Britannin as a novel NLRP3 inhibitor, suppresses inflammasome activation in macrophages and alleviates NLRP3-related diseases in mice.

Overactivation of the NLRP3 inflammasomes induces production of pro-inflammatory cytokines and drives pathological processes. Pharmacological inhibition of NLRP3 is an explicit strategy for the treatment of inflammatory diseases. Thus far no drug specifically targeting NLRP3 has been approved by the FDA for clinical use. This study was aimed to discover novel NLRP3 inhibitors that could suppress NLRP3-mediated pyroptosis. We screened 95 natural products from our in-house library for their inhibitory activity on IL-1ß secretion in LPS + ATP-challenged BMDMs, found that Britannin exerted the most potent inhibitory effect with an IC50 value of 3.630 µM. We showed that Britannin (1, 5, 10 µM) dose-dependently inhibited secretion of the cleaved Caspase-1 (p20) and the mature IL-1ß, and suppressed NLRP3-mediated pyroptosis in both murine and human macrophages. We demonstrated that Britannin specifically inhibited the activation step of NLRP3 inflammasome in BMDMs via interrupting the assembly step, especially the interaction between NLRP3 and NEK7. We revealed that Britannin directly bound to NLRP3 NACHT domain at Arg335 and Gly271. Moreover, Britannin suppressed NLRP3 activation in an ATPase-independent way, suggesting it as a lead compound for design and development of novel NLRP3 inhibitors. In mouse models of MSU-induced gouty arthritis and LPS-induced acute lung injury (ALI), administration of Britannin (20 mg/kg, i.p.) significantly alleviated NLRP3-mediated inflammation; the therapeutic effects of Britannin were dismissed by NLRP3 knockout. In conclusion, Britannin is an effective natural NLRP3 inhibitor and a potential lead compound for the development of drugs targeting NLRP3.

Synthetic Routes and Clinical Application of Representative Small-Molecule EGFR Inhibitors for Cancer Therapy.

The epidermal growth factor receptor (EGFR) plays a pivotal role in cancer therapeutics, with small-molecule EGFR inhibitors emerging as significant agents in combating this disease. This review explores the synthesis and clinical utilization of EGFR inhibitors, starting with the indispensable role of EGFR in oncogenesis and emphasizing the intricate molecular aspects of the EGFR-signaling pathway. It subsequently provides information on the structural characteristics of representative small-molecule EGFR inhibitors in the clinic. The synthetic methods and associated challenges pertaining to these compounds are thoroughly examined, along with innovative strategies to overcome these obstacles. Furthermore, the review discusses the clinical applications of FDA-approved EGFR inhibitors such as erlotinib, gefitinib, afatinib, and osimertinib across various cancer types and their corresponding clinical outcomes. Additionally, it addresses the emergence of resistance mechanisms and potential counterstrategies. Taken together, this review aims to provide valuable insights for researchers, clinicians, and pharmaceutical scientists interested in comprehending the current landscape of small-molecule EGFR inhibitors.

One novel naphthalene derivative and other constituents with anti-complementary activities from the aerial parts of Dracocephalum moldavica.

One novel naphthalene derivative, 2-octa-2',4',6'-atriynenaphthalene (1), together with eighteen known compounds (2-19) were isolated from the aerial parts of Dracocephalum moldavica L. Compounds 2, 8, 10, 13, 15-17 and 19 were obtained from the family Lamiaceae for the first time, and compounds 11 and 18 were firstly identified from the genus of Dracocephalum. All the isolates were evaluated for anti-complementary activities through the classical and alternative pathways, and the targets of the most active compounds on the complement activation cascade were also investigated.

Two new phenolic glycosides from the fruits of Illicium verum.

Two new phenolic glycosides (1-2) and eleven known compounds (3-13) were isolated from the fruits of Illicium verum Hook.f. using silica-gel column and preparative middle pressure liquid chromatography (MPLC). The structures of the compounds were elucidated by NMR spectroscopic data. Among them, compounds 3, 5, and 10 were isolated from the family Magnoliaceae for the first time. Additionally, all the compounds were evaluated for their anti-complementary activities against the classical pathway (CP) and the alternative pathway (AP).

Synthesis, antitumor and antibacterial activities of cordycepin derivatives.

