Archiv der Pharmazie最新文献

Drug-resistant cancer is a major obstacle to effective treatment, causing poor clinical outcomes, financial pressure, and healthcare burdens, highlighting the urgent need for new chemotherapeutics. Indole derivatives are valuable anticancer scaffolds with multitargeted effects. Indole hybrids, in particular, exert multitargeted actions that address drug resistance mechanisms, offering unique advantages for overcoming resistant cancers. The present manuscript aims to summarize the current landscape of indole hybrids, with therapeutic potential against drug-resistant cancers, covering literature published since 2021. Additionally, the structure–activity relationships and mechanisms of action are addressed to inform the further rational design of novel candidates.

Dilated cardiomyopathy (DCM) is a progressive myocardial disorder with limited therapeutic options. Recent studies suggest that metabolic reprogramming, including lactate accumulation and protein lactylation, contributes to heart failure pathogenesis, but their roles in DCM remain poorly defined. We analyzed the global burden of cardiomyopathy and myocarditis using GBD data and performed transcriptomic profiling using GSE120895 and GSE5406 datasets. Weighted gene co-expression network analysis (WGCNA), differential gene expression, and known lactylation-related genes (LRGs) were integrated to identify key targets. LASSO regression was applied to construct a diagnostic model. Validation was conducted in an Lmna^E82K transgenic mouse model using qRT-PCR, Western blot analysis, immunofluorescence, and biochemical assays. Global analysis showed the rising age-standardized prevalence of cardiomyopathy and myocarditis by 2021. Bioinformatics revealed 1988 DEGs in DCM, 11 of which overlapped with LRGs and WGCNA modules. LASSO modeling identified DDX39A, SPR, and HNRNPC as core diagnostic biomarkers. In vivo validation confirmed upregulation of these genes in Lmna^E82K mice. Elevated lactate and protein lactylation levels were detected, alongside increased NEFA, MDA, and oxidative stress markers, implicating lactylation in metabolic dysfunction. We identify DDX39A, SPR, and HNRNPC as novel lactylation-associated biomarkers of DCM and reveal a pathophysiological link between lactate-driven protein lactylation, oxidative stress, and cardiac dysfunction. These findings offer new molecular targets for DCM diagnosis and intervention.

In the pursuit of developing targeted therapies, novel furo[2,3-d]pyrimidine compounds were synthesized, incorporating the characteristic structural features of EGFR tyrosine kinase inhibitors. These compounds were screened for antiproliferative effects across 60 human cancer cell lines. Compound 3f was the most effective. Further evaluation at five concentrations to determine its GI₅₀, TGI, and LC₅₀. In vitro studies were conducted to evaluate its impact on EGFR signaling, cell cycle progression, apoptosis induction, and caspase-3 activation in T-47D cells. Compound 3f showed greater selectivity toward cancerous T-47D cells over normal breast cells (MCF10a). Notably, compound 3f displayed potent EGFR inhibition at submicromolar levels, with an IC₅₀ of 0.121 ± 0.004 μM, which was comparable to the reference inhibitor, erlotinib. Further investigations revealed that compound 3f caused cell cycle arrest at the G2/M phase in T-47D cells. Apoptosis analysis confirmed that compound 3f induced cell death through programmed cell death, with a nearly 19-fold increase in total apoptosis. This apoptotic mechanism was validated by a substantial rise in active caspase-3 levels. Molecular docking studies showed favorable binding of compound 3f within the EGFR active site. Molecular dynamics simulations further confirmed the stability of compound 3f within the active site over a 100-ns simulation period, supporting its sustained interaction with key residues. Based on predictions of toxicity, compound 3f was predicted to possess a favorable safety profile across 30 potential toxicities. Encouraged by its strong anticancer efficacy and safety profile, compound 3f represents a compelling lead candidate for further development as a targeted treatment for breast cancer.

