Discovery of novel third generation P-glycoprotein inhibitors bearing an azo moiety with MDR-reversing effect.

P-glycoprotein (P-gp)-caused multidrug resistance (MDR) is a crucial factor in the cancer chemotherapy failure. Herein, a total of twenty two azo-containing WK-X-34 (WK34, a third generation P-gp inhibitor) derivatives were synthesized as novel P-gp inhibitors. Biological evaluation revealed that compound 7i effectively reversed P-gp-mediated MDR in K562/A02 cells, with a higher reversal fold (RF) value than WK34 (142.

Exploration of 1-(indolin-1-yl)-2-(thiazol-2-yl)ethan-1-one derivatives as novel anti-HBV agent with potential TLR7-agonistic effect.

Hepatitis B virus (HBV) infection, as a serious global public health issue, is closely related to the immune dysfunction. Herein, thirty-seven 1-(indolin-1-yl)-2-(thiazol-4-yl)ethan-1-one derivatives were prepared as potential immunomodulatory anti-HBV agents. Anti-HBV activity evaluation confirmed compound 11a could significantly suppress the HBV DNA replication in both wild and resistant HBV stains, with IC values of 0.

N-3, a novel synthetic derivative of bifendate, inhibits metastasis of triple-negative breast cancer via decreasing p38-regulated FOXC1 protein stability.

Triple-negative breast cancer (TNBC) is an aggressive breast cancer subtype with high invasiveness, metastatic potential, and poor prognosis. Epithelial-mesenchymal transition (EMT) is pivotal in TNBC progression, becoming a promising target for TNBC treatment. Our study evaluated N-3, a novel synthetic bifendate derivative, which inhibited the EMT-associated migration and invasion of MDA-MB-231 and 4T1 TNBC cells.

Design and Synthesis of Triazole-Containing HDAC Inhibitors That Induce Antitumor Effects and Immune Response.

Histone deacetylase (HDAC) is an epigenetic antitumor drug target, but most existing HDAC inhibitors show limited antitumor activity and their use is often accompanied by serious adverse effects. To overcome these problems, we designed and synthesized a series of triazole-containing compounds as novel HDAC inhibitors. Among them, compound exhibited potent and selective inhibition of HDAC1, with good antiproliferative activity in vitro and an excellent pharmacokinetic profile.

Design and evaluation of dibenzoazepine-tetrahydroisoquinoline hybrids as potential P-glycoprotein inhibitors against multidrug resistant K562/A02 cells.

Multidrug resistance (MDR) caused by P-glycoprotein (P-gp) is a main barrier to the success of cancer chemotherapies. In this study, fourteen novel dibenzoazepine-tetrahydroisoquinoline hybrids were prepared as potential P-gp inhibitors to surmount MDR caused by P-gp. Amongst them, 8a displayed the most potent inhibition effect on P-gp, thus effectively reversing P-gp-mediated drug resistance with a reversal fold (RF) value of 93.

Optical-Controlled Kinetic Switch: Fine-Tuning of the Residence Time of an Antagonist Binding to the Vasopressin V Receptor in , Ex Vivo, and In Vivo Models of ADPKD.

The pharmacological activity of a small-molecule ligand is linked to its receptor residence time. Therefore, precise control of the duration for which a ligand binds to its receptor is highly desirable. Herein, we designed photoswitchable ligands targeting the vasopressin V receptor (VR), a validated target for autosomal dominant polycystic kidney disease (ADPKD).

Inhibition of S100A8/A9 ameliorates renal interstitial fibrosis in diabetic nephropathy.

Background: Renal interstitial fibrosis (RIF) is one of the main features of diabetic nephropathy (DN), but the molecular mechanisms mediating RIF in DN has yet been fully understood. S100A8 and S100A9 are the proteins associated with immune and inflammation response. Here we reported the expression of S100A8 and S100A9 were significantly increased on tubular epithelial cells in diabetic kidneys through a proteomic analysis.

Discovery of benzimidazole substituted 1, 2, 4-oxadiazole compounds as novel anti-HBV agents with TLR8-agonistic activities.

