Current medicinal chemistry最新文献

The novel coronavirus that caused the epidemic and pandemic resulting in the acute respiratory illness known as coronavirus disease 2019 (COVID-19) has plagued the world. This is unlike other coronavirus outbreaks that have occurred in the past, such as Middle East respiratory syndrome (MERS) or severe acute respiratory syndrome (SARS). COVID-19 has spread more quickly and posed special challenges due to the lack of appropriate treatments and vaccines. Real-time polymerase chain reaction (RTPCR) and rapid antibody tests (surveillance tests) are the two most used tests (confirmation tests). However, the latter takes hours to complete, and the former may produce false positives. Scientists have invested significant effort to create a COVID-19 diagnostic system that is both highly sensitive and reasonably priced. Early detection of COVID-19 is a major area of focus for sensing devices based on nanomaterials. This overview enhanced insights into potential coronavirus biomarkers and, compared to earlier studies, introduced new avenues. Further, it covers the development of COVID-19 diagnostic systems from an analytical point of view, including clinical markers and their subsequent applications with biosensors.

Histone deacetylases (HDACs) play a crucial role in the regulation of cancer progression and have emerged as key targets for antitumor therapy. Histone Deacetylase Inhibitors (HDACis) effectively suppress tumor cell proliferation, induce apoptosis, and cause cell cycle arrest, demonstrating broad-spectrum antitumor activity. This article primarily focuses on enhancing the selectivity of HDACis through structural modification using natural compounds. It provides detailed insights into the structure modification of histone deacetylase 8 (HDAC8) and histone deacetylase 10 (HDAC10), as well as dual-- target inhibitors and their pharmacological effects. Furthermore, conventional HDAC inhibitors are susceptible to off-target effects and the development of drug resistance. Our research focuses on augmenting the targeting specificity of HDAC inhibitors through their combination with proteolysis targeting chimera (PROTAC). Lastly, the latest advancements in clinical research on HDAC inhibitors were summarized, revealing that these inhibitors possess limitations in their clinical applications due to intrinsic or acquired resistance. Consequently, this article primarily focuses on summarizing the current status and prospects of structural modifications for HDAC inhibitors, with the aim of inspiring researchers to develop novel HDAC inhibitors exhibiting enhanced activity for improved application in clinical research.

Branched-chain amino acids (BCAAs) are essential amino acids for humans and play an indispensable role in many physiological and pathological processes. Branched-chain amino acid aminotransferase (BCAT) is a key enzyme that catalyzes the metabolism of BCAAs. BCAT is upregulated in many cancers and implicated in the development and progress of some other diseases, such as metabolic and neurological diseases; and therefore, targeting BCAT might be a potential therapeutic approach for these diseases. There are two isoforms of BCAT, i.e., cytoplasmic BCAT1 (or BCATc) and mitochondrial BCAT2 (or BCATm). The discovery of BCAT inhibitors was initiated by Warner-Lambert, a subsidiary of Pfizer, in 2000, followed by many other pharmaceutical companies, such as GlaxoSmithKline (GSK), Ergon, Icagen, Agios, and Bayer. Strategies of high-throughput screening (HTS), DNA-Encoded library technology (ELT), and fragment-based screening (FBS) have been employed for hit identification, followed by structural optimization. Despite low selectivity, both BCAT1 and BCAT2 selective inhibitors were individually developed, each with a few chemical structural classes. The most advanced BCAT1 inhibitor is BAY-069, discovered by Bayer, which has a potent enzymatic inhibitory activity against BCAT1 and a decent in vitro and in vivo pharmacokinetic profile but displayed weaker cellular inhibitory activity and almost no anti-proliferative activity. There are no BCAT inhibitors currently under investigation in clinical trials. Further studies are still needed to discover BCAT inhibitors with a more druggable profile for proof of concept. This review focuses on the latest progress of studies on the understanding of the physiology and pathology of BCAT and the discovery and development of BCAT inhibitors. The structure-activity relationship (SAR) and the druggability, and the challenges of BCAT inhibitors are discussed, with the aim of inspiring the discovery and development of BCAT inhibitors in the future.

