A Novel Class of Multi-substituted Diaryl Scaffold Derivatives Inhibit Glioblastoma Progression by Targeting CD155.

Glioblastoma (GBM) is the most formidable malignancy in the brain, characterized by a significant resistance to treatment. The immune targeting of glioblastoma stem cells (GSCs) holds great promise. In this study, structural modifications of the lead compound clofoctol is conducted and structure-activity relationship analyses are performed against GBM, yielding a novel blood-brain barrier-permeable compound, B7, featuring a pivotal multi-substituted diaryl scaffold.

Adipocyte-derived glutathione promotes obesity-related breast cancer by regulating the SCARB2-ARF1-mTORC1 complex.

Obesity is a major risk factor for poor breast cancer outcomes, but the impact of obesity-induced tumor microenvironment (TME) metabolites on breast cancer growth and metastasis remains unclear. Here, we performed TME metabolomic analysis in high-fat diet (HFD) mouse models and found that glutathione (GSH) levels were elevated in the TME of obesity-accelerated breast cancer. The deletion of glutamate-cysteine ligase catalytic subunit (GCLC), the rate-limiting enzyme in GSH biosynthesis, in adipocytes but not tumor cells reduced obesity-related tumor progression.

Substituted indole derivatives as UNC-51-like kinase 1 inhibitors: Design, synthesis and anti-hepatocellular carcinoma activity.

The five-year survival rate for patients with hepatocellular carcinoma (HCC) is only 20 %, highlighting the urgent need to identify new therapeutic targets and develop potential therapeutic options to improve patient prognosis. One promising approach is inhibiting autophagy as a strategy for HCC treatment. In this study, we established a virtual docking conformation of the autophagy promoter ULK1 binding XST-14 derivatives.

Osteoporosis: Emerging targets on the classical signaling pathways of bone formation.

Osteoporosis is a multifaceted skeletal disorder characterized by reduced bone mass and structural deterioration, posing a significant public health challenge, particularly in the elderly population. Treatment strategies for osteoporosis primarily focus on inhibiting bone resorption and promoting bone formation. However, the effectiveness and limitations of current therapeutic approaches underscore the need for innovative methods.

Design and synthesis of dabigatran etexilate derivatives with inhibiting thrombin activity for hepatocellular carcinoma treatment.

Hepatocellular carcinoma (HCC) is one of the most fatal solid malignancies worldwide. Evidence suggests that thrombin stimulates tumor progression via fibrin formation and platelet activation. Meanwhile, we also found a correlation between thrombin and HCC through bioinformatics analysis.

Efficacy, Mechanism, and Structure-Activity Relationship of 6-Methoxy Benzofuran Derivatives as a Useful Tool for Senile Osteoporosis.

Most patients with senile osteoporosis (SOP) are severely deficient in bone mass, and treatments using bone resorption inhibitors, such as bisphosphonates, have shown limited efficacy. Small-molecule osteogenesis-promoting drugs are required to improve the treatment for this disease. Previously, we demonstrated that a compound with a benzofuran-like structure promoted bone formation by upregulating BMP-2, and it exhibited a therapeutic effect in SAMP-6 mice, glucocorticoid-induced osteoporosis rats, and ovariectomized rats.

Structure-based virtual screening identified novel FOXM1 inhibitors as the lead compounds for ovarian cancer.

Ovarian cancer (OC) is a gynecological tumor with possibly the worst prognosis, its 5-year survival rate being only 47.4%. The first line of therapy prescribed is chemotherapy consisting of platinum and paclitaxel.

Synthesis and anti-ovarian cancer effects of benzimidazole-2-substituted pyridine and phenyl propenone derivatives.

Given the benzimidazole derivatives have anti-ovarian cancer effects, the authors aimed to determine whether benzimidazole-2-substituted pyridine and phenyl propenone derivatives exert anti-ovarian cancer activity. 21 derivatives were synthesized and assayed for their antiproliferative activities. Western blotting in A2780 cells was used to detect the effects of compound A-6 on apoptosis-related proteins.

Small molecule targeting FOXM1 DNA binding domain exhibits anti-tumor activity in ovarian cancer.

FOXM1 is a potent oncogenic transcription factor essential for cancer initiation, progression, and drug resistance. FOXM1 regulatory network is a major predictor of adverse outcomes in various human cancers. Inhibition of FOXM1 transcription factor function is a potential strategy in cancer treatment.

Structure-based virtual screening towards the discovery of novel FOXM1 inhibitors.

Given the importance of FOXM1 in the treatment of ovarian cancer, we aimed to identify an excellent specific inhibitor and examined its underlying therapeutic effect. The binding statistics for FDI-6 with FOXM1 were calculated through computer-aided drug design. We selected XST-119 through virtual screening, performed surface plasmon resonance and cell antiproliferative activity analysis and evaluated its antitumor efficacy in a mouse model.

Synthesis and Bioactivity of -(4-Chlorophenyl)-4-Methoxy-3-(Methylamino) Benzamide as a Potential Anti-HBV Agent.

Introduction: Hepatitis B virus (HBV) is a global health concern that can cause acute and chronic liver diseases. Thus, there is an urgent need to research novel anti-HBV agents. Our previous reports show that -phenylbenzamide derivatives exert broad-spectrum antiviral effects against HIV-1, HCV, and EV71 by increasing intracellular levels of APOBEC3G (A3G).

