Molecular Diversity最新文献

The p53 protein is regarded as the "Guardian of the Genome," but its mutation is tumor progression and present in more than half of malignant tumors. The pro-metastatic property of mutant p53 makes a strong argument for targeting mutant p53 with new therapeutic strategies. However, mutant p53 was considered as a challenging target for drug discovery due to the lack of small molecular binding pockets. Among them, mutant p53 Y220C creates a narrow crevice since the side chains dynamics on protein surface, which is suitable for designing small molecules to occupy the cavity and recovery the tumor suppressing function. Here, we describe the mechanism of p53 related signal pathway and how p53 Y220C regulate the tumorigenesis. We review the two types of p53 Y220C modulators including restoring the conformation of mutant p53 Y220C protein to wild-type p53 protein and recruiting histone acetyltransferase p300/CBP to acetylate p53 Y220C thus enables p53 Y220C dependent upregulation of apoptotic genes and downregulation of DNA damage response pathways. We also report clinical advances and challenges of these molecules in p53 Y220C medicated tumor therapy.

Buspirone, a well-established anxiolytic agent, has gained attention for its potential role as an antidepressant, primarily due to its unique pharmacological profile and the ability to modulate serotonin receptors effectively. Late-stage functionalization is considered as a pivotal strategy in drug synthesis that enhances the therapeutic efficacy of existing molecules. This review summarizes various late-stage functionalization techniques applicable to Buspirone, including photocatalyzed, metal-catalyzed, and enzyme-catalyzed reactions.

Parasitic diseases remain a significant global health challenge, especially in developing countries, contributing to approximately one million deaths annually. Notably, among the 143 FDA-approved antiparasitic drugs, thirty-four possess chlorine in their chemical structure, highlighting the importance of chlorine substitution. This underscores the significance of chlorine atoms in elucidating structure-activity relationships crucial for drug discovery, aiming to develop safer, more selective, and environmentally friendly molecules with enhanced efficacy. Of particular interest some are naturally occurring chlorinated metabolites derived from PKS, NRPS, and PKS-NRPS biosynthetic pathways, which offer the potential for further manipulation. However, there is limited literature on antiparasitic chlorinated compounds from microbial sources. To address this, we conducted a comprehensive literature survey from 1963 to the present, identifying 28 chlorinated compounds with confirmed antiparasitic properties. This review underscores the potential of enzymatic machinery for selective chlorine substitution, offering insights for biochemists and synthetic chemists to develop versatile chlorinated compounds through synthetic biology, combinatorial chemistry, and organic synthesis.

Acquired immunodeficiency syndrome (AIDS) poses a significant threat to life. Antiretroviral therapy is employed to diminish the replication of the human immunodeficiency virus (HIV), extending life expectancy and improving the quality of patients' lives. These HIV-1 integrase inhibitors form robust covalent interactions with Mg²⁺ ions, contributing to their tight binding, thereby inhibiting the integration of viral DNA into the CD4 cell DNA. The second-generation INSTIs, the most recently approved, exhibit a higher genetic barrier compared to first-generation drugs. Hence, there is a need to develop novel and safe compounds as inhibitors of HIV-1 integrase. This article presents an overview of the current landscape of anti-HIV-1 integrase inhibitors, emphasizing the structure-activity relationship (SAR) of small molecules. The molecules discussed include monocyclic rings consisting of triazoles moiety, and pyrimidine analog along with bicyclic rings with nitrogen-containing moieties. Researchers are exploring anti-HIV-1 integrase inhibitors from natural sources like marine environments, plant extracts, and microbial products, emphasizing the importance of diverse bioactive compounds in combating the virus, which have also been included in the manuscript. The current manuscript will be helpful to the scientific community engaged in the manipulation of small molecules as anti-HIV integrase inhibitors for designing newer leads.

Cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) emerges as a key single-chain transmembrane glycoprotein predominantly expressed in effector T cells and regulatory T cells. It plays a crucial role in tumor immunity by modulating T cell responses. Specifically, CTLA-4 dampens T cell activation and proliferation while bolstering the survival of regulatory T cell through its competitive interaction with B7 family molecules, thereby aiding tumor cells in eluding immune detection. Given CTLA-4's significant influence on tumor immune dynamics, an array of anti-CTLA-4 antibody therapeutics have been clinically developed to combat various malignancies, including melanoma, renal cell carcinoma, colorectal carcinoma, hepatocellular carcinoma, non-small cell lung carcinoma, and pleural mesothelioma, demonstrating notable clinical therapeutic effects. This paper aims to delve into CTLA-4's integral role in tumor immunity and to encapsulate the latest advancements in the clinical research of anti-CTLA-4 antibody.

The synthesis of sulfonamides, a class of compounds with significant pharmaceutical and medicinal applications, has seen remarkable advancements with the advent of magnetic nanocatalysts. Magnetic nanocomposites are one of the most efficient and widely used catalysts, and they are in complete harmony with the principles of modern green chemistry from the point of view of catalysis. These catalysts, typically composed of metal complexes supported on magnetic nanoparticles, offer unique advantages such as ease of recovery and reusability, which are crucial for sustainable and eco-friendly chemical processes. This review comprehensively examines recent developments in applying magnetic nanocatalysts to prepare sulfonamides. Key focus areas include the design and synthesis of various magnetic nanocatalysts (MNC), their catalytic performance in different reaction conditions, and mechanistic insights into their catalytic activity. By summarizing the latest research and technological advancements, this article aims to provide a valuable resource for researchers and practitioners in catalysis and pharmaceutical chemistry.