Type 2 diabetes mellitus (T2DM) is considered the “pandemic of the 21st century.” It is a complex multifactorial disease associated with chronic hyperglycemia, causing further complications that result in disability and early mortality. Due to the fact that the main focus of T2DM therapy is to reduce the patient's blood sugar levels, avoiding drug-induced hypoglycemia is important. Free fatty acid receptor 1 (FFAR1) agonists are considered promising hypoglycemic agents without the risk of hypoglycemia. In the future, FFAR1 agonists may expand the range of safer hypoglycemic agents with a mechanism of action not currently used in T2DM therapy. In this study, the hypoglycemic effect of a novel and potent FFAR1 agonist based on benzyloxyphenylpropanoic acid's core containing an aminobornyl fragment was investigated in a long-term experiment on C57BL/6 Ay/a (Agouti Yellow) mice. The results demonstrated a reduction in insulin resistance, attributed to the hepatoprotective effect of the compound. Additionally, the analgesic effect of the compound was evaluated in experimental pain models. It appeared that the compound exhibited a moderate analgesic effect at high doses. Furthermore, the FFAR1-mediated mechanism of action was confirmed through experiments with an FFAR1 antagonist coadministration, which suppressed both hypoglycemic and analgesic effects.

Accumulating evidence has demonstrated that the overactivation of phosphoinositide 3-kinase (PI3K) is closely linked to the development and progression of pancreatic cancer, establishing it as a potential therapeutic target. Although several PI3K inhibitors have been developed, few have shown efficacy in treating pancreatic cancer. Consequently, there is an ongoing need for a deeper understanding of the anticancer effects exerted by PI3K inhibitors in this context. In this study, we selected copanlisib, the first marketed PI3K inhibitor, as a research tool to systematically evaluate its antipancreatic cancer effects, with the aim of validating the feasibility of using PI3K inhibitors for the treatment. In vitro studies demonstrated that copanlisib inhibited the proliferation and colony-forming ability of typical pancreatic ductal adenocarcinoma cell lines. Additionally, it induced G2/M phase arrest in pancreatic cancer cells, thereby promoting apoptosis in tumor cells. In in vivo studies, copanlisib treatment effectively inhibited pancreatic cancer growth and reduced Ki-67 expression by suppressing the PI3K signaling pathway in a xenograft mouse model. Collectively, these findings provide preliminary validation for the concept that PI3K inhibitor copanlisib significantly inhibits pancreatic cancer cell proliferation and tumor growth in both in vitro and in vivo settings, promoting apoptosis and suppressing the PI3K signaling pathway, which indicates its potential in pancreatic cancer treatment. We anticipate that these findings will serve as a reference for the clinical application of PI3K inhibitors in managing pancreatic cancer.

In the current study, a series of 22 prenylated arylidene appended thiazolidinedione derivatives were designed, synthesized, and evaluated for pancreatic lipase (PL) inhibitory activity. The study led to the identification of compounds exhibiting potent to moderate inhibitory activities with IC₅₀ values ranging between 6.18 ± 0.46 and 52.75 ± 2.34 µM. Among them, compound 22b demonstrated remarkable PL inhibitory activity with an IC₅₀ value of 6.18 ± 0.46 µM. Enzyme kinetics studies revealed a reversible competitive mode of inhibition for 22b with a K_i value of 4.1 μM. The results of in vitro findings further supported the outcome of in silico studies, which correlate the strong binding affinity of compound 22b for PL. Molecular docking studies confirmed satisfactory binding mode of compounds within the active site of PL by exhibiting various interactions such as H-bonding, π–π stacking, and hydrophobic interactions. A 100 ns molecular dynamics simulation study of protein–ligand complex with compound 22b revealed good binding and stability. The MM-GBSA analysis revealed strong binding affinity toward the active site of PL as compared with the reference ligand. Further, all derivatives were predicted to exhibit good pharmacokinetic properties, devoid of toxicity (toxicity class 4) and drug likeness.