Hepatitis B virus (HBV) infection is a public health threat worldwide and characterized by a dysfunctional immune response. In the present work, a new series of benzimidazole substituted 1, 2, 4-oxadiazole compounds were designed as immunomodulatory anti-HBV agents. Data showed compound 11o displayed significant in vitro anti-HBV activities against wild-type and nucleos(t)ide analogues-resistant HBV with IC values of 0.

Design and synthesis of novel quinazolinone derivatives as anti-HBV agents with TLR8 agonist effect.

Hepatitis B virus (HBV) infection is a worldwide threat to public health. In this work, a series of novel quinazolinone derivatives (5a-q) were synthesized and evaluated as novel anti-HBV agents. Among them, compound 5l exhibited potent inhibitory effect on HBV DNA replication in both wild type and drug resistant (lamivudine and entecavir) HBV strains with IC values of 0.

Synthesis and Evaluation of Novel Quinazolinone Derivatives as Potential Anti-HCC Agents.

Hepatocellular carcinoma (HCC), a common malignancy worldwide, has a high mortality rate and limited effective therapeutic options. In this work, a series of quinazolinone compounds (6a-t and 7a-i) were synthesized as potential anti-HCC agents. Among them, compound 7b more potently inhibited HepG2, HUH7 and SK-Hep-1 cells proliferation than classical anti-HCC drug sorafenib, indicating its potential anti-HCC effect.

Novel Chalcone BDD-39 Mitigated Diabetic Nephropathy through the Activation of Nrf2/ARE Signaling.

Background: In this study, we investigated the Nrf2/ARE signaling pathway activating capacity of Biphenyl Diester Derivative-39 (BDD-39) in diabetic nephropathy in order to elucidate the mechanism surrounding its antidiabetic potential.

Objectives: Protein expressions of Nrf2, HO-1, NQO-1 and biomarkers of kidney fibrosis were executed after which mRNA levels of Nrf2, HO-1 and NQO-1 were estimated after creating the models following BBD-39 treatment.

Methods: Type 2 diabetes model was established in mice with high-fat diet feeding combined with streptozocin intraperitoneal administration.

Signaling pathways and proteins targeted by antidiabetic chalcones.

Chalcones have shown a broad spectrum of biological activities with clinical potential against various diseases. The biological activities are mainly attributed to the presence of α, β-unsaturated carbonyl system, perceived as potential Michael acceptors. In this review, we discussed the antioxidant potential of chalcones and elucidated the mechanisms of pathways and proteins such as carbohydrate digestive enzymes (α-amylase and α-glucosidase), aldose reductase, SGLT-2, and Nrf2 that are targeted by antidiabetic chalcones.

Assessment of Thiosemicarbazone-Containing Compounds as Potential Antileukemia Agents against P-gp Overexpressing Drug Resistant K562/A02 Cells.

P-Glycoprotein (P-gp) overexpression is considered to be the leading cause of multidrug resistance (MDR) and failure of chemotherapy for leukemia. In this study, seventeen thiosemicarbazone-containing compounds were prepared and evaluated as potential antileukemia agents against drug resistant K562/A02 cell overexpressing P-gp. Among them, N-hydroxy-6-({(2E)-2-[(3-nitrophenyl)methylidene]hydrazinecarbothioyl}amino)hexanamide could significantly inhibit K562/A02 cells proliferation with an IC value of 0.

Synthesis and evaluation of new phenyl acrylamide derivatives as potent non-nucleoside anti-HBV agents.

As a continuation of our previous work, a series of new phenyl acrylamide derivatives (4Aa-g, 4Ba-t, 5 and 6a-c) were designed and synthesized as non-nucleoside anti-HBV agents. Among them, compound 4Bs could potently inhibit HBV DNA replication in wild-type and lamivudine (3TC)/entecavir resistant HBV mutant strains with IC values of 0.19 and 0.

Discovery of thiosemicarbazone-containing compounds with potent anti-proliferation activity against drug-resistant K562/A02 cells.

P-glycoprotein (P-gp)-mediated multidrug resistance (MDR) is a major obstacle to successful chemotherapy for leukemia. In this study, a series of thiosemicarbazone-containing compounds (4a-b, 7a-q) were synthesized. Biological evaluation showed that the most active compound 7e displayed potent anti-leukemia activity against P-gp overexpressing drug-resistant K562/A02 cells, with an IC value of 0.

