Electron Lock Manipulates the Catalytic Selectivity of Nanozyme.

Nanomaterials with enzyme-mimicking functions, termed nanozymes, offer attractive opportunities for biocatalysis and biomedicine. However, manipulating nanozyme selectivity poses an insurmountable hurdle. Here, we propose the concept of an energy-governed electron lock that controls electron transfer between nanozyme and substrates to achieve selectivity manipulation of enzyme-like catalysis. An electron lock can be constructed and opened, via modulating the nanozyme's electron energy to match the energy barrier of enzymatic reactions. An iron-doped carbon dot (FeCD) nanozyme with easy-to-regulate electron energy is selected as a proof of concept. Through regulating the conduction band which dominates electron energy, activatable oxidase and selective peroxidase (POD) with substrate affinity 123-fold higher than that of natural horseradish peroxidase (HRP) is achieved. Furthermore, while maintaining selectivity, FeCDs exhibit catalytic kinetics comparable to that of HRP upon transforming photons into electrons. Superior selectivity, efficient catalysis, and undetectable biotoxicity energize FeCDs as potent targeted drugs on antibiotic-resistant bacterial abscesses. An electron lock provides a robust strategy to manipulate selectivity toward advanced nanozymes.

Bioinspired hot-spot engineering strategy towards ultrasensitive SERS sandwich biosensor for bacterial detection.

Surface-enhanced Raman spectroscopy (SERS) sandwich biosensors have received tremendous attention in early diagnosis of bacterial infections. However, efficiently engineering nanoscale plasmonic hots pots (HS) towards ultrasensitive SERS detection still remains challenging. Herein, we propose a bioinspired synergistic HS engineering strategy to construct ultrasensitive SERS sandwich bacterial sensor (named USSB), by coupling bioinspired signal module and plasmonic enrichment module to synergistically boost the number and intensity of HS. The bioinspired signal module is based on dendritic mesoporous silica nanocarrier (DMSN) loaded with plasmonic nanoparticles and SERS tag, while magnetic Fe3O4 nanoparticles coated with Au shell are employed in plasmonic enrichment module. We demonstrate that DMSN effectively shrank nanogaps between plasmonic nanoparticles to improve HS intensity. Meanwhile, plasmonic enrichment module contributed to plenty of additional HS inside and outside individual "sandwich". Ascribing to the boosted number and intensity of HS, the constructed USSB sensor exhibits ultrahigh detection sensitivity (7 CFU/mL) and selectivity towards model pathogenic bacteria of Staphylococcus aureus. Remarkably, the USSB sensor enables fast and accurate bacterial detection in real blood samples of septic mice, achieving early diagnosis of bacterial sepsis. The proposed bioinspired synergistic HS engineering strategy opens up a new direction for constructing ultrasensitive SERS sandwich biosensors, and may promote their advancing applications in the early diagnosis and prognosis of devastating diseases.

Association between Micronutrients and Hyperhomocysteinemia: A Case-Control Study in Northeast China.

Hyperhomocysteinemia (HHcy) is an independent risk factor for cardiovascular and cerebrovascular diseases where the plasma homocysteine (Hcy) concentration exceeds 15 µmol/L. HHcy is affected by vitamins B12, B6, and folic acid (fol); however, its relationship with other nutrients is not fully understood. We investigated the nutritional and genetic factors associated with HHcy and the possible dose-response relationships or threshold effects in patients in Northeast China. Genetic polymorphisms and micronutrients were tested with polymerase chain reaction and mass spectrometry, respectively. This trial was registered under trial number ChiCTR1900025136. The HHcy group had significantly more males and higher body mass index (BMI), methylenetetrahydrofolate reductase (MTHFR 677TT) polymorphism proportion, and uric acid, Zn, Fe, P, and vitamin A levels than the control group. After adjusting for age, sex, BMI, vitamin B12, fol, and MTHFR C677T, the lowest Zn quartile reduced the odds ratio of HHcy compared with the highest Zn quartile. The dose-response curves for the association between plasma Zn and HHcy were S-shaped. High plasma Zn concentrations were significantly correlated with high HHcy odds ratios, and the curve leveled off or slightly decreased. Most importantly, HHcy risk decreased with decreasing plasma Zn concentration; the threshold was 83.89 µmol/L. Conclusively, individuals residing in Northeast China, especially those with the MTHFR 677TT polymorphism, must pay attention to their plasma Zn and Hcy levels.

