Chemical Biology & Drug Design最新文献

Hepatocellular carcinoma (HCC) is the sixth most prevalent malignant tumor. Hepatocellular carcinogenesis is closely linked to apoptosis, autophagy, and inflammation. Diosmetin and chrysin, are two flavonoid compounds, exhibit anti-inflammatory and anticancer properties. In this study, the TCGA database was utilized to identify differentially expressed genes between normal subjects and HCC patients. Molecular docking and molecular dynamics analyses were employed to assess the binding affinity of chrysin and diosmetin to key proteins in the PI3K/AKT/mTOR/NF-κB signaling pathway. Western blotting and RT-qPCR were used to measure the protein and gene expression within this pathway. The results indicated that HCC patients had elevated levels of PI3K, AKT, mTOR, and P65 proteins compared to normal subjects, which adversely affected patient survival. Molecular docking and dynamics studies demonstrated that diosmetin and chrysin are effectively bound to these four proteins. In vitro experiments revealed that the combination of diosmetin and chrysin could induce apoptosis, enhance autophagy, reduce inflammatory mediator production, and improve the tumor cell microenvironment by inhibiting the PI3K/AKT/mTOR/NF-κB signaling pathway. Notably, the synergy score for the combination of diosmetin (25 μM) and chrysin (10 μM) was 16. Thus, the diosmetin–chrysin combination shows promise as an effective therapeutic approach for hepatocellular carcinoma due to its strong synergistic effect.

Splicing modulation by a small compound offers therapeutic potential for diseases caused by splicing abnormality. However, only a few classes of compounds that can modulate splicing have been identified. We previously identified BAY61-3606, a multiple kinase inhibitor, as a compound that relaxes the splicing fidelity at the 3′ splice site recognition. We have also reported the synthesis of derivatives of BAY61-3606. In this study, we tested those compounds for their splicing modulation capabilities and identified two contrasting compounds. These compounds were further investigated for their effects on the whole transcriptome, and analysis of changes in transcription and splicing revealed that the highly active derivative in the splicing reporter assay also showed significantly higher activity in modulating the splicing of endogenously expressed genes. Particularly, cassette exon inclusion was highly upregulated by this compound, and clustering analysis revealed that these effects resembled those in splicing factor 3b subunit 1 (SF3B1) K700E mutant cells but contrasted with those of the splicing inhibitor H3B-8800. Additionally, a group of serine/arginine-rich (SR) protein genes was identified as representatively affected, likely via modulation of poison exon inclusion. This finding could guide further analysis of the mode of action of these compounds on splicing, which could be valuable for developing drugs for diseases associated with splicing abnormalities.

Preliminary ab initio calculations led to the synthesis of novel substituted thiazolium salts, analogs of Alagebrium, which were further explored in vitro for their potential as inhibitors of the glycation reaction utilizing three distinct assays: inhibition of fluorescent AGEs formation, anticrosslinking, and deglycation. Despite the unidirectionality of the assays, distinct differences were observed in the mechanisms of interference and activity manifestation by the compounds. The gathered data permitted the formation of hypotheses about the molecular fragments of the studied antiglycators that are of utmost significance in each assay, thereby guiding future design endeavors. Potential mechanisms of actions are discussed therein. The compound 4-meth-yl-3-[2-(4-methylbiphenyl-4-yl)-2-oxoethyl] thiazolium bromide displayed high activity across all three assays, establishing it as a lead compound. The cytotoxicological properties of the compounds were evaluated using LDH and MTT assays. However, the lead compound exhibited cytotoxicity, indicating the need for additional investigations aimed at decreasing toxicity while maintaining activity. The targeted thiazolium salts were synthesized through an N-alkylation reaction between the corresponding thiazoles and phenacyl bromides.

Novel benzophenone–thiazole hybrids with different substituents were synthesized and evaluated for anti-inflammatory activity using an ex vivo human whole-blood assay. All hybrids (3c and 5a–h) showed significant anti-inflammatory activity via prostaglandin E2 (PGE2) release inhibition. Moreover, 5c (82.8% of PGE2 inhibition), 5e (83.1% of PGE2 inhibition), and 5h (82.1% of PGE2 inhibition) were comparable to the reference drugs. Molecular docking revealed potential preferable binding to the active sites of cyclooxygenase 2 (COX-2) and microsomal prostaglandin E synthase-1 (mPGES-1) enzymes. This study provides the first evidence that benzophenone–thiazole hybrids may also dock in mPGES-1, a new attractive anti-inflammatory drug target, besides providing promising ex vivo anti-inflammatory activity. Thus, the novel hybrids are promising anti-inflammatory lead compounds and highlight the significance of optimal substituent selection in the design of potent PGE2 inhibitors.

Guided by the idea that the presence of a heterocyclic aromatic core and tyramine moiety, under the umbrella of a single molecular scaffold could bring interesting biological properties, herein we present synthesis, characterization, with two crystal structures reported, and biological evaluation of some tyramine derivates. Cytotoxic and antimigratory potential was addressed by using a colorectal cancer cell line as a model system. Although possessing no cytotoxic effects, two compounds have shown strong antimigratory potential in low doses, with no effect on healthy MRC-5 cells. Evaluation of their antimicrobial activities suggested prominent antimicrobial activity, where Compound 4 outperformed streptomycin against Escherichia coli and Proteus mirabilis. Hormone-dependent types of cancer, such as prostate, ovary, and breast, are highly dependent on human sex hormone–binding globulin (SHBG) blood levels. A molecular docking study has shown that 1 has high affinity to bind and therefore compete with natural steroids for the SHBG steroid-binding site. DNA-binding study have shown that 4 interacts with CT-DNA in a groove-binding mode. In silico ADME/T study revealed that all compounds have suitable physicochemical properties for oral bioavailability and druglikeness, while toxicity tests for 1, 4, and 6 suggested potential for mutagenicity (4, 6), hepatotoxicity (6), and skin sensation (1).

