 (Nod-like receptor protein 3) belongs to the NOD-like receptor family, which is activated by pathogen and damage-associated signals to form a multimeric protein complex, known as the NLRP3 inflammasome. NLRP3 inflammasome activation leads to release of proinflammatory cytokines IL-1β and IL-18, thus inducing pyroptosis, a programmed cell death mechanism. Dysregulation of the NLRP3 inflammasome pathway is closely related to the development of many human diseases, such as neuroinflammation, metabolic inflammation, and immune inflammation.

Glycyrrhetinic acid-modified graphene oxide mediated siRNA delivery for enhanced liver-cancer targeting therapy.

Graphene oxide (GO) has attracted huge attention in biomedical field in recent years. However, limited attempts have been invested in utilizing GO on active targeted delivery for gene therapy in liver cancer treatments. Glycyrrhetinic acid (GA) has been reported to be widely used as a targeting ligand to functionalize nanomaterials to treat hepatocellular carcinoma.

Tubulin colchicine site binding agent LL01 displays potent antitumor efficiency both in vitro and in vivo with suitable drug-like properties.

Through rational drug design, we previously identified an indenoprazole derivative, 2-(6-ethoxy-3-(3-ethoxyphenylamino)-1-methyl-1,4-dihydroindeno[1,2-c]pyrazol-7-yloxy)acetamide (LL01), as a potent tubulin polymerization inhibitor targeting the tubulin colchicine binding site. In this study, we further demonstrated that LL01 was not a P-gp substrate. It potently inhibited the growth of a variety of tumor cells, including those with multidrug resistance, with GI values in the low nanomole ranges.

Design, synthesis and activity evaluation of indole-based double - Branched HDAC1 inhibitors.

Histone deacetylases inhibitors (HDACIs) represents effective treatments for cancer. In continuing our efforts to develop novel and potent HDACIs, a series of N-hydroxycinnamamide-based HDACIs with aromatic ring and various aliphatic linker have been successfully designed and synthesized. Biological evaluations established that compounds 4h, 4i, 4j, 4l, 4r showed superior inhibition on histone deacetylase and antiproliferative activity in some solid tumor cell lines [HeLa, SK-N-BE(2), PC-3] compared to the known inhibitor SAHA.

Synthesis and evaluation of novel GSK-3β inhibitors as multifunctional agents against Alzheimer's disease.

To target the multi-facets of Alzheimer's disease (AD), a series of novel GSK-3β inhibitors containing the 2,3-diaminopyridine moiety were designed and synthesized. The amide derivatives 5a-f showed moderate potency against GSK-3β with weak Cu, Zn and Al chelating ability. The imine derivatives 9a, 9b and 9e were potent GSK-3β inhibitors and selective Cuand Al chelators.

Advances on graphene-based nanomaterials for biomedical applications.

Graphene-based nanomaterials, such as graphene oxide and reduced graphene oxide, have been attracting increasing attention in the field of biology and biomedicine over the past few years. Incorporation of these novel materials with drug, gene, photosensitizer and other cargos to construct novel delivery systems has witnessed rapid advance on the basis of their large surface area, distinct surface properties, excellent biocompatibility and pH sensitivity. Moreover, the inherent photothermal effect of these appealing materials enables them with the ability of killing targeting cells via a physical mechanism.

Development of Bruton's Tyrosine Kinase Inhibitors for Rheumatoid Arthritis.

Rheumatoid Arthritis (RA) is a chronic autoimmune disease and becomes one of the major causes of disability and work force loss. The presence of abnormal B cell and autoantibodies produced by most RA patients, primarily ACPA and RF, indicate that the function of B cell was involved in the development of RA disease. Accordingly, the drug targeting B cell has become a hot spot in the treatment of RA.

Structure optimization and preliminary bioactivity evaluation of N-hydroxybenzamide-based HDAC inhibitors with Y-shaped cap.

Histone deacetylase inhibitors (HDACIs) are effective small molecules in the treatment of human cancers. In our continuing efforts to develop novel N-hydroxyterephthalamide-based HDACIs, herein we report the design and development of a new class of N-hydroxybenzamide-based HDACIs. In this new class of analogs, we inserted an ethylene moiety in the linker and used indole as a part of the Y-shaped cap group.

Development and Characterization of a Hydroxyl-Sulfonamide Analogue, 5-Chloro-N-[2-(4-hydroxysulfamoyl-phenyl)-ethyl]-2-methoxy-benzamide, as a Novel NLRP3 Inflammasome Inhibitor for Potential Treatment of Multiple Sclerosis.

In our efforts to develop novel small-molecule inhibitors for the NOD-like receptor family pyrin-domain-containing 3 (NLRP3) inflammasome as potential disease-modifying agents to treat neurological disorders including multiple sclerosis (MS), a hydroxyl sulfonamide analogue JC-171 has been rationally designed and biologically characterized both in vitro and in vivo. Our studies established that JC-171 dose dependently inhibited LPS/ATP-induced interleukin-1β (IL-1β) release from J774A.1 macrophages with an IC of 8.

Design, synthesis and tumor cell growth inhibitory activity of 3-nitro-2H-cheromene derivatives as histone deacetylaes inhibitors.

As a continuous research for the discovery of coumarin-based targeted anticancer agents, we designed and synthesized a series of novel histone deacetylases (HDAC) inhibitors using the 8-ethoxy-3-nitro-2H-chromene as the surface binding or cap group, linear dicarboxylic acid or ω-amino acid moiety with different length as the linking motif, ortho-aminoanilides, amides or α-aminoamides as the zinc binding group and the internal cavity motifs. Most of these 3-nitro-2H-chromene derivatives exhibited good growth inhibitory activity against K562, A549, MCF-7, PC3 and Hela cells and were more potent than the reference drug SAHA and MS-275. At the concentration of 10µM, the ortho-aminoanilide series and the d-Phe derived α-aminoamide derivatives 16a and 16b displayed more potent activity toward HADC1 over HADC2, and only moderate to weak activity over HADC6.

Selective HDAC inhibitors with potent oral activity against leukemia and colorectal cancer: Design, structure-activity relationship and anti-tumor activity study.

Previously, we reported the discovery of a series of N-hydroxycinnamamide-based HDAC inhibitors, among which compound 11y exhibited high HDAC1/3 selectivity. In this current study, structural derivatization of 11y led to a new series of benzamide based HDAC inhibitors. Most of the compounds exhibited high HDACs inhibitory potency.

Design, synthesis, and preliminary bioactivity evaluation of N -hydroxyterephthalamide derivatives with indole cap as novel histone deacetylase inhibitors.

Histone deacetylases inhibitors (HDACIs) have been widely recognized as significant therapeutic approach to cancers. In our efforts to develop novel histone deacetylases inhibitors (HDACIs) as potential anticancer agents, a series of N -hydroxyterephthalamide derivatives with an indole cap group were designed and synthesized. Compound 12m was identified to be the most potent one (IC  = 0.

Discovery of a novel chimeric ubenimex-gemcitabine with potent oral antitumor activity.

Herein, a novel mutual prodrug BC-A1 was discovered by integrating ubenimex and gemcitabine into one molecule. Biological characterization revealed that compound BC-A1 could maintain both the anti-CD13 activity of ubenimex and the cytotoxic activity of gemcitabine in vitro. Further characterization also demonstrated that compound BC-A1 exhibited significant anti-invasion and anti-angiogenesis effects in vitro.