Confined Cascade Metabolic Reprogramming Nanoreactor for Targeted Alcohol Detoxification and Alcoholic Liver Injury Management.

Alcoholic liver injury (ALI) is the leading cause of serious liver disease, whereas current treatments are mostly supportive and unable to metabolize alcohol directly. Here we report a metabolic reprogramming strategy for targeted alcohol detoxification and ALI management based on a confined cascade nanoreactor. The nanoreactor (named AA@mMOF) is designed by assembling natural enzymes of alcohol oxidase (AOx) and aldehyde dehydrogenase (ALDH) in the cavity of a mesoporous metal organic framework (mMOF) nanozyme with intrinsic catalase (CAT)-like activity. By conducting confined AOx/CAT/ALDH cascade reactions, AA@mMOF enables self-accelerated alcohol degradation (>0.5 mg·mL-1·h-1) with negligible aldehyde diffusion and accumulation, reprogramming alcohol metabolism and allowing high-efficiency detoxification. Administered to high-dose alcohol-intoxicated mice, AA@mMOF shows surprising liver targeting and accumulation performance and dramatically reduces blood alcohol concentration and rapidly reverses unconsciousness and acute liver injury to afford targeted alcoholism treatment. Moreover, AA@mMOF dramatically alleviates fat accumulation and oxidative stress in the liver of chronic alcoholism mice to block and reverse the progression of ALI. By conducting confined AOx/CAT/ALDH cascade reactions for high-efficiency alcohol metabolism reprogramming, AA@mMOF nanoreactor offers a powerful modality for targeted alcohol detoxification and ALI management. The proposed confined cascade metabolic reprogramming strategy provides a paradigm shift for the treatment of metabolic diseases.

[Expression of HSP27 and BAX/BCL-2 apoptosis factor in silicosis rat model of fibrosis].

OBJECTIVE: To study the expression of heat shock protein 27(HSP27), BAX and BCL-2 apoptosis in silicosis rat model, and to explore the correlation between HSP27 and BAX and BCL-2 apoptosis. METHODS: Silicosis model was established by the oropharyngeal and endotracheal intubation. Forty SPF healthy adult Wistar male rats were randomly divided into 4 groups, with 10 rats in each group. Silicosis group for 6 weeks(feeding for 6 weeks), silicosis group for 8 weeks(feeding for 8 weeks): oropharyngeal and tracheal perfusion of 50 mg/mL SiO_2 suspension 1.0 mL/mouse; Model control group for 6 weeks and model control group for 8 weeks: 1.0 mL saline was infused into the oropharynx and trachea. Immunohistochemical staining was used to detect the expression of HSP27, BAX and BCL-2 in the right lower lung of silicosis model group at 6 and 8 weeks and model control group at 6 and 8 weeks. Western blot was used to detect the protein expression of HSP27, BAX and BCL-2 in the left lower lobe lung tissue of silicosis model group at 6 and 8 weeks and model control group at 6 and 8 weeks, respectively. Immunofluorescence staining was used to detect the colocalization of HSP27 with pro-apoptotic factor BAX and HSP27 with anti-apoptotic factor BCL-2. RESULTS: Compared with the model control group at 6 weeks and 8 weeks, the expression of HSP27 and pro-apoptotic factor BAX in fibrotic region increased, and the expression of anti-apoptotic factor BCL-2 decreased in silicosis model group at 6 weeks and 8 weeks(P<0.05). Immunofluorescence staining showed that there was colocalization of HSP27 and pro-apoptotic factor BAX in the fibrotic region. Correlation analysis showed that the correlation coefficient between HSP27 and pro-apoptotic factor BAX was r=0.94, indicating a positive correlation between them, while the correlation coefficient between HSP27 and anti-apoptotic factor BCL-2 was r=-0.81, indicating a negative correlation between them. CONCLUSION: High expression of HSP27 and pro-apoptotic factor BAX and low expression of anti-apoptotic factor BCL-2 exist in silicosis rats, and their expression is correlated.

