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BACKGROUND: Natural products have a long history in drug discovery. Lycorine is an alkaloid derived from Amaryllidaceae plants, demonstrating significant pharmacological potential. Lycorine and its hydrochloride salt, lycorine hydrochloride, have shown outstanding anticancer effects both in vitro and in vivo. PURPOSE: This review aims to comprehensively summarize recent research advancements regarding the anticancer potential of lycorine and lycorine hydrochloride. It intends to elucidate current research limitations, optimization strategies, and future research directions to guide clinical translation. METHODS: Various databases, e.g., Web of Science, PubMed, and Chinese National Knowledge Infrastructure, are systematically searched for relevant articles using keywords such as lycorine, cancer, pharmacokinetics, and toxicity. The retrieved literature is then categorized and summarized to provide an overview of the research advancements in the anticancer potential of lycorine and lycorine hydrochloride. RESULTS: Lycorine and lycorine hydrochloride demonstrate significant anticancer activities against various types of cancer both in vitro and in vivo, employing diverse mechanisms such as inducing cell cycle arrest, triggering cellular senescence, regulating programmed cell death, inhibiting angiogenesis, suppressing metastasis, and modulating immune system. Furthermore, pharmacokinetic profiles and toxicity data are summarized. Additionally, this review discusses the druggability, limitations, optimization strategies, and target identification of lycorine, offering insights for future preclinical studies. CONCLUSION: The anticancer effects and safety profile of lycorine and lycorine hydrochloride suggest promising potential for clinical applications. Further research on their in-depth mechanisms and optimization strategies targeting their limitations will enhance the understanding and druggability of lycorine and lycorine hydrochloride.
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Triple-negative breast cancer (TNBC) is a highly lethal malignancy, and its clinical management encounters severe challenges due to its high metastatic propensity and the absence of effective therapeutic targets. To improve druggability of aurovertin B (AVB), a natural polyketide with a significant antiproliferative effect on TNBC, a series of NO donor/AVB hybrids were synthesized and tested for bioactivities. Among them, compound 4d significantly inhibited the proliferation and metastasis of TNBC in vitro and in vivo with better safety than that of AVB. The structure-activity relationship analysis suggested that the types of NO donor and the linkers had considerable effects on the activities. Mechanistic investigations unveiled that 4d induced apoptosis and ferroptosis by the reduction of mitochondrial membrane potential and the down-regulation of GPX4, respectively. The antimetastatic effect of 4d was associated with the upregulation of DUSP1. Overall, these compelling results underscore the tremendous potential of 4d for treating TNBC.
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Antineoplásicos , Apoptosis , Ferroptosis , Donantes de Óxido Nítrico , Neoplasias de la Mama Triple Negativas , Animales , Femenino , Humanos , Ratones , Antineoplásicos/farmacología , Antineoplásicos/química , Antineoplásicos/síntesis química , Antineoplásicos/uso terapéutico , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Descubrimiento de Drogas , Ensayos de Selección de Medicamentos Antitumorales , Ferroptosis/efectos de los fármacos , Ratones Endogámicos BALB C , Ratones Desnudos , Estructura Molecular , Donantes de Óxido Nítrico/farmacología , Donantes de Óxido Nítrico/química , Donantes de Óxido Nítrico/uso terapéutico , Donantes de Óxido Nítrico/síntesis química , Relación Estructura-Actividad , Neoplasias de la Mama Triple Negativas/tratamiento farmacológico , Neoplasias de la Mama Triple Negativas/patología , Neoplasias de la Mama Triple Negativas/metabolismo , Oxadiazoles/química , Oxadiazoles/farmacología , Piranos/química , Piranos/farmacologíaRESUMEN
OBJECTIVES: The economic implications of combining rezvilutamide with androgen deprivation therapy (ADT) remain uncertain, despite the observed survival advantages compared with bicalutamide plus ADT. Therefore, this study evaluates the cost-effectiveness of rezvilutamide plus ADT as the first-line treatment of metastatic hormone-sensitive prostate cancer (mHSPC) from the perspective of the Chinese healthcare system. DESIGN: A partitioned survival model was developed to assess the cost-effectiveness of rezvilutamide combined with ADT. Clinical data were obtained from the CHART trial. Costs and utility values were obtained from local estimate and published literature. Only direct medical costs were included in the model. INTERVENTIONS: Rezvilutamide was administered at 240 mg daily or bicalutamide at 50 mg daily until progression. OUTCOME MEASURES: The main outputs of the model included costs and quality-adjusted life years (QALYs), which were used to determine the incremental cost-effectiveness ratio (ICER). One-way and probabilistic sensitivity analysis (PSA) were used to explore model uncertainties. RESULTS: The rezvilutamide group showed an expected gain of 2.28 QALYs and an incremental cost of US$60 758.82 compared with the bicalutamide group. The ICER for rezvilutamide group versus bicalutamide group was US$26 656.94 per QALY. The variables with the greatest impact on the model results were the utility for progression-free survival state and the price of rezvilutamide. PSA revealed that rezvilutamide group had 100% probability of being cost-effective at a willingness-to-pay threshold of US$35707.5 per QALY. CONCLUSION: Rezvilutamide in combination with ADT is more cost-effective compared with bicalutamide plus ADT as the first-line treatment of mHSPC from the perspective of the Chinese healthcare system.