Substituted benzothiophene and benzofuran derivatives as a novel class of bone morphogenetic Protein-2 upregulators: Synthesis, anti-osteoporosis efficacies in ovariectomized rats and a zebrafish model, and ADME properties.

The bone morphogenetic protein (BMP) pathway is a promising new target for the design of therapeutic agents for the treatment of low bone mass. This study optimized the structure of the anti-osteoporosis compound 38 by balancing its lipophilicity and improving its stability. Twenty derivatives which were not reported in the literature were designed and synthesized.

The role of the key autophagy kinase ULK1 in hepatocellular carcinoma and its validation as a treatment target.

Although macroautophagy/autophagy is involved in hepatocellular carcinoma (HCC) initiation and development and has been identified as a mechanism of HCC therapy resistance, the role of ULK1 (unc-51 like autophagy activating kinase 1) in HCC remains unclear. Here, we report that both knockdown and knockout of inhibited human HCC cell proliferation and invasion, and deletion abrogated tumor growth in a xenograft mouse model. Furthermore, ablation in combination with sorafenib significantly inhibited HCC progression compared with sorafenib treatment alone or vehicle control.

Novel cathepsin K inhibitors block osteoclasts and increase spinal bone density in zebrafish.

Cathepsin K (Cat K) is a predominant cysteine protease and highly potent collagenase expressed in osteoclasts. Cat K inhibitors are anti-resorptive agents to treat osteoporosis. A novel scaffold of cathepsin K inhibitors, exemplified by lead compound 1x, was used as the template for designing and synthesizing a total of 61 derivatives that have not been reported before.

Synthesis of a novel class of substituted benzothiophene or benzofuran derivatives as BMP-2 up-regulators and evaluation of the BMP-2-up-regulating effects in vitro and the effects on glucocorticoid-induced osteoporosis in rats.

The BMP pathway is a promising new target for the design of therapeutic agents for the treatment of low bone mass. To enrich our understanding of SAR and based on our previously concluded structure-effect relationship, 23 derivatives were prepared in this work. The synthesis, up-regulating activities on BMP-2 expression, and bone loss prevention efficacies of these compounds in rats with glucocorticoid-induced osteoporosis are presented.

Design, synthesis and antiproliferative activity of a novel class of indole-2-carboxylate derivatives.

Based on the chemical structure of Pyrroloquinoline quinone (PQQ), a novel class of indole-2-carboxylate derivatives was designed, synthesized and assayed for antiproliferative activity in cancer cells in vitro. The biological results showed that some derivatives exhibited significant antiproliferative activity against HepG2, A549 and MCF7 cells. Notably, the novel compounds, methyl 6-amino-4-cyclohexylmethoxy-1H-indole-2-carboxylate (6e) and methyl 4-isopropoxy-6-methoxy-1H-indole-2-carboxylate (9l) exhibited more potent antiproliferative activity than the reference drugs PQQ and etoposide in vitro, with IC50 values ranging from 3.

Design, synthesis and in vitro and in vivo antitumour activity of 3-benzylideneindolin-2-one derivatives, a novel class of small-molecule inhibitors of the MDM2-p53 interaction.

A novel class of small-molecule inhibitors of MDM2-p53 interaction with a (E)-3-benzylideneindolin-2-one scaffold was identified using an integrated virtual screening strategy that combined both pharmacophore- and structure-based approaches. The hit optimisation identified several compounds with more potent activity than the hit compound and the positive drug nutlin-3a, especially compound 1b, which exhibited both the highest binding affinity to MDM2 (Ki = 0.093 μM) and the most potent antiproliferative activity against HCT116 (wild type p53) cells (GI50 = 13.

Synthesis and anti-influenza virus activities of a novel class of gastrodin derivatives.

A series of substituted aryl glycoside analogues of gastrodin have been identified as potential anti-influenza agents. The most potent inhibitor 1a exhibited moderate inhibitory activity against the A/Hanfang/359/95(H3N2) and A/FM/1/47(H1N1) strains of the influenza A virus (IC(50) values of 44.40 and 34.

Synthesis and antiviral activities of synthetic glutarimide derivatives.

A series of novel glutarimide compounds were synthesized and their antiviral activities were evaluated. The compounds displaying the strongest antiviral activities included 5, 6f, 7e and 9 against coxsackievirus B3 (Cox B3), 10 and 6f against influenza virus A (influenza A) and 7a against herpes simplex virus 2 (HSV-2). However, most of the synthetic glutarimides showed comparatively much weaker activity against influenza A, Cox B3 and HSV-2 than the natural glutarimide compounds tested.

Substituted benzothiophene or benzofuran derivatives as a novel class of bone morphogenetic protein-2 up-regulators: synthesis, structure-activity relationships, and preventive bone loss efficacies in senescence accelerated mice (SAMP6) and ovariectomized rats.

In this work, substituted benzothiophene and benzofuran compounds were found to be a new class of potential anabolic agents by enhancing BMP-2 expression. A series of benzothiophene and benzofuran derivatives have been synthesized, and their activities of up-regulating BMP-2 and bone loss prevention efficacies in SAMP6 mice and OVX rats have been studied. Benzothiophenes 1, 3, 14, 4a, 7a, 8a, and benzofuran analogue 2 showed higher BMP-2 up-regulation rates in vitro.