Fluoride regulates the differentiation and atrophy through FGF21/ERK signaling pathway in C2C12 cells.

Excess intake of fluoride leads to a serious health issue called fluorosis. Fluorosis patients exhibit the symptom of muscle damage, but the specific mechanism remains unclear. Fibroblast growth factor 21 (FGF21) is a novel myokine that is involved in the regulation of myogenic differentiation, but whether fluoride induces skeletal muscle damage via FGF21 signaling has not been reported yet. In the current study, C2C12 cells were used to investigate the impact of fluoride on myogenic development and the involved regulatory role of FGF21/ERK signaling pathway. The expressions of the markers of myoblasts development and FGF21/ERK signaling pathway-related molecules were detected after fluoride treatment. The results indicated that fluoride notably inhibited the expressions of myogenic regulatory genes MyoD, MyoG and MyHC in C2C12 cells. In addition, fluoride increased the expressions of muscle atrophy-related markers MuRF1 and MAFbx. We proved that fluoride significantly inhibited the expression of FGF21 based on the RNA-seq results, and detected the expressions of downstream molecules FGFR1, KLB, Raf, MEK and ERK. Moreover, FGF21 pretreatment reversed the adverse effect of fluoride on the C2C12 cells and alleviated the atrophy of myotubes. Taken together, these findings indicated that fluoride suppressed differentiation and aggravated atrophy via FGF21/ERK signaling pathway in C2C12 cells. Our study has provided new evidence for the role of FGF21/ERK in fluoride-induced skeletal muscle damage and FGF21 may be one of the potential targets for prevention and treatment of fluorosis.

Serum Sirtuin1 level decreases in Parkinson's disease and vascular parkinsonism: A prospective observational study.

OBJECTIVE: The present study aimed to investigate levels and clinical significance of serum SIRT1 in Parkinson's disease (PD) and Vascular parkinsonism (VP). METHODS: This prospective observational research enrolled a total of 165 VP and 159 PD patients who were admitted during March 2018 to December 2021. Blood samples and medical characteristics were also obtained from 160 healthy volunteers. The serum Sirtuin1 (SIRT1) and cytokines levels of all subjects were measured by enzyme-linked immunosorbent assay (ELISA) method. Demographic and clinical data were also collected. Statistical analysis was conducted using SPSS software with P < 0.05 as statistically different. RESULTS: The mean age, the UPDRSIII score of VP patients was significantly higher compared with the PD patients (p<0.05), while the MMSE score of VP patients was significantly lower than the PD patients (p<0.001). The serum SIRT1 levels of the VP patients were remarkably lower than the PD patients or the healthy persons (p<0.05). Pearson's analysis showed that SIRT1 levels were negatively correlated with levels of IL-6, TNF- α and hcy. The UPDRSIII of SIRT1 low levels group was remarkably higher than the SIRT1 high levels group (p=0.048), while the MMSE score was lower than the SIRT1 high levels group (p<0.001). In addition, ROC curves showed that SIRT1 could be a potential diagnostic biomarker of VP. SIRT1 was a risk factor for VP. CONCLUSION: Our present study indicated that SIRT1 associated with disease severity and could discriminate PD from VP.

Decoy Nanozymes Enable Multitarget Blockade of Proinflammatory Cascades for the Treatment of Multi-Drug-Resistant Bacterial Sepsis.

