Drug Development Research最新文献

Metal-based complexes have greatly advanced anticancer therapy, but limitations of traditional drugs like cisplatin have driven the search for more stable and targeted metallodrugs. In this study, two novel Ir(III) complexes, PNIC and PNIT, incorporating a rigid Schiff base ligand (PNN) derived from 1,10-phenanthroline-5,6-dione and N,N-bis(4-formylphenyl)-N, N-diphenylbenzidine, were synthesized and characterized by NMR, FT-IR, HRMS, and UV–Vis spectroscopy. Both complexes exhibited large Stokes shifts (60 and 47 nm), high stability in GSH and PBS, and strong binding affinity toward DNA and HSA through hydrophobic and hydrogen bonding interactions. They also exhibited notable antioxidant activity and potent cytotoxicity against A549 lung cancer cells, with IC₅₀ values of 19.69 µM for PNIC and 16.86 µM for PNIT, and good selectivity toward normal HEK293 cells (SI = 10.5 and 13.6, respectively). These findings highlight the potential of both PNIC and PNIT as multifunctional Ir(III)-based anticancer candidates possessing excellent bio-stability and target selectivity.

Among multiple complications of Kawasaki disease (KD), coronary artery lesions (CALs) emerge as the clinically paramount concern. Aspirin therapy can reduce the incidence of KD with CAL, yet its mechanism remains unclear. This study principally investigated the mechanism by which aspirin is effective in treating KD with CAL. Peripheral blood samples from healthy, KD, and KD + CAL children were analyzed using RT-qPCR, western blot, and ELISA to assess the levels of TNF receptor associated factor 6 (TRAF6), signal transducer and activator of transcription 3 (STAT3), and Th17 cells. Spleen CD4⁺ T cells extracted from mouse were initially activated and subsequently differentiated into Th17 cells for subsequent experiments. After aspirin treatment and the downregulation of TRAF6, IF, ELISA, western blot, and RT-qPCR assessed Th17 differentiation and TRAF6/STAT3 expression. Conversely, the effects of TRAF6 overexpression coupled with MG132 treatment on STAT3 expression were evaluated using RT-qPCR and western blot. Additionally, IP and IF assays were conducted to detect the interaction and ubiquitination modifications between TRAF6 and STAT3. The STRING online tool predicted the interacting proteins of TRAF6, which were then validated through cell experiments. In KD with CAL children, elevated Th17 cell count, reduced TRAF6 expression, and heightened STAT3 expression were observed in the peripheral blood. In cell experiments, aspirin boosted TRAF6 expression, downregulated STAT3, inhibited Th17 differentiation. Dampening TRAF6 expression in cells reversed the impact of aspirin. TRAF6 facilitated the ubiquitination of STAT3, triggering its protein degradation, while UBE2N interacted with TRAF6 to modulate STAT3 expression. This study found that aspirin upregulates TRAF6 to ubiquitinate STAT3, inhibiting Th17 differentiation and improving KD with CAL.

Angelicin (AGN), an angular furocoumarin, exhibits notable anti-inflammatory and biological activities. However, its potential for managing pain and diarrhea, and the underlying mechanisms, remain poorly explored. This study aimed to investigate the analgesic and antidiarrheal properties of AGN and elucidate its possible mechanisms of action through in vivo and in silico approaches. Mice received AGN (2.5, 5, and 10 mg/kg, i.p), DFS (25 mg/kg, p.o), LOP (3 mg/kg p.o), and BSS (10 mg/kg, p.o), after 30 min of administration, for an analgesic test; 0.7% acetic acid at 10 mL/kg (i.p) induced writhing, observed latency, and number of writhing. Antidiarrheal activity was assessed by using castor oil (0.5 mL, p.o) induced diarrhea in mice, observing latency and number of diarrhea secretions over 3 h. Additionally, Molecular docking studies were performed to analyze AGN's interactions with cyclooxygenase (COX-1/2) enzymes and the µ-opioid receptor (MOR). Drug-likeness and toxicity profiles were predicted using SwissADME and ProTox-III. AGN demonstrated significant, dose-dependent analgesic and antidiarrheal effects. Its combination with standard drugs (DFS, LOP, BSS) showed enhanced efficacy. Molecular docking revealed strong binding affinities of AGN for COX-1 (−7.4 kcal/mol), COX-2 (−8.0 kcal/mol), and MOR (−7.1 kcal/mol). Pharmacokinetic predictions indicated good drug-likeness, and toxicity profiling suggested a favorable safety margin. These results strongly suggest that AGN is a promising dual-action therapeutic candidate for pain and diarrhea, likely mediated through COX inhibition and MOR interaction. Further studies are warranted to validate these mechanisms and develop optimized AGN-based formulations for clinical translation.

