Chemical Biology & Drug Design最新文献

Fibroblast Activation Protein (FAP) is highly expressed in the tumor microenvironment, promoting cancer growth and spread. FAP inhibitors (FAPIs) labeled with radionuclides are increasingly used for cancer diagnosis and therapy. The present study aims to explore how structural features relate to the inhibitory action of radiopharmaceuticals, representing a novel approach in the field of radiopharmacy. The 2D-QSAR using multiple linear regression analysis via the stepwise variable selection method showed promising results for both internal and external predictive ability of the model (R²_train = 0.877, Q²_LOO = 0.830, pred_R² = 0.740). This analysis based on the genetic algorithm was also robust (R²_train = 0.846, Q²_LOO = 0.768, pred_R² = 0.608). A 3D-QSAR model using partial least squares analysis showed better parametric results for CoMFA descriptors (R² = 0.988, Q²_LOO = 0.518 and pred_R² = 0.642) than the CoMSIA model as well. Our findings revealed that the steric, hydrophobic, and hydrogen-bonding properties notably impact the pIC₅₀ values of FAPI radiopharmaceuticals. Based on virtual screening on the FDA-approved drugs, 23 potential inhibitors of the FAP enzyme were identified. To the best of our knowledge, this is the first QSAR study on radiopharmaceuticals with FAP inhibitory action, the results of which can be helpful in designing more potent ones.

The antioxidant and enzyme inhibition properties of the isoflavone genistein (1) and the alkaloid 11-α-hydroxyerysotrine (2) isolated from the leaves of Erythrina speciosa were assessed. Both compounds exhibited notable in vitro antioxidant activities; 11-α-hydroxyerysotrine (2) demonstrated stronger effects than genistein in DPPH, ABTS, CUPRAC, and FRAP assays. On the other hand, genistein (1) demonstrated a higher metal chelating activity than 11-α-hydroxyerysotrine (2). Regarding enzyme inhibition, 11-α-hydroxyerysotrine (2) inhibited both acetyl- (AchE) and butyryl- (BchE) cholinesterases, though to a lesser extent than the standard drug galanthamine. Both compounds inhibited tyrosinase, yet a good inhibition was observed for 11-α-hydroxyerysotrine (2) as compared to genistein (1). Genistein (1) showed a lower α-amylase inhibition effect (IC₅₀: 3.43 mg/mL, p < 0.05) compared to the standard acarbose (IC₅₀: 0.80 mg/mL). Regarding α-glucosidase inhibition, genistein (1) (IC₅₀: 1.02 mg/mL, p < 0.05) was more active than acarbose (IC₅₀: 1.78 mg/mL). 11-α-Hydroxyerysotrine (2) exhibited lower α-amylase (IC₅₀: 4.09 mg/mL) and α-glucosidase (IC₅₀: 4.48 mg/mL) inhibition effects. The in vitro biological results were further supported by network pharmacology approaches on Alzheimer's disease and in silico studies performed on AChE, BChE, tyrosinase, α-amylase, and β-glucosidase enzymes. The results of our study suggest 11-α-hydroxyerysotrine as a potential drug candidate for further investigation in managing oxidative stress-related conditions, Alzheimer's disease, and hyperpigmentation disorders.

Verbascum L., a member of the Scrophulariaceae family, is the second-largest genus in Turkish flora. It is represented by over 250 species, many of which have been used as folk medicine. This study aims to determine the cholinesterase inhibitory potential of secondary metabolites of Verbascum uschakense (Murb.) Hub.-Mor, an endemic species to Türkiye that has not been studied phytochemically before. Gluroside, an iridoid glucoside, was isolated from V. uschakense through acetylcholinesterase (AChE) inhibitory activity-guided fractionation alongside four other iridoid glucosides: ajugol, harpagide, aucubin, and catalpol. Additionally, three phenylethanoid glycosides—verbascoside, martinoside, and forsythoside B—were isolated from the antioxidant fractions evaluated using DPPH radical scavenging activity. Gluroside emerged as the most active compound against butyrylcholinesterase (BChE) with an IC₅₀ of 2.5 ± 0.02 μg/mL, exhibiting selectivity over AChE (37.69% inhibition at 200 μg/mL). Molecular modeling predicted strong electrostatic interactions between the glucosides and the catalytic residues of BChE. This is the first report of the isolation of gluroside from a Verbascum species and its cholinesterase inhibitory activity, underpinning the importance of V. uschakense and its secondary metabolites as a new class of cholinesterase inhibitors.

