Mini reviews in medicinal chemistry最新文献

Stress granules (SGs) are membraneless cytoplasmic condensates formed through liquidliquid phase separation (LLPS) in response to diverse cellular stressors. These dynamic macromolecular complexes serve as critical signaling hubs that orchestrate adaptive responses by sequestering translationally stalled mRNAs, RNA-binding proteins, and key signaling molecules. Substantial evidence implicates SGs in the pathogenesis of numerous disorders, where they dysregulate essential cellular pathways, including stress-induced cell death cascades. While regulated cell death constitutes a physiological process vital for tissue homeostasis, aberrant or excessive cell death represents a pathogenic driver in neurodegeneration, ischemic injuries, autoimmune disorders, infectious diseases, and oncological pathologies. Consequently, deciphering the molecular governance of cell death holds great potential for developing novel therapeutics. Although proteomic analyses reveal that SGs sequester multiple cell death regulators, the precise mechanisms through which these components modulate death pathways remain incompletely resolved. This review systematically examines the causal relationships between SGs dynamics and major cell death modalities, including apoptosis, necroptosis, pyroptosis, and ferroptosis. By synthesizing recent advances in SG biology and cell death regulation, we elucidate how stress-adapted SG proteomes functionally contribute to death pathway activation or suppression. This mechanistic synthesis not only resolves current controversies regarding SGs' function in different cell death models but also identifies targetable vulnerabilities at the SGs-death pathway interface, offering innovative frameworks for treating SGsassociated pathologies.

Background: This review discusses recent advances in 4-hydroxycoumarin (4-HC) and its derivatives, emphasising its promise as a versatile pharmacological agent with diverse bioactivities.

Introduction: 4-Hydroxycoumarin (4-HC) represents a pivotal heterocyclic compound widely recognized in medicinal and pharmaceutical chemistry, serving as a central scaffold for the development of various therapeutic agents. The derivatives of 4-HC have garnered considerable attention due to their broad range of pharmacological activities, including antibacterial, antiviral, antifungal, anti-inflammatory, and anticancer effects.

Method: This review employs a combined bibliosemantic and analytical approach, utilizing major bibliographic databases and specialized chemical repositories to extract, categorize, and evaluate relevant studies on 4-HC derivatives. Emphasis is placed on literature from 2018 onwards.

Result: The review presents a systematic overview of structurally diverse 4-HC derivatives, elucidating the synthetic strategies employed for their functionalization. Their pharmacological profiles are critically examined across distinct therapeutic domains. Structurally and mechanistically relevant analogues, such as clinically established anticoagulants, are highlighted. The derivatives are discussed according to their primary bioactivities to ensure clarity and prevent redundancy.

Discussion: The study highlights 4-HC as an important scaffold in medicinal chemistry. Structural adaptability and functionalization enable the synthesis of derivatives with targeted pharmacological effects. While significant advancement has been made, further investigation into structure-activity relationships and mechanistic insights will improve the rational design of next-generation therapeutics.

Conclusion: 4-Hydroxycoumarin and its derivatives exhibit substantial promise as lead scaffolds in drug discovery. Their structural adaptability and diverse biological targets position them as valuable candidates for generating novel therapeutic agents across multiple disease spectra.