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Antagonistas de Andrógenos , Anilidas , Análisis Costo-Beneficio , Nitrilos , Neoplasias de la Próstata , Años de Vida Ajustados por Calidad de Vida , Compuestos de Tosilo , Humanos , Masculino , Compuestos de Tosilo/uso terapéutico , Compuestos de Tosilo/economía , Anilidas/economía , Anilidas/uso terapéutico , Nitrilos/uso terapéutico , Nitrilos/economía , Neoplasias de la Próstata/tratamiento farmacológico , Neoplasias de la Próstata/economía , Neoplasias de la Próstata/patología , Antagonistas de Andrógenos/economía , Antagonistas de Andrógenos/uso terapéutico , Anciano , China , Persona de Mediana Edad , Análisis de Costo-EfectividadRESUMEN
Triple-negative breast cancer (TNBC) is characterized by high mortality rates primarily due to its propensity for metastasis. Addressing this challenge necessitates the development of effective antimetastatic therapies. This study aimed to identify natural compounds with potential antimetastatic properties mainly based on the high-throughput phenotypic screening system. This system, utilizing luciferase reporter gene assays combined with scratch wound assays, evaluates compounds based on their influence on the epithelial-mesenchymal transition (EMT) marker E-cadherin. Through this approach, aurovertin B (AVB) was revealed to have significant antimetastatic capability. Notably, AVB exhibited substantial metastasis suppression in many TNBC cell lines, including MDA-MB-231, HCC1937 and 4T1. Also, its remarkable antimetastatic activity was demonstrated in vivo via the orthotopic breast cancer mouse model. Further exploration revealed a pronounced association between AVB-induced upregulation of DUSP1 (dual-specificity phosphatase 1) and its inhibitory effect on TNBC metastasis. Additionally, microarray analysis conducted to elucidate the underlying mechanism of the AVB-DUSP1 interaction identified ATF3 (activating transcription factor 3) as a critical transcription factor instrumental in DUSP1 transcriptional activation. This discovery, coupled with observations of enhanced ATF3-DUSP1 expression and consequent reduction in TNBC metastatic foci in response to AVB, provides novel insights into the molecular mechanisms driving metastasis in TNBC. Significance Statement We construct a high-throughput phenotypic screening system utilizing EMT marker E-cadherin promoter luciferase reporter gene combined with scratch wound assays. Aurovertin B was revealed to possess significant antimetastatic activity through this approach, which was further demonstrated via in vivo and in vitro experiments. The discovery of the regulatory role of the ATF3-DUSP1 pathway enriches our understanding of TNBC metastasis mechanism and suggests the potential of ATF3 and DUSP1 as biomarkers for diagnosing TNBC metastasis.
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OBJECTIVES: We aimed to evaluate and compare the risk of hematological adverse events (AEs) associated with CDK4/6 inhibitors using data from randomized controlled trials (RCTs) and Food and Drug Adverse Event Reporting System (FAERS) database. METHODS: The PubMed, Embase, and Cochrane Library databases were searched for RCTs related to abemaciclib, palbociclib, and ribociclib. A network meta-analysis (NMA) was conducted to compare the risks of hematological AEs, and a disproportionality analysis was performed to detect signals of hematological AEs. RESULTS: 16 RCTs comprising 16,350 breast cancer patients were included. Palbociclib and ribociclib had similar risks for hematological AEs, except a higher risk of grade 3-4 leukopenia observed with palbociclib (risk ratio [RR]: 7.84, 95% confidence interval [95%CI]: 1.33-41.28). Abemaciclib had a higher risk of anemia than both ribociclib (grade 1-4: RR: 2.23, 95% CI: 1.25 - 3.96; grade 3-4: RR: 3.52, 95% CI: 1.59 - 8.11) and palbociclib (grade 1-4: RR: 1.65, 95%CI: 1.03 - 2.59), but a lower risk of grade 3-4 of both leukopenia (RR: 0.12, 95%CI: 0.02 - 0.49) and neutropenia (RR: 0.15, 95%CI: 0.04 - 0.52) compared with palbociclib. Signals indicating occurrence of leukopenia, neutropenia, anemia, and thrombocytopenia were identified for three CDK4/6 inhibitors. CONCLUSION: Abemaciclib, palbociclib, and ribociclib showed significant but inconsistent hematological toxicity risks.