In the past, mechanochemical approaches in organic synthesis were largely overlooked, but their perception within the synthetic community has shifted in recent years, marking a trend toward becoming mainstream. Mechanochemical multicomponent organic synthesis has garnered significant interest from both the academic and industrial chemical sectors. The efficiency and environmental friendliness of procedures conducted through mechanical activation have established mechanical procedures as prominent green techniques. Notably, utilizing solid starting materials under mechanochemical conditions empowers the development of novel multicomponent reactions that are often unfeasible in traditional solution-based processes. This capability not only enhances the diversity of accessible organic compounds but also sparks new avenues for innovative synthetic strategies. This approach facilitates the effective fulfillment of sustainable chemistry goals. In this context, we emphasize the major progress and advancements in mechanochemical multicomponent reactions from 2017 to 2024. This article covers the foremost multicomponent mechanosynthesis for developing organic molecules through carbon-carbon and carbon-heteroatom coupling reactions and multicomponent mechanosynthesis for monocyclic and fused heterocycles.

Drug repositioning (DR) has emerged as a critical research strategy for uncovering novel therapeutic applications of existing drugs, demonstrating considerable clinical significance. Despite promising advancements in computational methods for predicting drug-disease associations, most algorithms exhibit three major limitations. First, they inadequately capture high-order relationships within drug-disease networks. Second, they fail to concurrently model both local interaction strengths and global network topologies. Most importantly, current models lack biological interpretability and are incapable of extracting meaningful biological patterns from numerical data. To address these challenges, we propose a novel drug repositioning framework, MMADPE. This framework constructs a similarity network supporting multi-hop aggregation and leverages the linear complexity of Graph Mamba to efficiently integrate multi-order neighborhood information, thereby significantly enhancing the modeling of long-range drug-disease interactions. Subsequently, a dual-modal graph positional encoding is employed, capturing global network topology via Laplacian eigenvectors and characterizing local node association strengths through random walk statistics. Finally, the framework incorporates a GraphGPS hybrid architecture that fuses gated graph convolution with Transformer attention mechanisms to extract molecular biochemical features and their semantic relationships, achieving a deep integration of topological structures and biological semantics. Extensive experiments on three benchmark datasets demonstrate that MMADPE consistently outperforms state-of-the-art methods in drug repositioning tasks. Notably, case studies on two common diseases combined with molecular docking experiments not only validate the effectiveness of our approach but also provide novel mechanistic insights into MMADPE's ability to identify previously unrecognized drug-disease associations.

The sodium-glucose co-transporter 2 (SGLT2) plays an important role in mediating glucose reabsorption within the renal filtrate and regulating blood glucose levels, which makes it a well-known target for diabetes mellitus. A number of SGLT2 inhibitors (SGLT2i) have been established as important antidiabetic drugs, and research on new SGLT2i with high affinity is ongoing. Herein, 101 compounds were screened from a compound library (approximately 16,000 compounds) using a virtual screening workflow that integrated various docking programs, pharmacophore modeling, and druggability filter. To verify the results of virtual screening, we established a HK-2 cell model with d-glucose derivative 2-[N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl) amino]-2-deoxy-d-glucose (2-NBDG) for measuring glucose uptake via SGLT2. 12 candidate compounds were selected and purchased for subsequent experimental validation. Among these, 3 non-glycoside compounds significantly inhibited the 2-NBDG uptake in a dose-dependent manner and their IC₅₀ values for SGLT2 were 71.43 μM, 72.66 μM, and 91.44 μM, respectively. Mechanism studies demonstrated that all 3 compounds significantly downregulated SGLT2 level and activated silent information regulator 1 (SIRT1) expression in high-glucose-induced cell injury models. These findings confirmed the ability of these compounds to bind to SGLT2 and also revealed their potential mechanisms in regulating oxidative stress and metabolism. Furthermore, molecular dynamics simulation indicated the high binding stability of SGLT2 and 3 compounds complexes during a 100-ns simulation period. In conclusion, our results identified 3 potential SGLT2i and preliminarily elucidated their mechanism of action, which lays the foundation for the development of novel and potent non-glycoside SGLT2i in future.

Metabolomics accounts for the metabolic alterations and identification of novel biomarkers in the war to combat cancer. This review explores advancements in metabolomics, emphasizing its application in understanding cancer-associated metabolic pathways and phytochemical interactions. Herein, we have explored the literature overview on the spectrometric integration of nuclear magnetic resonance with mass spectrometric methods for comprehensive metabolite profiling, enabling the identification and the documentation of critical biomarkers, allowing the early cancer detection, and monitoring its prognosis. We also look at metabolic dysregulations in cancer, such as oncometabolites and the Warburg effect, which aid in the growth of tumors. Natural products have been thoroughly examined for their anticancer potential, and metabolomics provides a systematic approach to evaluating their efficacy. This review highlights various plant-based bioactive compounds, including curcumin, genistein, and withaferin A, which have demonstrated anticancer properties through metabolomic profiling. Furthermore, we discuss next-generation metabolomics and pharmaco-metabolomics for precision oncology and personalized cancer treatment. By integrating metabolomics with emerging bioinformatics tools, this review provides a comprehensive framework for biomarker discovery, early cancer detection, and therapeutic advancements. The insights presented herein underscore the potential of metabolomics in bridging traditional cancer research with innovative prevention strategies, ultimately contributing to the advancement of more precise and effective targeted cancer therapies.