Lung cancer remains a significant contributor to cancer mortality for several reasons. First, lung cancer is a molecularly heterogeneous disease. When combined with the dramatic resistance to treatment mediated by a tumor microenvironment (TME) that is inherently immunosuppressive, this explains the continued high mortality associated with lung cancer. The new era of treating non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC), as well as achieving long-lasting treatment responses, is driven by immune checkpoint inhibitors (ICIs) targeting PD- 1, PD-L1, and CTLA-4. This treatment revolution may, in the future, be applied to isolated cases of relapse and recurrent disease, resulting in sustained therapeutic responses. In this review, we outline recent advances, including novel agent combinations and combination regimens tested in clinical trials that have become milestones, such as Nivolumab, Pembrolizumab, Durvalumab, and emerging bispecific combinations. Targeted therapeutic delivery is now possible through nanotechnology and biomaterials, such as polymer nanoparticles and smart hydrogels, which allow high local drug concentration at the tumor site while reducing systemic toxicity. Predictive biomarkers, including PD-L1 expression, tumor mutational burden (TMB), circulating tumor DNA (ctDNA), and radiomic features, are increasingly used to select patients and assess treatment responses in real time. Despite these advances, resistance to immunotherapy and immunerelated adverse events (irAEs) remain major challenges, emphasizing the need for ongoing innovation in personalized management, toxicity mitigation, and treatment strategies. Industry leaders are now exploring artificial intelligence to optimize treatment selection and predict adverse events and outcomes early. Ultimately, improved survival rates and enhanced patient experiences may be achieved through the integration of novel biomarkers, precision technologies, and more effective immunotherapies for lung cancer patients. Significant research is still required to overcome resistance mechanisms, optimize combination therapies, and enable individualized care in this rapidly advancing field.

Anthelmintic resistance in livestock is an escalating global concern, as synthetic anthelmintics tend to lose their efficacy within 2-10 years of their routine usage. This rapid development of resistance results in significant economic losses and threatens the sustainability of livestock production systems. Gastrointestinal (GI) parasitism, a primary health challenge in ruminants, significantly impairs productivity, fertility, and overall animal welfare. Environmental factors such as high humidity, temperature fluctuations, and poor management practices further predispose animals to certain parasitic infections. In recent years, the search for alternative solutions has led to a growing interest in plant-derived anthelmintics. These botanical compounds, rich in bioactive phytochemicals, offer a promising and eco-friendly approach to controlling parasites by targeting their metabolism, reproduction, and structural integrity. Unlike synthetic drugs, herbal anthelmintics are often associated with fewer side effects, reduced toxicity, and a lower risk of developing possible resistance. Several medicinal plants, such as Azadirachta indica, Allium sativum, Artemisia absinthium, and Fumaria parviflora, have demonstrated potent anthelmintic properties in both in vitro and in vivo studies. Furthermore, synergistic effects among multiple phytochemicals can enhance efficacy and broaden the spectrum of activity against diverse helminths. This review highlights the efficacy, mechanisms of action, and practical applications of herbal remedies in controlling parasitic infections in ruminants. Emphasizing the integration of natural remedies into sustainable livestock health programs, this approach holds great potential to reduce reliance on synthetic drugs while improving animal health, productivity, and farm profitability.

Phenothiazine and its N-substituted derivatives are pivotal in heterocyclic chemistry, serving as potential building blocks in chemical and pharmaceutical sciences. Over the past decade, extensive research has focused on the medicinal potentials of these compounds, exploring their anticancer, analgesic, anti-tumor, anti-inflammatory, and antibacterial properties. Due to their distinctive chemical compositions, phenothiazine and its N-substituted derivatives have facilitated the development of novel substitutions that are less hazardous. This paper reviews recent advancements in the synthesis of phenothiazine and its N-substituted derivatives, with an emphasis on their potential biological roles, including combating cancer, viruses, fungi, bacteria, histamine, inflammation, multidrug resistance (MDR), seizures, and free radicals. Numerous investigations have identified various types of phenothiazine and its N-substituted derivatives that exhibit compelling biological characteristics. The review analyses synthetic challenges and advancements in the applications of these derivatives in pharmaceutical and synthetic chemistry reported in recent decades. It discusses the impact of different functional groups on phenothiazine at the N-substitution, specifically Cl, CF₃, OH, N(C₂H₅)₂, and (CH₂)₅CH₃. Furthermore, the relationship between the biological activities and the structural characteristics of the compounds is examined, identifying the chemical groups and structural alterations that enhance bioactivity, reduce toxicity, and improve handling.