Sepsis is a life-threatening organ dysfunction characterized by severe systemic inflammatory response to infection. Effective treatment of bacterial sepsis remains a paramount clinical challenge, due to its astonishingly rapid progression and the prevalence of bacterial drug resistance. Here, we present a decoy nanozyme-enabled intervention strategy for multitarget blockade of proinflammatory cascades to treat multi-drug-resistant (MDR) bacterial sepsis. The decoy nanozymes (named MCeC@MΦ) consist mesoporous silica nanoparticle cores loaded with CeO2 nanocatalyst and Ce6 photosensitizer and biomimetic shells of macrophage membrane. By acting as macrophage decoys, MCeC@MΦ allow targeted photodynamic eradication of MDR bacteria and realize simultaneous endotoxin/proinflammatory cytokine neutralization. Meanwhile, MCeC@MΦ possess intriguing superoxide dismutase and catalase-like activities as well as hydroxyl radical antioxidant capacity and enable catalytic scavenging of multiple reactive oxygen species (ROS). These unique capabilities make MCeC@MΦ to collaboratively address the issues of bacterial infection, endotoxin/proinflammatory cytokine secretion, and ROS burst, fully cutting off the path of proinflammatory cascades to reverse the progression of bacterial sepsis. In vivo experiments demonstrate that MCeC@MΦ considerably attenuate systemic hyperinflammation and rapidly rescue organ damage within 1 day to confer higher survival rates (>75%) to mice with progressive MDR Escherichia coli bacteremia. The proposed decoy nanozyme-enabled multitarget collaborative intervention strategy offers a powerful modality for bacterial sepsis management and opens up possibilities for the treatment of cytokine storm in the COVID-19 pandemic and immune-mediated inflammation diseases.

pH-switchable nanozyme cascade catalysis: a strategy for spatial-temporal modulation of pathological wound microenvironment to rescue stalled healing in diabetic ulcer.

The management of diabetic ulcer (DU) to rescue stalled wound healing remains a paramount clinical challenge due to the spatially and temporally coupled pathological wound microenvironment that features hyperglycemia, biofilm infection, hypoxia and excessive oxidative stress. Here we present a pH-switchable nanozyme cascade catalysis (PNCC) strategy for spatial-temporal modulation of pathological wound microenvironment to rescue stalled healing in DU. The PNCC is demonstrated by employing the nanozyme of clinically approved iron oxide nanoparticles coated with a shell of glucose oxidase (Fe3O4-GOx). The Fe3O4-GOx possesses intrinsic glucose oxidase (GOx), catalase (CAT) and peroxidase (POD)-like activities, and can catalyze pH-switchable glucose-initiated GOx/POD and GOx/CAT cascade reaction in acidic and neutral environment, respectively. Specifically, the GOx/POD cascade reaction generating consecutive fluxes of toxic hydroxyl radical spatially targets the acidic biofilm (pH ~ 5.5), and eradicates biofilm to shorten the inflammatory phase and initiate normal wound healing processes. Furthermore, the GOx/CAT cascade reaction producing consecutive fluxes of oxygen spatially targets the neutral wound tissue, and accelerates the proliferation and remodeling phases of wound healing by addressing the issues of hyperglycemia, hypoxia, and excessive oxidative stress. The shortened inflammatory phase temporally coupled with accelerated proliferation and remodeling phases significantly speed up the normal orchestrated wound-healing cascades. Remarkably, this Fe3O4-GOx-instructed spatial-temporal remodeling of DU microenvironment enables complete re-epithelialization of biofilm-infected wound in diabetic mice within 15 days while minimizing toxicity to normal tissues, exerting great transformation potential in clinical DU management. The proposed PNCC concept offers a new perspective for complex pathological microenvironment remodeling, and may provide a powerful modality for the treatment of microenvironment-associated diseases.

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. In cellular level, the BSMDC 1 NPs targeted asialoglycoprotein receptor (ASGPR)-overexpressing HepG2 cells, were effectively taken up in the cells and released in tumor microenvironments, inhibited the HepG2 cell proliferation, arrested HepG2 cell in G2/M phase and induced tumor cell apoptosis. In HepG2 xenograft nude mice, the BSMDC 1 NPs were high specific to target the tumor and demonstrated a higher antitumor efficiency than BSMDC 1, having no apparent influences on mice body weights and major organs, supporting our BSMDC nanomedicine design concept. Therefore, this new strategy may find applications for cancer targeted and precision chemotherapy.