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Herein, we describe an electroreductive cross-electrophile coupling protocol for the construction of valuable monofluoroalkenes from easily accessible alkyl or alkenyl halides with gem-difluoroalkenes. The reaction can be conducted under sustainable and mild conditions delivering valuable and functionalized monofluoroalkenes with excellent Z-selectivity. The protocol's most notable advantage is the in situ release of nickel catalyst from the inexpensive electrodes without the addition of extra hazardous metal catalyst and superstoichiometric reductant.
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In our search for neuroprotective agents, six previously undescribed highly oxidized guaiane sesquiterpenes, linderaggrols A-F (1-6), together with three known sesquiterpenes, were isolated from the roots of Lindera aggregata (Sims) Kosterm. Their structures including absolute configurations were established by a combination of NMR spectroscopic techniques and single crystal X-ray diffraction experiments. Compounds 1-6 represented the first instances of guaiane 12(8),15(6)-dilactones. Additionally, compound 6 possessed a rare 1,8-O-bridge. Neuroprotective effects against erastin-induced ferroptosis on HT-22 cells showed that some compounds demonstrated neuroprotective effects at 20.0 µM.
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Lindera , Fármacos Neuroprotectores , Raíces de Plantas , Fármacos Neuroprotectores/farmacología , Fármacos Neuroprotectores/química , Fármacos Neuroprotectores/aislamiento & purificación , Raíces de Plantas/química , Lindera/química , Estructura Molecular , Oxidación-Reducción , Sesquiterpenos de Guayano/química , Sesquiterpenos de Guayano/farmacología , Sesquiterpenos de Guayano/aislamiento & purificación , Ratones , Lactonas/farmacología , Lactonas/química , Lactonas/aislamiento & purificación , Animales , Supervivencia Celular/efectos de los fármacos , Línea Celular , Relación Estructura-Actividad , Relación Dosis-Respuesta a Droga , Modelos MolecularesRESUMEN
Cyclic peptides are gaining attention for their strong binding affinity, low toxicity, and ability to target "undruggable" proteins; however, their therapeutic potential against intracellular targets is constrained by their limited membrane permeability, and researchers need much time and money to test this property in the laboratory. Herein, we propose an innovative multimodal model called Multi_CycGT, which combines a graph convolutional network (GCN) and a transformer to extract one- and two-dimensional features for predicting cyclic peptide permeability. The extensive benchmarking experiments show that our Multi_CycGT model can attain state-of-the-art performance, with an average accuracy of 0.8206 and an area under the curve of 0.8650, and demonstrates satisfactory generalization ability on several external data sets. To the best of our knowledge, it is the first deep learning-based attempt to predict the membrane permeability of cyclic peptides, which is beneficial in accelerating the design of cyclic peptide active drugs in medicinal chemistry and chemical biology applications.
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Aprendizaje Profundo , Permeabilidad de la Membrana Celular , Química Farmacéutica , Péptidos Cíclicos/farmacología , PermeabilidadRESUMEN
An electroreductive cross-electrophile coupling protocol was developed for the construction of valuable 1,3-dienes from vinyl bromides. Furthermore, this scalable method can also be used to forge complex [4 + 2] cycloadducts in a one-pot manner. One of the most important advantages of this green and sustainable protocol is the in situ release of nickel catalyst from the inexpensive electrodes without the addition of extra harmful metal catalysts and reductant.
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It has been 11 years since ferroptosis, a new mode of programmed cell death, was first proposed. Natural products are an important source of drug discovery. In the past five years, natural product-derived ferroptosis regulators have been discovered in an endless stream. Herein, 178 natural products discovered so far to trigger or resist ferroptosis are classified into 6 structural classes based on skeleton type, and the mechanisms of action that have been reported are elaborated upon. If pharmacodynamic data are sufficient, the structure and bioactivity relationship is also presented. This review will provide medicinal chemists with some effective ferroptosis regulators, which will promote the research of natural product-based treatment of ferroptosis-related diseases in the future.
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Productos Biológicos , Ferroptosis , Fosfolípido Hidroperóxido Glutatión Peroxidasa/metabolismo , Fosfolípido Hidroperóxido Glutatión Peroxidasa/farmacología , Peroxidación de Lípido , Apoptosis , Productos Biológicos/farmacologíaRESUMEN
Linderagatins C-F (1-4), the first examples of naturally occurring diaryltetrahydrofuran-type 7,9'-dinorlignans, were characterized from the roots of Lindera aggregata (Sims) Kosterm. The structures of these dinorlignans were elucidated by extensive spectroscopic analysis. The absolute configurations were determined based on calculated and experimental ECD data. A biosynthetic pathway for these dinorlignans was hypothetically proposed. Compounds 2 and 3 showed significant neuroprotective effects on erastin-induced ferroptosis in HT-22 cells with EC50 values of 23.4 and 21.8 µM, respectively.
