Archiv der Pharmazie最新文献

Novel biguanide hydrochloride salts were synthesized through the reaction of N-substituted-semi(thiosemi)carbazides with cyanoguanidine in an acidic medium. Antidiabetic properties of the synthesized biguanides were evaluated for their antidiabetic properties. All biguanide compounds showed promising effects, which revealed a significant decrease in the elevated glucose in comparison with metformin on oral treatment of hyperglycemic rats with the synthesized biguanide derivatives. The monosubstituted thiourea showed an improvement by about 1.48-fold of metformin. The effect of the synthesized biguanides on liver function enzyme activities, lipid profiles, and renal functions was investigated and discussed as compared with normal control rats; some urea derivatives showed improvement results that were nearly equal to those of metformin. Regarding lipid profile, the N-phenylurea moiety showed improved results higher than metformin. Regarding the effect on kidney function markers, some urea derivatives showed results that were higher than those of metformin. Also, antioxidant biomarkers and inflammatory markers were detected in diabetic rats and discussed; the results of all tested derivatives were equal to twofold of the results of metformin. Moreover, the histopathological examination of hepatic, kidney, and pancreatic tissues reveals that all of the tested compounds showed significant, promising activity.

Cancer remains a leading cause of mortality worldwide, with treatment resistance posing a major obstacle to effective therapies. Natural compounds, including quassinoids such as bruceantin and brusatol, derived from Brucea javanica (L.) Merr., have demonstrated potential as novel cancer chemopreventive agents. Bruceantin exhibits cytotoxic effects against diverse cancer cell lines, including leukemia, lymphoma, and myeloma, primarily through inhibition of protein synthesis and induction of apoptosis via caspase and mitochondrial pathways. Similarly, brusatol has shown broad-spectrum anticancer activities by modulating cellular processes such as apoptosis, cell-cycle arrest, autophagy, and attenuation of epithelial–mesenchymal transition. Mechanistically, it targets key oncogenic signaling pathways, including PI3K/AKT/mTOR and Keap1/NRF2, and enhances chemosensitivity and radiosensitivity. This review evaluates preclinical findings on the pharmacological properties, mechanisms of action, and anticancer efficacy of bruceantin and brusatol. Their structural modifications, safety profiles, and challenges such as poor bioavailability and systemic toxicity are also explored. Advances in semi-synthetic derivatives and drug delivery systems are discussed as strategies to enhance therapeutic potential. Comprehensive insights are provided into the molecular and cellular mechanisms underlying their anticancer effects, supported by in vitro and in vivo evidence. Collectively, these findings highlight the promise of bruceantin and brusatol as therapeutic agents and underscore the need for further translational research to optimize their clinical utility. These quassinoids represent a compelling avenue for the development of targeted and adjunctive cancer therapies, potentially overcoming limitations of conventional treatments.

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.