A transformable gold nanocluster aggregate-based synergistic strategy for potentiated radiation/gene cancer therapy.

Nano-radiosensitizers provide a powerful tool for cancer radiation therapy. However, their limited tumor retention/penetration and the inherent or adaptive radiation resistance of tumor cells hamper the clinical success of radiation therapy. Herein, we report a synergistic strategy for potentiated cancer radiation/gene therapy based on transformable gold nanocluster aggregates loaded with antisense oligonucleotide-targeting survivin mRNA (named AuNC-ASON). AuNC-ASON exhibited acidic pH-triggered structure splitting from a gold nanocluster aggregate (around 80 nm) to gold nanocluster (<2 nm), leading to the tumor microenvironment-responsive size transformation of the nano-radiosensitizer and activated release of the loaded antisense oligonucleotides to perform gene silencing. The in vitro experiments demonstrated that AuNC-ASON could amplify and improve the radio-sensitivity of tumor cells (the sensitization enhancement ratio was about 1.81) as a result of the synergistic effect of the transformable gold nanocluster radiosensitizer and survivin gene interference. Remarkably, the size transformation capability realized the high tumor retention/penetration and renal metabolism of AuNC-ASON in vivo and boosted the radio-susceptibility of cancer cells with the assistance of survivin gene interference, synergistically achieving potentiated tumor radiation/gene therapy. The proposed concept of transformable nano-radiosensitizer aggregate-based synergistic therapy can be utilized as a general strategy to guide the design of activatable multifunctional nanosystems for cancer theranostics.

In vitro and in vivo antihypertensive and antioxidant activities of fermented roots of Allium hookeri.

Objective: To evaluate antihypertensive and antioxidant activities of Allium hookeri root (AHR) fermented with Lactobacillus plantarum, Leuconostoc mesenteroides, and Weissella cibaria. Methods: The novel fermented AHR products using L. plantarum, L. mesenteroides, and W. cibaria were developed and ACE inhibitory activity, DPPH radical scavenging activity, hydroxyl radical scavenging activity, superoxide anion radical scavenging activity, total phenolic content, and total thiosulfinate content were determined. The antihypertensive and antioxidant effects of fermented AHR were further investigated in spontaneously hypertensive rats (SHRs). Results: Administration of fermented AHR to SHRs had an attenuating effect on both diastolic and systolic blood pressure. The SHRs treated with fermented AHR showed lower plasma ACE activity and higher plasma NO levels. Furthermore, fermented AHR administration led to parallel improvements in plasma oxidative stress biomarkers in SHRs. Conclusion: Our results highlight the potential usefulness of fermented AHR for the prevention of hypertension.

SAR Investigation and Discovery of Water-Soluble 1-Methyl-1,4-dihydroindeno[1,2-c]pyrazoles as Potent Tubulin Polymerization Inhibitors.

Taking the previously discovered 1-methyl-1,4-dihydroindeno[1,2c]pyrazol derivative LL01 as a lead, systematic structural modifications were made at the phenolic 6- and 7-positions and the aniline at the 3-position of the indenopyrazole core to investigate the SARs and to improve water solubility. Among the designed indenopyrazoles ID01-ID33, a series of potent MTAs were identified. As the hydrochloride salt(s), ID09 and ID33 showed excellent aqueous solubility and favorable Log P value and displayed noteworthily low nanomolar potency against a variety of tumor cells, including those taxol-resistant ones. They inhibited tubulin polymerization, disrupted cellular microtubule networks by targeting the colchicine site, and promoted HepG2 cell cycle arrest and cell apoptosis. In the HepG2 xenograft mouse model, ID09 and ID33 effectively inhibited tumor growth at an oral dose of 25 mg/kg. At an intravenous (iv) injection dose of 10 mg/kg every other day, ID09 suppressed tumor growth by 68% without obvious toxicity.