Twelve novel cordycepin derivatives were designed and synthesized with modification at positions of 2', 5'-hydroxyl and N6 amino groups of cordycepin. The results showed that the inhibitory activities of 3, 4b, 6c and 6d on A549 were comparable to the positive control gefitinib, and the inhibitory activity of 6a on A549 was better than that of gefitinib. Also, the inhibitory activities of twelve cordycepin derivatives against E. coli 1924, S. aureus 4220 and S. mutans 3289 were studied. Among them, 4b showed certain inhibitory on S. mutans 3289, while 6b showed certain inhibition on S. aureus 4220.

Two new stilbene glucosides and a new benzoic acid derivative from Tournefortia sibirica.

Two new stilbene glucosides, trans-3,5-dihydroxy-4-methoxystilbene 3-O-ß-D-glucopyranoside (1), cis-3,5-dihydroxy-4-methoxystilbene 3-O-ß-D-glucopyranoside (2), one new benzoic acid derivative, cis-4-hydroxy-3-hydroxymethyl-2-butenyl benzoate 4-O-ß-D-glucopyranoside (3), and four known compounds (4 - 7) were isolated from Tournefortia sibirica L. The structures of these compounds were elucidated on the basis of spectral data. Anti-inflammatory effects of compounds (1 - 7) were evaluated in terms of inhibition on production of NO, TNF-α and IL-6 in LPS-induced RAW 264.7 cells. Compounds 1, 2 and 5 - 7 could inhibit the levels of NO, TNF-α and IL-6 in LPS-induced RAW264.7 cells with IC50 values ranging from 40.96 to 88.76 µM.

Clinical effects and gut microbiota changes of using probiotics, prebiotics or synbiotics in inflammatory bowel disease: a systematic review and meta-analysis.

PURPOSE: Probiotics have been reported to be beneficial for inflammatory bowel disease (IBD), but the types, number of strains, dosage, and intervention time of probiotics used remain controversial. Furthermore, the changes of gut microbiota in IBD's patients are also intriguing. Thus, this meta-analysis was to explore the clinical effects and gut microbiota changes of using probiotics, prebiotics and synbiotics in IBD. METHODS: The search was performed in PubMed, Web of Science and the Cochrane library from inception to April 2020. Qualified randomized controlled trials were included. IBD's remission rate, disease activity index and recurrence rate were extracted and analyzed. Changes in the gut microbiota of patients with IBD are comprehensively described. RESULTS: Thirty-eight articles were included. Probiotics, prebiotics and synbiotics can induce/maintain IBD's remission and reduce ulcerative colitis (UC) disease activity index (RR = 1.13, 95% CI 1.02, 1.26, P < 0.05; SMD = 1.00, 95% CI 0.27, 1.73, P < 0.05). In subgroup analyses of IBD remission rate and UC disease activity index, we obtained some statistically significant results in some subgroup (P < 0.05). To some extent, probiotic supplements can increase the number of beneficial bacteria (especially Bifidobacteria) in the intestinal tract of patients with IBD. CONCLUSIONS: Our results support the treatment of IBD (especially UC) with pro/pre/synbiotics, and synbiotics are more effective. Probiotic supplements that are based on Lactobacillus and Bifidobacterium or more than one strain are more likely to be beneficial for IBD remission. The dose of 1010-1012 CFU/day may be a reference range for using probiotics to relieve IBD.

Synthesis and clinical application of representative small-molecule dipeptidyl Peptidase-4 (DPP-4) inhibitors for the treatment of type 2 diabetes mellitus (T2DM).

Diabetes mellitus is a chronic metabolic disorder characterized by high blood glucose levels, which can cause many diseases, including osteoporosis, fractures, arthritis, and foot complications. The inhibitors of dipeptidyl peptidase-4 (DPP-4), an enzyme involved in glucose metabolism regulation, are essential for managing Type 2 Diabetes Mellitus (T2DM). The inhibition of DPP-4 has become a promising treatment approach for T2DM because it can increase levels of active glucagon-like peptide-1 (GLP-1), leading to improved insulin secretion in response to glucose and reduced release of glucagon. The review commences by elucidating the role of DPP-4 in glucose homeostasis and its significance in T2DM pathophysiology. Furthermore, it presents the mechanism of action, preclinical pharmacodynamics, clinical efficacy, and toxicity profiles of small-molecule DPP-4 inhibitors across various clinical stages. This comprehensive review provides valuable insights into the synthesis and clinical application of DPP-4 inhibitors, serving as an invaluable resource for researchers, clinicians, and pharmaceutical professionals interested in diabetes therapeutics and drug development.

Synthesis and clinical application of new drugs approved by FDA in 2023.