Introduction: Assisted reproductive techniques still have limitations regarding embryonic development and the achievement of clinical pregnancy. Animal venoms represent a biological library with the potential to trigger relevant cellular mechanisms. This study aimed to evaluate, through a literature review and computational screening, the activity of natural venoms and their derivatives on germ cells.

Materials and methods: A literature review was conducted in PubMed, Embase, Scopus, and Web of Science databases.

Inclusion criteria: experimental studies involving oocytes, spermatozoa, or embryos in vitro/in vivo.

Exclusion criteria: review articles, letters to the editor, abstracts, books, and studies outside the scope. Extracted data included the type of venom, source species, experimental model, effects, mechanisms, and administration routes. Methodological quality was assessed using funnel plots, forest plots, and the SYRCLE tool. Computational screening was performed targeting hormonal receptors.

Results: Of the 584 articles analyzed, only 19 met the eligibility criteria. Among these, 57% investigated snake venom, 16% spider venom, 16% bee venom, and 10% sea anemone/scorpion venom. High heterogeneity was observed in the effects on sperm motility (I² = 97%) and sperm concentration (I² = 95%), although a positive effect on concentration was detected. All molecules showed activity on estrogen receptors.

Discussion: The findings suggest that venoms and their derivatives can modulate gamete functions, with effects influenced by the chemical diversity of toxins and variations in experimental models. Computational screening highlights potential molecular interactions with hormonal pathways, reinforcing their relevance as modulators of reproductive processes.

Conclusion: Animal venoms and their derivatives can exert biological activity on germ cells (oocytes, spermatozoa, and embryos).

Polysaccharide-based iron oxide nanoparticles, particularly PSC-iron oxide nanoparticles, have emerged as promising agents for brain cancer diagnosis and therapy. Originally approved for anemia treatment, PSC-iron oxide nanoparticles leverage extended circulation time, biocompatibility, and MRI contrast capabilities to serve dual diagnostic and therapeutic roles. This review highlights its application in brain tumor management, focusing on enhanced MRI visualization of tumor vascularization and macrophage activity compared to gadolinium-based agents, which improve tumor delineation and treatment monitoring. Additionally, PSC-iron oxide nanoparticles exhibit immune- modulating properties that promote anti-tumor macrophage responses. Preclinical evidence supports the synergistic effects of this approach with existing therapies and its potential in hyperthermia applications. Challenges in clinical translation, including dosage optimization and safety, require further investigation. This review highlights the potential of PSC-iron oxide nanoparticles in current findings to advance precision medicine or nanomedicine approaches for brain tumors.

Despite recent advances in both preclinical and cancer therapies, the growing problem of treatment resistance remains one of the most critical challenges in oncology. To overcome the drawbacks of current oncologic treatments, there is a pressing need for new approaches and potential therapeutic strategies. The interaction between the host microbiome and cancer has recently attracted significant research. Among the various routes of microbiome-cancer interaction, microbiome- derived exosomes also offer an intriguing avenue. Exosomes, which are small extracellular vesicles, originate from several distinct types of cells, including microbiome-associated cells. These vesicles participate in intra- and intercellular communication as well as alteration of the tumour microenvironment. Emphas In light of their possible functions as treatment response modifiers and mediators, this review seeks to explain an intricate link between cancer therapy resistance and exosomes produced from the microbiome. Preclinical studies reveal that microbiome-derived exosomes operate through horizontal transfer of resistance-conferring enzymes and TLR4/MYD88-dependent signalling, demonstrating 2-5 fold upregulation of resistance-associated miRNAs in drug-resistant models. Clinical evidence shows Akkermansia muciniphila improves anti-PD-1 immunotherapy outcomes. Fusobacterium nucleatum- derived vesicles promote oxaliplatin resistance through autophagy activation. We investigate how microbiota-derived exosomes might leverage resistance to conventional cancer treatments and their consequences for these treatments. However, limitations include inter-individual microbiome variability, challenging isolation protocols, and regulatory hurdles under FDA guidelines. We examine the possible applications of microbiome-derived exosomes as therapeutic and diagnostic tools, thereby reflecting the applicability of these findings in clinical practice. This offers an interesting path for new therapeutic approaches meant to solve treatment resistance and raise patient survival.