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 GI50 values in the low nanomole ranges. In vitro liver microsome stability assay, LL01 was modest stable in the liver microsomes of human, mouse and rat, but was fast metabolized in dog. After single oral administration of LL01 at a dose of 10 mg/kg in SD male rats, LL01 showed acceptable PK properties with a mean bioavailability of 41%. In human HepG2 hepatoma xenograft, at the oral doses of 25 mg/kg/day and 12.5 mg/kg/day, LL01 inhibited the tumor growth by 61.27%, and 43.74%, respectively, which is much better than the positive drug sorafenib (29.45%; 30 mg/kg/day). Therefore, LL01 might be a potential drug candidate for further investigation for hepatocellular carcinoma therapy.

The discovery of novel indazole derivatives as tubulin colchicine site binding agents that displayed potent antitumor activity both in vitro and in vivo.

Tubulin inhibitors that bind to the colchicine site are widely studied anticancer agents. In continuous our researches, we designed a series of novel indazole derivatives as microtubule-targeting agents (MTAs). The structure-activity relationships (SARs) investigations indicated that a 3,4,5-trimethoxyphenyl moiety and a methyl or methoxy substitution were preferred for the better antiproliferative activity. The indazole derivatives 3c and 3f showed noteworthy low nanomolar potency against HepG2, HCT116, SW620, HT29 and A549 tumor cells. In mechanism studies, 3c and 3f were proved to target the colchicine site, inhibited tubulin polymerization and disrupted cellular microtubule networks, arrested HCT116 cell in G2/M phase and induced cell apoptosis. In the HCT116 xenografts mouse model, 3c and 3f suppressed tumor growth by 45.3% and 58.9% at an orally dose of 25 mg/kg without causing obvious weight loss. The indazole 3f may serve as a good lead or drug candidate for colorectal cancer therapy.

Antioxidant Activity and Main Chemical Components of a Novel Fermented Tea.

In the present study, we aimed to develop a novel fermented tea (NFT) product and to evaluate their in vitro antioxidant potential and chemical composition. We found that NFT contained a high level of total phenolic compounds (102.98 mg gallic acid equivalents/g extract) and exhibited diverse antioxidant activities, such as scavenging of 1,1-diphenyl-2-picryl-hydrazyl (DPPH) and hydroxyl radicals, as well as reducing power. The total catechins in NFT were comparable to those of Lipton black tea (LBT), but lower than those of Boseong green tea (BGT) or Tieguanyin oolong tea (TOT). Among all catechins tested, epigallocatechin (EGC) and epigallocatechin-3-O-gallate (EGCG) were the predominant compounds in NFT. In particular, the contents of total theaflavins (TFs), theaflavin (TF), theaflavin-3-gallate (TF3G), and theaflavin-3'-gallate (TF3'G) in NFT were significantly higher than that of BGT, TOT, or LBT. NFT had the highest level of total essential amino acid and γ-aminobutyric acid (GABA) compared with BGT, TOT and LBT. Furthermore, the sensory evaluation results showed that NFT had satisfactory color, aroma, taste, and overall acceptability scores. Our results highlight the potential usefulness of this novel fermented tea as a nutraceutical food/ingredient with special functional activities.

Synthesis of Novel Pyrazole Derivatives and Their Tumor Cell Growth Inhibitory Activity.

To find novel antitumor agents, a series of 1H-benzofuro[3,2-c]pyrazole derivatives 4a-e were designed and synthesized. The treatment of 6-methoxybenzofuran-3(2H)-one 3 with LiHMDS in anhydrous tetrahydrofuran (THF) followed by reaction with 3-substitued phenyl isothiocyanate gave the thioamide intermediates, which underwent condensation with hydrazine monohydrate in dioxane/EtOH (1:1) to provide the benzofuropyrazole derivatives 4a⁻e as well as the unexpected pyrazole derivatives 5a⁻e. In tumor cell growth inhibitory assay, all the benzofuropyrazole derivatives were not active against the breast tumor MCF-7 cell, only 4a was highly active and more potent than ABT-751 against the leukemia K562 (GI50 = 0.26 µM) and lung tumor A549 cells (GI50 = 0.19 µM), while other benzofuropyrazoles showed very weak inhibitory activity. In contrast, the pyrazoles 5a-e were in general more potent than the benzofuropyrazoles 4a⁻e. Compound 5a exhibited a similar tendency to that of 4a with high potency against K562 and A549 cells but weak effects on MCF-7 cell. Both pyrazoles 5b and 5e exhibited high inhibitory activities against K562, MCF-7 and A549 cells. The most active compound 5b was much more potent than ABT-751 against K562 and A549 cells with GI50 values of 0.021 and 0.69 M, respectively. Moreover, 5b was identified as a novel tubulin polymerization inhibitor with an IC50 of 7.30 M.