Gastrointestinal tumors, including colorectal and liver cancer, are among the most prevalent and lethal solid tumors. These malignancies are characterized by worsening prognoses and increasing incidence rates. Traditional therapeutic approaches often prove ineffective. Recent advancements in high-throughput sequencing and sophisticated RNA modification detection technologies have uncovered numerous RNA chemical alterations significantly associated with the pathogenesis of various diseases, notably cancer. These discoveries have opened new avenues for therapeutic intervention. This article delves into epigenetic modifications, with a particular emphasis on RNA alterations such as N6-methyladenosine (m6A), 5-methylcytosine (m5C), 1-methyladenosine (m1A), 7-methylguanosine (m7G), and N4-acetylcysteine (ac4C). It examines the functions and mechanisms of action of regulatory entities known as "Writers," "Readers," and "Erasers" to these modifications. Additionally, it outlines various methodologies for detecting these RNA modifications. Conventional techniques include radioactive isotope incorporation, two-dimensional thin-layer chromatography (2D-TLC), mass spectrometry, and immunological detection methods. Specialized methods such as bisulfite sequencing and reverse transcription stops are also discussed. Furthermore, the article underscores the significance of these modifications in the development, progression, and therapeutic targeting of gastrointestinal tumors, including esophageal, gastric, colorectal, liver, and pancreatic cancers. This exploration provides foundational insights for enhancing diagnostic accuracy, treatment efficacy, and prognostic assessment in gastrointestinal oncology.

Background: Hyperuricemia (HUA) is a condition characterized by excessive uric acid production and/or inadequate uric acid excretion due to abnormal purine metabolism in the human body. Uric acid deposits resulting from HUA can lead to complications such as renal damage. Currently, drugs used to treat HUA lack specificity and often come with specific toxic side effects.

Objective: This study aimed to investigate the renal protective effects of an optimized tea polyphenol formula and allopurinol in a rat model of hyperuricemia following renal resection. The goal was to explore the mechanisms underlying these effects.

Methods: Initially, a blend was formulated based on the distinctive functions of catechins, thearubigins, tea polysaccharides, and theanine. Orthogonal experiments were then employed to select a rational combination. A 5/6 renal resection rat model was successfully established, and the animals were fed a 2% oxonic acid diet to induce hyperuricemia. Urinary protein content was measured using the biuret method, and serum levels of uric acid, creatinine, and urea nitrogen were determined biochemically. Kidney pathology was examined through HE staining and renal tubulointerstitial pathological scoring. The expression of α-SMA, CD34, PCNA, and TGF-β in renal tissue was detected using immunohistochemistry. Apoptosis of renal tubular epithelial cells was assessed using the TUNEL method.

Results: Hyperuricemia markedly worsens renal damage in rats following nephrectomy, while tea polyphenols demonstrate the ability to reduce levels of blood uric acid, urea nitrogen, creatinine, and urinary protein. Additionally, tea polyphenols enhance smooth muscle proliferation in renal glomerular arterioles, prevent the loss of interstitial capillaries, alleviate apoptosis of renal tubular epithelial cells, promote their proliferation, and reduce interstitial fibrosis. A significant improvement in the severity of renal damage is observed in rats subjected to nephrectomy combined with hyperuricemia, and this effect surpasses that of allopurinol.

Conclusion: Tea polyphenols could effectively alleviate renal damage in rats with nephrectomy combined with hyperuricemia. They demonstrate high cost-effectiveness and minimal side effects, positioning them as a promising new therapeutic option for hyperuricemia- induced renal damage.

CDK2 plays a pivotal role in controlling the cell cycle progression in eukaryotes and for this reason, it has been the subject of several studies for suitable inhibitors in the last decades. But more than 30 years of basic research have not generated an inhibitor as marketed drugs. Some inhibitors are to date in early phase clinical development. Moreover, most efforts to develop CDK2 inhibitors have been oriented towards orthosteric inhibitors, which block the kinase activity by binding to the ATP binding site, competing directly with ATP. These compounds have off-target kinase activity, because of the structural homology of the active sites of several other kinases. Targeting the CDK2 allosteric binding pocket could produce successful CDK2 inhibitors. Few examples of high-affinity allosteric CDK2 inhibitors are known. Despite promising research results, none has been approved for marketing. In recent years, various methodologies have been reported capable of identifying new and never-discovered portions of the target protein, which present adequate druggability characteristics. In this paper, we have highlighted and discussed the more recent findings on allosteric inhibitors intending to encouraging further exploration mainly focused on in silico drug discovery.