Psoriasis is a chronic inflammatory skin disorder affecting 2-3% of the global population. It is increasingly recognized for its systemic comorbidities, especially cardiovascular diseases (CVDs). Notably, severe psoriasis independently increases cardiovascular disease (CVD) risk. This elevation occurs beyond conventional risk factors, such as hypertension and diabetes. It suggests that shared inflammatory pathways underlie the association between severe psoriasis and atherosclerotic conditions, like coronary artery disease (CAD). Atherosclerosis, characterized by lipid-laden plaque formation in arterial walls, remains a leading contributor to CVD-related morbidity and mortality. Emerging evidence underscores the interplay of inflammatory cell heterogeneity and immune dysregulation in its pathogenesis, mirroring mechanisms observed in psoriasis. The overlapping systemic inflammation and immune dysfunction in both diseases suggest potential therapeutic synergies. CD4+ regulatory T cells (Tregs), pivotal immunosuppressive modulators, have shown promise in mitigating autoimmune responses, yet their therapeutic exploitation in psoriasis-atherosclerosis comorbidity remains underexplored. This review summarizes current insights into Tregs' roles in psoriasis and atherosclerosis, emphasizing their dual regulatory functions; in psoriasis, Treg dysfunction exacerbates interleukin-17 (IL-17)/23-driven keratinocyte hyperproliferation, while in atherosclerosis, impaired Treg activity permits pro-inflammatory cytokine cascades and foam cell formation. We, herein, highlight emerging approaches to enhance Treg stability and function, such as nanotechnology-based targeting antibodies and traditional Chinese medicine (TCM). By delineating Treg-centric mechanisms across both diseases, this review proposes a paradigm shift toward immunomodulatory therapies addressing psoriasis-atherosclerosis crosstalk, offering novel strategies to alleviate systemic inflammation and cardiovascular burden in psoriatic patients. Further research into Treg heterogeneity and microenvironmental cues may unlock precision therapies for this comorbid axis.

The extensive array of Natural Products (NPs), ranging from plants to microbes, is wellknown for their varied chemical characteristics and significant biological activity. Historically significant in drug discovery, natural products provide distinctive stereochemistry and complexity generated by diverse biosynthetic pathways. Structural alterations improve effectiveness and diminish adverse effects, driven by advancements in screening, chemistry, and bioinformatics. Natural products have been approved as drug candidates despite the laborious process involved in their isolation and elucidation, demonstrating their relevance. Cinnamaldehyde (CA), derived from Cinnamomum tree bark, exhibits antibacterial, anti-inflammatory, anticancer, antioxidant, neuroprotective, antifungal, and anti-diabetic properties by affecting cellular processes and signaling pathways like PI3K/AKT/mTOR, TGF-β/Smad, NF-κB, TLR4/MyD88/NF-κB, MAPKs, JAK/STAT, and Nrf2/HO-1. Small molecular entities, along with the presence of α,β-unsaturated carbonyl functionality, offer intriguing possibilities within the research framework of synthetic chemistry. Synthetic analogues of CA have been produced; nonetheless, their biological actions remain largely unexamined. The review highlights the pharmacological significance of cinnamoyl functionality, indicating its potential for creating multi-targeted drugs through unexamined structural changes. This review adopts a comprehensive study design, featuring an extensive search of databases like PubMed, Science Direct and Scopus using keywords such as "cinnamoyl compounds," "synthetic derivatives," "therapeutic flexibility," and "pharmacological pathways." Studies were selected based on their relevance to the pharmacological activities of cinnamoyl compounds' synthetic derivatives and their effects on multiple signaling pathways in therapeutic contexts, including experimental data. This article aims to provide theoretical support for the promising development of cinnamoyl compounds as potential candidates for new discoveries and therapeutic advancements.