In 2023, the U.S. Food and Drug Administration (FDA) granted approval to a total of 55 new drugs, comprising 29 new chemical entities (NCEs) and 25 new biological entities (NBEs). These drugs primarily focus on oncology, the central nervous system, anti-infection, hematology, cardiovascular, ophthalmology, immunomodulatory and other therapeutic areas. Out of the 55 drugs, 33 (60 %) underwent an accelerated review process and received approval, while 25 (45 %) were specifically approved for the treatment of rare diseases. The purpose of this review is to provide an overview of the clinical uses and production techniques of 29 newly FDA-approved NCEs in 2023. Our intention is to offer a comprehensive understanding of the synthetic approaches employed in the creation of these drug molecules, with the aim of inspiring the development of novel, efficient, and applicable synthetic methodologies.

A comprehensive review of small-molecule drugs for the treatment of type 2 diabetes mellitus: Synthetic approaches and clinical applications.

Type 2 diabetes mellitus (T2DM) is a long-term metabolic disorder characterized by the body's resistance to insulin and inadequate production of insulin. Small molecule drugs to treat T2DM mainly control blood sugar levels by improving insulin sensitivity, increasing insulin secretion, or reducing liver glycogen production. With the deepening of research on the pathogenesis of diabetes, many drugs with new targets and mechanisms of action have been discovered. The targets of the drugs for T2DM are mainly dipeptidyl peptidase IV inhibitors (DPP4), sodium/glucose cotransporter 2 inhibitors (SGLT2), sulfonylurea receptor modulators (SUR), peroxisome proliferator-activated receptor γ agonists (PPARγ), etc. We are of the opinion that acquiring a comprehensive comprehension of the synthetic procedures employed in drug molecule production will serve as a source of inventive and pragmatic inspiration for the advancement of novel, more potent, and feasible synthetic methodologies. This review aims to outline the clinical applications and synthetic routes of some representative drugs to treat T2DM, which will drive the discovery of new, more effective T2DM drugs.

Fluorine in the pharmaceutical industry: Synthetic approaches and application of clinically approved fluorine-enriched anti-infectious medications.

The strategic integration of fluorine atoms into anti-infectious agents has become a cornerstone in the field of medicinal chemistry, owing to the unique influence of fluorine on the chemical and biological properties of pharmaceuticals. This review examines the synthetic methodologies that enable the incorporation of fluorine into anti-infectious drugs, and the resultant clinical applications of these fluorine-enriched compounds. With a focus on clinically approved medications, the discussion extends to the molecular mechanisms. It further outlines the specific effects of fluorination, which contribute to the heightened efficacy of anti-infective therapies. By presenting a comprehensive analysis of current drugs and their developmental pathways, this review underscores the continuing evolution and significance of fluorine in advancing anti-infectious treatment options. The insights offered extend valuable guidance for future drug design and the development of next-generation anti-infectious agents.

Harmonizing the craft of crafting clinically endorsed small-molecule BCR-ABL tyrosine kinase inhibitors for the treatment of hematological malignancies.

The advancement and practical use of small-molecule tyrosine kinase inhibitors (TKIs) that specifically target the BCR-ABL fusion protein have introduced a revolutionary era of precision medicine for the treatment of chronic myeloid leukemia (CML) and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL). This review offers a comprehensive exploration of the synthesis, mechanisms of action, and clinical implementation of clinically validated TKIs in the context of BCR-ABL, emphasizing the remarkable strides made in achieving therapeutic precision. We delve into the intricate design and synthesis of these small molecules, highlighting the synthetic strategies and modifications that have led to increased selectivity, enhanced binding affinities, and reduced off-target effects. Additionally, we discuss the structural biology of BCR-ABL inhibition and how it informs drug design. The success of these compounds in inhibiting aberrant kinase activity is a testament to the meticulous refinement of the synthetic process. Furthermore, this review provides a detailed analysis of the clinical applications of these TKIs, covering not only their efficacy in achieving deep molecular responses but also their impact on patient outcomes, safety profiles, and resistance mechanisms. We explore ongoing research efforts to overcome resistance and enhance the therapeutic potential of these agents. In conclusion, the synthesis and utilization of clinically validated small-molecule TKIs targeting BCR-ABL exemplify the transformative power of precision medicine in the treatment of hematological malignancies. This review highlights the evolving landscape of BCR-ABL inhibition and underscores the continuous commitment to refining and expanding the therapeutic repertoire for these devastating diseases.