The medical and cosmetic industries have developed in recent years, there has been a growing demand for new materials. Gold nanoparticles (Au NPs) and chitosan (CS) have been known and used for many years. Unfortunately, despite their numerous advantages and possible applications, such materials may possess certain disadvantages and limitations that constitute a problem in medical or cosmetic applications. Au NPs may have potential toxicity depending on their size, shape, charge, surface coatings, and tendency to agglomerate into larger clusters. On the other hand, the CS production process requires strict control due to the possibility of uncontrolled hydrolysis or chemical modifications during polymer isolation. The combination of Au NPs and CS that differ in chemical and phase in one composite (Au/CS) allows for acquiring of new material with many advantages. The obtained composite has good mechanical properties and is biocompatible due to the presence of CS and the antibacterial properties of Au NPs. Therefore, it can be successfully used in many branches of medicine, including gene delivery, cell encapsulation, wound healing process, or as a preservative ingredient of cosmetics. Moreover, Au/CS nanocomposites are used in the food industry and environmental protection. This review highlights the preparation routes, properties, and applications of Au NPs and CS as separate materials. Moreover, the last part presents the advantages of combining these two materials into one nanocomposite. Specifically, we described the role of CS in the synthesis of Au NPs and possible subsequent applications of such nanomaterials as an element of biosensors, scaffolds, and an intelligent drug release system or tissue engineering.

Introduction/objective: The responsiveness to dietary interventions is influenced by complex, multifactorial interactions among genetics, diet, lifestyle, gut microbiome, environmental factors, and clinical characteristics, such as the metabolic phenotype. Detailed metabolic and microbial phenotyping using large human datasets is essential for better understanding the link between diet, the gut microbiome, and host metabolism in cardiovascular diseases (CVD). This review provides an overview of the interplay between diet, genome, metabolome, and gut microbiome in CVD.

Methods: A literature review was conducted using PubMed and Scopus databases to identify pertinent cohort studies published between January 2022 and May 2024. This review focused on English articles that assessed the interplay of diet, genome, metabolome, and gut microbiome in relation to CVD in humans.

Results: This narrative review explored the role of single-omics technologies-genomics, metabolomics, and the gut microbiome-and multi-omics approaches to understand the molecular basis of the relationship between diet and CVD. Omics technologies enabled the identification of new genes, metabolites, and molecular mechanisms related to the association of diet and CVD. The integration of multiple omics approaches allows for more detailed phenotyping, offering a broader perspective on how dietary factors influence CVD.

Conclusion: Omics approaches hold great potential for deciphering the intricate crosstalk between diet, genome, gut microbiome, and metabolome, as well as their roles in CVD. Although large-scale studies integrating multiple omics in CVD research are still limited, notable progress has been made in uncovering molecular mechanisms. These findings could guide the development of targeted dietary strategies and guidelines to prevent CVD.

Chronic pain lasting more than three months or persisting after normal healing is a significant global health issue. In a healthcare system, it is crucial to ensure proper chronic pain management. Traditional pharmacological and non-pharmacological pain management techniques may not fully meet the requirements of physicians regarding effectiveness and safety. Therefore, researchers are exploring natural analgesics. Plant-based phytoconstituents show promise in relieving chronic pain associated with various diseases. This study aims to review the latest advances in discovering natural bioactive compounds that can help alleviate chronic pain. It discusses the pathways of chronic pain and a multifactorial treatment strategy. It also organizes data on using plant- derived substances, such as cannabinoids, terpenoids, phenolics, and crude extracts. Additionally, it delves into the pharmacodynamics of cannabinoids, including their route of administration and elimination. The review presents the results of 22 clinical trials on various cannabinoids for pain relief. It is important to note that opioids and other alkaloids from plants are not covered in this article due to their primary use in controlling acute rather than chronic pain.