As a key molecule for improving cardiovascular diseases, Apelin-13 was surveyed in this work to explain its actions in controlling inflammation, pyroptosis, and myocardial hypertrophy. First, mouse models with myocardial hypertrophy were established. Then, assessments were made on the pathological variation in the heart of mouse, on the cardiac functions, as well as on the expressions of cardiac hypertrophy markers (β-MHC, ANP, and BNP), inflammatory factors (TNF-α, COX2, IL-6, ICAM-1, and VCAM-1), myocardial cell pyroptosis markers (NLRP3, ASC, c-caspase-1, and GSDMD-N), and Hippo pathway proteins (p-YAP, YAP, LATS1, and p-LATS1) by HE staining, echocardiography scanning, and western blot tests separately. The expressions of such inflammatory factors as in myocardial tissue were acquired by ELISA. After inducing the phenotype of H9c2 cell hypertrophy by noradrenaline, we used CCK-8 kits to know about the activity of H9c2 cells treated with Apelin-13, and performed ɑ-actinin staining to measure the changes in volumes of such cells. As unraveled through this work, Apelin-13 refrained the activation of the Hippo pathway, which in turn attenuated the hypertrophy, inflammation, and pyroptosis of myocardial tissue and H9c2 cells. Hence, Apelin-13 can be considered as a target for hypertension treatment.

Apitherapy has started to gain tremendous recognition because of extraordinary pharmacological importance of honeybee-related ingredients and their derivatives. There has been a renewed interest in the bee venom–based therapies. Interdisciplinary researchers are studying the chemistry and translational value of venom for effective cancer treatment. Bee venom and its major component, melittin, are cytotoxic in cancer cells. In this study, MTT and scratch assays were performed for analysis of melittin-mediated antimetastatic effects. QPCR was used for expression profiling of metastasis-related genes. Three anti-metastatic genes (BRMS1, DRG1, and KAI1/CD82) were studied for the first time after bee venom and melittin treatment in MDA-MB-231 breast cancer cells compared with normal breast cells, and two prometastatic genes (EGFR and WNT7B) were also examined. KAI1/CD82 and BRMS1 are the negative regulators of EGFR. WNT7B is a negative regulator of KAI1/CD82. Selective cytotoxicity of bee venom and melittin was found to be higher as compared to cisplatin. Melittin induced an increase in the expression of BRMS1 and DRG1, whereas bee venom upregulated DRG1 and KAI1/CD82 expression in breast cancer. WNT7B was downregulated in bee venom–treated breast cancer cells. Results suggested that bee venom/melittin exerted antimetastatic effects primarily through upregulation of BRMS1, DRG1, and KAI1/CD82, and downregulation of WNT7B.

Misfolding and aggregation of TAR DNA-binding protein, TDP-43, is linked to devastating proteinopathies such as ALS. Therefore, targeting TDP-43's aggregation is significant for therapeutics. Recently, green tea polyphenol, EGCG, was observed to promote non-toxic TDP-43 oligomer formation disallowing TDP-43 aggregation. Here, we investigated if the anti-aggregation effect of EGCG is mediated via EGCG's binding to TDP-43. In silico molecular docking and molecular dynamics (MD) simulation suggest a strong binding of EGCG with TDP-43's aggregation-prone C-terminal domain (CTD). Three replicas, each having 800 ns MD simulation of the EGCG-TDP-43-CTD complex, yielded a high negative binding free energy (ΔG) inferring a stable complex formation. Simulation snapshots show that EGCG forms close and long-lasting contacts with TDP-43's Phe-313 and Ala-341 residues, which were previously identified for monomer recruitment in CTD's aggregation. Notably, stable physical interactions between TDP-43 and EGCG were also detected in vitro using TTC staining and isothermal titration calorimetry which revealed a high-affinity binding site of EGCG on TDP-43 (K_d, 7.8 μM; ΔG, −6.9 kcal/mol). Additionally, TDP-43 co-incubated with EGCG was non-cytotoxic when added to HEK293 cells. In summary, EGCG's binding to TDP-43 and blocking of residues important for aggregation can be a possible mechanism of its anti-aggregation effects on TDP-43.

Alzheimer's disease (AD) is a chronic progressive, age-related neurodegenerative brain disorder characterized by the irreversible decline of memory and other cognitive functions. It is one of the major health threat of the 21st century, which affects around 60% of the population over the age of 60 years. The problem of this disease is even more major because the existing pharmacotherapies only provide symptomatic relief without addressing the basic factors of the disease. It is characterized by the extracellular deposition of amyloid β (Aβ) to form senile plaques, and the intracellular hyperphosphorylation of tau to form neurofibrillary tangles (NFTs). Due to the complex pathophysiology of this disease, various hypotheses have been proposed, including the cholinergic, Aβ, tau, oxidative stress, and the metal–ion hypothesis. Among these, the cholinergic and Aβ hypotheses are the primary targets for addressing AD. Therefore, continuous advances have been made in developing potential cholinesterase inhibitors and N-methyl-D-aspartate (NMDA) receptor antagonists to delay disease progression and restore cholinergic neurotransmission. In this review article, we tried to comprehensively summarize the recent advancement in NMDA receptor antagonist (memantine) and their hybrid analogs as potential disease-modifying agents for the treatment of AD. Furthermore, we also depicted the design, rationale, and SAR analysis of the memantine-based hybrids used in the last decade for the treatment of AD.