[Comparative study of transmission and reflection hyperspectral imaging technology for potato damage detection].

The randomly placed damage parts of potato will affect the detection accuracy, this paper used transmission and reflection hyperspectral imaging technology to acquire potato images of three directions(the damage part facing to the camera, back to the camera, side to the camera), and then processed the comparative study for damage detection. Independent component (IC) analysis was used to analyze the transmission and reflection hyperspectral images and to extract the features, the resulting char acteristics were used for the secondary IC analysis of the reflected images and the variable selection of the transmittance and re flectance spectroscopy. Finally, the potato injury qualitative recognition model was established based on the reflection images, the reflectance spectral and the transmittance spectral; Further optimization was done for high recognition accuracy of model, and secondary variable selection was carried out for the transmission spectrum by the Sub-window Permutation Analysis(SPA) and the optimal model for damage identification of potato randomly placed was established. The results of experiments show that the accuracy of the identification model based on the reflection image and the reflection spectrum is low, wherein the potato bruise based on the reflection images falls into the lowest recognition accuracy of 43. 10% when it is side to the camera; The accuracy of the model for identification based on the transmittance spectroscopy information is the highest, the recognition accuracy with the damage part facing and back to the camera is 100%t, and 99. 53% when it is side to the camera. The accuracy of the optimal model for identification based on the 3 kinds of transmittance spectroscopy information of randomly placed potato is 97. 39%. Then the application of transmission hyperspectral imaging technology could detect potato injury in any orientation, and the research can provide technical support for the online detection of potato quality.

Synthesis and clinical application of small-molecule inhibitors of Janus kinase.

Janus kinase (JAK) plays a crucial role in intracellular signaling pathways, particularly in cytokine-mediated signal transduction, making them attractive therapeutic targets for a wide range of diseases, including autoimmune disorders, myeloproliferative neoplasms, and inflammatory conditions. The review provides a comprehensive overview of the development and therapeutic potential of small-molecule inhibitors targeting JAK family of proteins in various clinical trials. It also discusses the mechanisms of action, specificity, and selectivity of these inhibitors, shedding light on the challenges associated with achieving target selectivity while minimizing off-target effects. Moreover, the review offers insights into the clinical applications of JAK inhibitors, summarizing the ongoing clinical trials and the Food and Drug Administration (FDA)-approved JAK inhibitors currently available for various diseases. Overall, this review provides a thorough examination of the synthesis and clinical use of typical small-molecule JAK inhibitors in different clinical stages and offers a bright future for the development of novel small-molecule JAK inhibitors.

Recent advance of clinically approved small-molecule drugs for the treatment of myeloid leukemia.

Myeloid leukemia denotes a hematologic malignancy characterized by aberrant proliferation and impaired differentiation of blood progenitor cells within the bone marrow. Despite the availability of several treatment options, the clinical outlook for individuals afflicted with myeloid leukemia continues to be unfavorable, making it a challenging disease to manage. Over the past, substantial endeavors have been dedicated to the identification of novel targets and the advancement of enhanced therapeutic modalities to ameliorate the management of this disease, resulting in the discovery of many clinically approved small-molecule drugs for myeloid leukemia, including histone deacetylase inhibitors, hypomethylating agents, and tyrosine kinase inhibitors. This comprehensive review succinctly presents an up-to-date assessment of the application and synthetic routes of clinically sanctioned small-molecule drugs employed in the treatment of myeloid leukemia. Additionally, it provides a concise exploration of the pertinent challenges and prospects encompassing drug resistance and toxicity. Overall, this review effectively underscores the considerable promise exhibited by clinically endorsed small-molecule drugs in the therapeutic realm of myeloid leukemia, while concurrently shedding light on the prospective avenues that may shape the future landscape of drug development within this domain.

Synthesis and application of small molecules approved for the treatment of lymphoma.

Lymphoma is a form of cancer that impacts the lymphatic system, which plays a crucial role in defending the body against infections and illnesses. It is characterized by the atypical proliferation of lymphocytes, a type of white blood cell, which can form tumors in the lymph nodes, bone marrow, spleen, etc. Lymphoma is usually treated using a combination of targeted therapy, chemotherapy, and radiation therapy. In recent years, there has been a growing interest in the development of new drugs to treat lymphoma, which has led to the discovery of several promising compounds. The primary targets for lymphoma treatment have been identified as Bruton's tyrosine kinase (BTK), phosphoinositide3-kinase (PI3K), histone deacetylase (HDAC), and DNA polymerase (POLA). This review aims to provide an overview of the clinical applications and synthesis of several notable drugs approved to treat lymphoma, to expedite the exploration of more potent novel medications for the management of lymphoma.