The unique physicochemical and structural flexibility of ionic liquids (ILs) allows for fine modulation of biological activity, thus offering potential as the next-generation anticancer lead compounds with improved selectivity and efficacy. In this study, a new series of benzyl functionalised imidazolium ILs with varying para substituents (R = H, CH₃, F, Cl, Br, NO₂, CN) is reported. Their cytotoxicity against human neuroblastoma (SHSY-5Y), estrogen-positive breast cancer cells (MCF-7), neuroblastoma (SHSY-5Y), lung carcinoma (A549), liver cancer cells (HepG2), colorectal adenocarcinoma (HT-29), and mouse embryonic fibroblasts (NIH 3T3) was evaluated. The ILs were cytotoxic against all tested cell lines but were generally more selective toward MCF-7. ILs bearing H, CH₃, F, Cl, and Br exhibited similar growth inhibition strength against MCF-7 (IC₅₀ ranged between 3.99 and 5.20 µM) that was superior to that of tamoxifen (IC₅₀ = 15.41 µM). However, the presence of NO₂ (IC₅₀ = 8.10 µM) and CN (IC₅₀ = 17.52 µM) significantly reduced their growth inhibition potentials (two- to four-fold) in NIH 3T3 (IC₅₀ > 40 µM). The NO₂-containing IL had a broad safety window against MCF-7 (selectivity index > 4). All the ILs have high drug-likeness (complied with all criteria stated in Lipinski's rule of five and Veber's rule). The most selective IL against MCF-7 (R = NO₂) induced caspase-dependent but reactive oxygen species independent pro-apoptosis in MCF-7 cells. Substituent modifications in the benzyl group regulated cytotoxicity and selectivity, thus reinforcing ILs as a valuable platform for the development of a new class of effective anticancer lead compounds.

Alzheimer's Disease (AD) is a neurological disorder characterized by progressive cognitive impairment and memory loss. In vitro artificial membrane permeability assays targeting the blood-brain barrier (BBB), such as the parallel artificial membrane permeability assay (PAMPA), are useful for pre-evaluating the BBB penetration of molecules during the early stages of drug development. Inhibitors of glycogen synthase kinase-3β (GSK-3β), casein kinase-1δ (CK-1δ), and acetylcholinesterase (AChE) exhibit neuroprotective effects, indicating a potential therapeutic approach for AD. This study aimed to assess the ability of 23 phenolic compounds derived from natural sources to penetrate the central nervous system (CNS) and examine their potential neuroprotective effects. Following the prediction of BBB penetration of the compounds by PAMPA, neuroprotective effects of CNS+ compounds were evaluated through in vitro inhibition of GSK-3β, CK-1δ, and AChE. Based on the data obtained, five flavonoids (hispidulin, nepetin, platanoside, apigenin, and kaempferol) and two furanocoumarins (isopimpinellin and bergapten) were predicted to penetrate the CNS. Apigenin (API) and kaempferol (KEM) exhibited the most potent dual inhibitory activity against CK-1δ and GSK-3β. Furthermore, API and KEM did not exhibit cytotoxic effects in SH-SY5Y cells. Molecular modeling studies, including molecular docking, molecular dynamics simulations, and dynophore analysis, were performed to understand the binding mechanism of these most potent compounds to their target enzymes. Overall, the current study offers a rational approach to designing new molecules inspired by natural compounds to treat Alzheimer's Disease.

Periodontal disease is a chronic inflammatory problem that has destructive effects on the tooth-supporting tissues. This disease affects a large portion of the population, influencing overall health and quality of life, and significant socioeconomic burden. Therefore, efforts to more effectively manage the problems caused by this disease are a necessity. This review describes the therapeutic potential of Trolox (a water-soluble analogue of vitamin E) and its modified derivatives as potential candidates for managing periodontal disease, highlighting their multifaceted pharmacological properties. Unlike the lipophilic molecule vitamin E, Trolox can be formulated into aqueous solutions, gels, mouthwashes, or rinses, ensuring optimal bioavailability at sites of inflammation and infection in the oral cavity. This compound can also help treat periodontal disease by combating oxidative stress, where its antioxidant properties neutralize harmful reactive oxygen species (ROS), reducing tissue damage and bone loss caused by undesired conditions such as bacterial imbalance. In addition to antioxidant and anti-inflammatory properties, Trolox and its derivatives exhibit various pharmacological activities against diabetes, Alzheimer's disease, Plasmodium falciparum malaria infection, and periodontopathogens, all of which are associated with the development of periodontal disease. In conclusion, this review suggests that Trolox and some of its derivatives with favorable activity/toxicity profiles have significant potential to be considered as new drug candidates for combating periodontal diseases.

Targeted protein degradation (TPD) is an emerging drug discovery approach aimed at enabling the selective removal of disease-associated proteins. While proteolysis-targeting chimeras (PROTACs) have advanced intracellular degradation via the ubiquitin–proteasome system, their limitation to cytosolic proteins excludes ~40% of the human proteome that is extracellular or membrane-bound. Lysosome-targeting chimeras (LYTACs) address this gap by harnessing lysosomal trafficking receptors, thereby mediating the degradation of extracellular and membrane proteins. More recently, methylarginine-targeting chimeras (MrTACs) have extended lysosomal strategies to certain intracellular targets, bypassing proteasomal dependence. This review critically examines the mechanistic underpinnings, design strategies, and bioanalytical challenges associated with lysosome-mediated degradation platforms. Emphasis is placed on their therapeutic implications, analytical evaluation, and potential for expanding druggable targets. Together, these emerging lysosomal chimeras offer a paradigm shift in TPD, with far-reaching applications in precision medicine and chemical biology.