Evaluation of WO2017018805: 1,3,4-oxadiazole sulfamide derivatives as selective HDAC6 inhibitors.

INTRODUCTION: There are great potential in the development of selective HDAC6 inhibitors for the treatment of infectious diseases, neoplasms, endocrine diseases, and other diseases associated with HDAC6 activity. Areas covered: The application claims 1,3,4-oxadiazole sulfamide derivatives as selective HDAC6 inhibitors for the treatment of infectious diseases, neoplasms, endocrine, nutritional, and metabolic diseases; mental and behavioral disorders; neurological diseases; diseases of the eye and adnexa; cardiovascular diseases; respiratory diseases; digestive diseases; diseases of the skin and subcutaneous tissue; disease of the musculoskeletal system and connective tissue; or congenital malformations, deformations and chromosomal abnormalities. Many of the exemplified compounds showed nanomole potency against HDAC6 and were more than 5000-fold selectivity for HDAC6 over HDAC1. Expert opinion: These 1,3,4-oxadiazole sulfamide derivatives have a unique zinc-binding group (ZBG) that provide good leads for the discovery of potent selective HDAC6 inhibitors for the treatment of a variety of diseases associated with HDAC6 activity.

Discovery of novel quinazolinone derivatives as high potent and selective PI3Kδ and PI3Kδ/γ inhibitors.

PI3Kδ and PI3Kγ regulate immune cell signaling. Selective PI3Kδ or PI3Kγ inhibitors and dual PI3Kδ/γ inhibitors have the potential for the treatment of immune cell-mediated diseases and hematological malignancies. Based on the quinazolinone pharmacophore, we used a pyrazolo[3,4-d]pyrimidin-4-amine portion as the hinge region binding moiety, an aromatic or a heteroaromatic substituent at the 3-position of the pyrazolo[3,4-d]pyrimidine core as the affinity element, and designed novel 2-tolyl and 2,6-dimethylphenyl quinazolinone derivatives as potential PI3Kδ inhibitors. Most of these compounds displayed high inhibitory rates (89-97%) against PI3Kδ at the concentration of 1 µM, with the IC50 values of 8.4 nM-106 nM. Among the 3-(2,6-dimethylphenyl)quinazolinone series, the introduction of an indol-5-yl substituent at the pyrazolo[3,4-d]pyrimidine 3-position led to a potent and selective PI3Kδ (IC50 = 8.6 nM) inhibitor 10d, that was more than 3630-fold, 390-fold and 40-fold selective for PI3Kδ over PI3Kα, ß and γ, while the substitution with a 3,4-dimethoxyphenyl resulted in a potent and selective dual PI3Kδ/γ inhibitor 10e with IC50 values of 8.4 nM and 62 nM against PI3Kδ and PI3Kγ, respectively. Compound 10e was also more than 1400-fold, 820-fold selective for PI3Kδ over PI3Kα and PI3Kß. In agreement with their remarkable PI3Kδ inhibitory activity, compounds 10d and 10e showed high antiproliferative activity against human B-cell SU-DHL-6 cells. Moreover, the dual PI3Kδ/γ inhibitor 10e had reasonable pharmacokinetic profiles with a good plasma exposure, low clearance, low volume distribution, and an acceptable oral bioavailability of 34.9%.