Discovery of novel quinazolinone derivatives as potential anti-HBV and anti-HCC agents.

As a continuation of earlier works, a series of novel quinazolinone derivatives (5a-s) were synthesized and evaluated for their in vitro anti-HBV and anti-hepatocellular carcinoma cell (HCC) activities. Among them, compounds 5j and 5k exhibited most potent inhibitory effect on HBV DNA replication in both drug sensitive and resistant (lamivudine and entecavir) HBV strains. Interestingly, besides the anti-HBV effect, compound 5k could significantly inhibit the proliferation of HepG2, HUH7 and SK- cells, with IC values of 5.

6H2L, a novel synthetic derivative of bifendate, induces apoptosis in hepatoma cells via mitochondrial and MAPK pathway.

Hepatocellular carcinoma (HCC) is a major cause of cancer-related death worldwide. Our previous study indicated that 6H2L, a novel synthetic bifendate derivative, shows multidrug resistance reversal activity, while its antitumor effect has not been revealed. Here, the potent antitumor effects of 6H2L on hepatoma cells both in vitro and in vivo were investigated.

Correction to: novel biphenyl diester derivative AB-38b inhibits NLRP3 inflammasome through Nrf2 activation in diabetic nephropathy.

Unfortunately, there are some tiny errors in the data for Fig. 1a-c and Fig. 2a-e in the published online paper.

Novel biphenyl diester derivative AB-38b inhibits NLRP3 inflammasome through Nrf2 activation in diabetic nephropathy.

Inflammation reaction mediated by NLRP3 inflammasome and Nrf2-related oxidative stress are vital participants in the development of diabetic nephropathy (DN) and closely associated to kidney fibrosis. Nrf2, a known antioxidative transcription factor, has been reported to activate NLRP3 inflammasome through its downstream factors (HO-1, NQO1, etc.) recently.

A novel compound AB38b attenuates oxidative stress and ECM protein accumulation in kidneys of diabetic mice through modulation of Keap1/Nrf2 signaling.

Extracellular matrix (ECM) deposition following reactive oxygen species (ROS) overproduction has a key role in diabetic nephropathy (DN), thus, antioxidant therapy is considered as a promising strategy for treating DN. Here, we investigated the therapeutic effects of AB38b, a novel synthetic α, β-unsaturated ketone compound, on the oxidative stress (OS) and ECM accumulation in type 2 diabetes mice, and tried to clarify the mechanisms underlying the effects in high glucose (HG, 30 mM)-treated mouse glomerular mesangial cells (GMCs). Type 2 diabetes model was established in mice with high-fat diet feeding combined with streptozocin intraperitoneal administration.

Synthesis and assessment of phenylacrylamide derivatives as potential anti-oxidant and anti-inflammatory agents.

Oxidative stress and inflammation are major causes of numerous life-threatening human diseases. In the present study, we synthesized a series of phenylacrylamide derivatives as novel anti-oxidant and anti-inflammatory agents. Biological evaluation showed that compound 6a could more potently protect HBZY-1 mesangial cells from HO-caused oxidative stress than positive controls resveratrol and sulforaphane by dose- and time-dependently impairing the ROS accumulation.

Assessment of quinazolinone derivatives as novel non-nucleoside hepatitis B virus inhibitors.

Hepatitis B virus (HBV) infection is a worldwide public health issue. Search for novel non-nucleoside anti-HBV agents is of great importance. In the present study, a series of quinazolinones derivatives (4a-t and 5a-f) were synthesized and evaluated as novel anti-HBV agents.

Assessment of a bifendate derivative bearing a 6,7-dihydro-dibenzo[,]azepine scaffold as a potential anti-metastatic agent.

Multidrug resistance (MDR) and metastasis are major causes of mortality in patients with cancer. We recently reported a bifendate derivative bearing a dibenzo[,]azepine scaffold () as a P-gp and BCRP-medicated MDR reversal agent. As a continuation of the previous research, its ability to inhibit cancer metastasis was investigated in MDA-MB-231 cells in the present work.