Advances of clinically approved small-molecule drugs for the treatment of non-small cell lung cancer.

Lung cancer continues to pose a significant challenge as a prominent contributor to global cancer-related mortality. Despite the considerable strides made in therapeutic interventions within the past decade, a substantial population of patients diagnosed with non-small cell lung cancer (NSCLC) still face the grim reality of an incurable condition. In the realm of optimal management strategies for individuals afflicted with locally advanced, yet amenable to surgical resection, NSCLC, a therapeutic approach encompassing chemoradiation stands as a fundamental component. Significant strides have been made in the therapeutic landscape of NSCLC during the preceding two decades, facilitating an enhanced comprehension of the underlying disease biology, and mechanisms governing tumor progression, as well as advancements in early detection modalities and multimodal therapeutic interventions. Nevertheless, the overall rates of curative interventions and survival outcomes for NSCLC continue to exhibit a discouragingly low trajectory, particularly in the context of metastatic disease. Hence, the imperative for sustained research endeavors in the realm of novel pharmaceutical agents and combinatorial therapeutic approaches remains paramount, with the overarching objective of broadening the scope of clinical advantages conferred upon a wider demographic of patients, thereby fostering tangible improvements in outcomes pertaining to NSCLC. The primary objective of this review is to provide an all-encompassing examination encompassing the clinical application and synthetic routes of specific drugs, with the explicit aim of disseminating invaluable knowledge that can inform future research and development endeavors focused on NSCLC.

Spectroscopic parameter and molecular constant investigations on low-lying states of BeF radical.

The potential energy curves (PECs) of X(2)∑(+), A(2)Π(r) and B(2)∑(+) states of BeF radical have been investigated using the complete active space self-consistent-field (CASSCF) method, followed by the highly accurate valence internally contracted multireference configuration interaction (MRCI) approach at the correlation-consistent basis sets, cc-pV5Z for Be and aug-cc-pV6Z for F. Based on the PECs of X(2)∑(+), A(2)Π(r) and B(2)∑(+) states, the spectroscopic parameters (D(e), R(e), ω(e), ω(e)χ(e), α(e) and B(e)) have also been determined in the present work. With the PECs determined at the present level of theory, vibrational states have been predicted for each state when the rotational quantum number J equals zero (J = 0). The vibrational levels, inertial rotation and centrifugal distortion constants are determined for the three states, and the classical turning points are also calculated for the X(2)∑(+) state. Compared with the available experiments and other theories, it can be seen that the present spectroscopic parameter and molecular constant results are more fully in agreement with the experimental findings.

A TD-DFT study on the hydrogen bonding of three esculetin complexes in electronically excited states: strengthening and weakening.

Time-dependent density functional theory (TD-DFT) method was used to study the excited-state hydrogen bonding of three esculetin complexes formed with aprotic solvents. The geometric structures, molecular orbitals (MOs), electronic spectra and the infrared (IR) spectra of the three doubly hydrogen-bonded complexes formed by esculetin and aprotic solvents dimethylsulfoxide (DMSO), tetrahyrofuran (THF) and acetonitrile (ACN) in both ground state S(0) and the first singlet excited state S(1) were calculated by the combined DFT and TD-DFT methods with the COSMO solvation model. Two intermolecular hydrogen bonds can be formed between esculetin and the aprotic solvent in each hydrogen-bonded complex. Based on the calculated bond lengths of the hydrogen bonds and the groups involved in the formation of the intermolecular hydrogen bonds in different electronic states, it is demonstrated that one of the two hydrogen bonds formed in each hydrogen-bonded complex is strengthened while the other one is weakened upon photoexcitation. Furthermore, it is found that the strength of the intermolecular hydrogen bonds formed in the three complexes becomes weaker as the solvents change from DMSO, via THF, to ACN, which is suggested to be due to the decrease of the hydrogen bond accepting (HBA) ability of the solvents. The spectral shifts of the calculated IR spectra further confirm the strengthening and weakening of the intermolecular hydrogen bonds upon the electronic excitation. The variations of the intermolecular hydrogen bond strengths in both S(0) and S(1) states are proposed to be the main reasons for the gradual spectral shifts in the absorption and fluorescence spectra both theoretically and experimentally.