Diabetic retinopathy (DR) remains a major cause of vision loss among working-age individuals, significantly impairing quality of life in diabetic patients. While no definitive cure exists, Procyanidin (PRO), a polyphenolic compound, has shown potential in mitigating diabetes-related complications. However, its mechanism of action in DR remains poorly understood. To explore this, we established an in vitro high glucose (HG) model using human retinal microvascular endothelial cells (hRMECs) and an in vivo diabetic rat model. Cells were cultured in normal glucose (NG, 5 mM) or HG (30 mM) for 48 h, followed by PRO treatment. Techniques including qRT-PCR, Western blotting, flow cytometry, histological staining, Transwell, tube formation, chromatin immunoprecipitation (ChIP), and dual-luciferase assays were employed. PRO treatment conferred protection against DR; however, this effect was reversed upon knockdown of activating transcription factor 1 (ATF1). Mechanistically, ATF1 enhanced transcription of synoviolin 1 (SYVN1), promoting HMGB1 degradation via ubiquitination and suppressing the HMGB1/toll-like receptor 4 (TLR4) signaling pathway. Findings from the in vitro model were validated in vivo. In conclusion, PRO alleviates DR by regulating the ATF1/SYVN1/HMGB1 axis and inhibiting pro-inflammatory signaling. These results provide novel insights into the molecular mechanism of PRO's protective role in DR and support its therapeutic potential.

Oligomycin A, initially identified as a macrolide antibiotic and a mitochondrial ATP synthase inhibitor, has recently transitioned from a laboratory tool to a multifaceted agent with promising therapeutic and industrial applications. Its irreversible inhibition of the F₀ subunit interrupts ATP synthesis and informs about metabolic susceptibilities in neoplastic cells, such as the Warburg effect and reversal of multidrug resistance by P-glycoprotein inhibition. Guided by structural studies of its interaction with the c10-ring of ATP synthase, analogs like bedaquiline were rationally designed as antibacterial candidates, and the analog spiropiperidine derivatives were inspired by improving ischemia–reperfusion injury. Although this derivative has great potential, clinical translation is limited by systemic toxicity, poor solubility, and environmental persistence. Emerging approaches like PEGylation and combination therapies (e.g., with docetaxel) have started to address selectivity and off-target effects. There are still challenges in balancing efficacy, safety, and environmental impact. This review summarizes the current knowledge and mechanisms of action of oligomycin A and its derivatives that should be of interest in the design of bioactive agents with potential therapeutic applications. This is intended to serve as a motivator for moving forward with future research avenues toward optimizing Oligomycin A-based therapeutics to derive as much of the potential benefit as possible while mitigating the harms associated.

Gestational diabetes mellitus (GDM) is a common pregnancy complication that leads to insulin resistance (IR) and adversely affects both maternal and fetal health. Kisspeptin-10 (Kp-10), a peptide acting via G Protein-Coupled Receptor 54 (Gpr54), has shown potential in modulating insulin secretion, but its role in GDM remains unclear. This study explores Kp-10's therapeutic effects on GDM by targeting IR in placental tissues. We used GDM rat models (induced by a high-fat diet and streptozotocin) and high-glucose-treated HTR8/SVneo trophoblast cells to investigate Kp-10's effects on glucose metabolism, insulin signaling, and the cAMP/PKA pathway. Our results show that Gpr54 expression was significantly downregulated in the placental tissues of GDM rats, which was associated with impaired glucose uptake and IR. Kp-10 treatment improved fasting blood glucose (FBG) levels, insulin sensitivity, and fetal outcomes, including increased fetal weight and decreased fetal blood glucose. Moreover, Kp-10 restored the cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA) signaling pathway and enhanced glucose uptake by upregulating Glut-4, Insr, and Irs1 expression in both placental tissues and HTR8/SVneo cells. The effects of Kp-10 were reversed by the cAMP inhibitor SQ22536, confirming the involvement of the cAMP/PKA pathway in its anti-IR effects. Our findings suggest that Kp-10 has the potential as a therapeutic agent for alleviating IR in GDM and improving maternal–fetal outcomes.

A novel series of triazole-linked indole derivatives was designed, synthesized, and evaluated as soluble epoxide hydrolase inhibitors (sEHIs) for their potential anticancer activity. These compounds exhibit strong binding affinity within the hydrophobic pockets of sEH, with compounds 9a and 9b emerging as the most potent inhibitors, achieving IC₅₀ values of 0.270 ± 0.014 nM and 0.358 ± 0.03 nM, respectively, in vitro. In addition, both compounds display significant cytotoxic activity against HeLa cells, with IC₅₀ values of 5.366 ± 0.91 μM and 5.686 ± 0.73 μM, respectively. Molecular docking studies, using the 1ZD5 crystal structure, reveal key hydrogen bond interactions analogous to those observed with 12-(3-adamantan-1-yl-ureido)-dodecanoic acid (AUDA), providing mechanistic insights into their inhibitory activity. Structure–activity relationship (SAR) analysis further informs the rational optimization of these derivatives for enhanced potency. Overall, these findings highlight triazole-linked indole derivatives as promising lead candidates for the development of sEH-targeted anticancer therapeutics.