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Lindera , Sesquiterpenos , Lindera/química , Sesquiterpenos/química , Raíces de Plantas/químicaRESUMEN
The genus of Ainsliaea embraces approximately 70 recognized species, many of which have been used to treat various diseases in folklore medicines. As the main metabolites of Ainsliaea plants, Ainsliaea sesquiterpenoids have drawn considerable attention in related scientific communities due to their intriguing structures and a variety of bioactivities. In this review, we intend to provide a full-aspect coverage of sesquiterpenoids reported from the genus of Ainsliaea, including 145 monomeric sesquiterpenoids and 30 oligomeric ones. Multiple aspects will be summarized, including their classification, distributions, structures, bioactivities, and biomimetic syntheses. In addition, their possible biosynthetic pathway will be discussed in detail.
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Asteraceae , Sesquiterpenos , Estructura Molecular , Sesquiterpenos/farmacología , Sesquiterpenos/química , Asteraceae/química , Extractos Vegetales/químicaRESUMEN
Cytisine derivatives are a group of alkaloids containing the structural core of cytisine, which are mainly distributed in Fabaceae plants with a wide range of pharmacological activities, such as resisting inflammation, tumors, and viruses, and affecting the central nervous system. At present, a total of 193 natural cytisine and its derivatives have been reported, all of which are derived from L-lysine. In this study, natural cytisine derivatives were classified into eight types, namely cytisine type, sparteine type, albine type, angustifoline type, camoensidine type, cytisine-like type, tsukushinamine type, and lupanacosmine type. This study reviewed the research progress on the structures, plant sources, biosynthesis, and pharmacological activities of alkaloids of various types.
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Alcaloides , Fabaceae , Alcaloides/farmacología , Alcaloides/química , Quinolizinas/farmacología , Azocinas/farmacología , Azocinas/químicaRESUMEN
Two polysaccharides, named APS2-I and APS3-I, were purified from the water extract of Radix Astragali. The average molecular weight of APS2-I was 1.96 × 106 Da and composed of Man, Rha, GlcA, GalA, Glc, Gal, Xyl, and Ara in a molar ratio of 2.3:4.8:1.7:14.0:5.8:11.7:2.8:12.6, while the average molecular weight of APS3-I was 3.91 × 106 Da and composed of Rha, GalA, Glc, Gal, and Ara in a molar ratio of 0.8:2.3:0.8:2.3:4.1. Biological evaluation showed APS2-I and APS3-I had significant antioxidant activity and myocardial protection activity. Furthermore, total polysaccharide treatment could significantly enhance hemodynamic parameters and improve cardiac function in rat ischemia and reperfusion isolated heart models. These results provided important information for the clinical application of APS in the field of cardiovascular disease and implied that Astragalus polysaccharides (APS) could be considered as a reference for the quality control of Radix Astragali.
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Planta del Astrágalo , Medicamentos Herbarios Chinos , Ratas , Animales , Polisacáridos/química , Medicamentos Herbarios Chinos/farmacología , Medicamentos Herbarios Chinos/química , Astragalus propinquus , Planta del Astrágalo/químicaRESUMEN
Compounds of natural sources are widespread discovered in the treatment of ischemic stroke. Alpha-mangostin, a natural prenylated xanthone, has been found to display a therapeutic potential to treat ischemic stroke. However, the direct application of α-mangostin is limited due to its cytotoxicity and relatively low efficacy. Herein, structural modification of α-mangostin was necessary to improve its drug-ability. Currently, 34 α-mangostin phenylcarbamoyl derivatives were synthesized and evaluated for their neuroprotective activities by glutamate-induced excitotoxicity and H2O2-induced oxidative damage models in vitro. The results showed that compound 2 had the most therapeutic potential in both models. Whereafter, 2 has been proved to have powerful therapeutic effects by the MCAO ischemic stroke model in rats, which might be due to inhibition of inflammatory reaction and free radical accumulation. Besides, acute toxicity assay in rats showed that compound 2 had excellent safety. Overall, 2 could be a promising neuroprotective agent for the treatment of ischemic stroke deserving further investigations.
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Accidente Cerebrovascular Isquémico , Fármacos Neuroprotectores , Accidente Cerebrovascular , Xantonas , Ratas , Animales , Fármacos Neuroprotectores/farmacología , Fármacos Neuroprotectores/uso terapéutico , Accidente Cerebrovascular Isquémico/tratamiento farmacológico , Peróxido de Hidrógeno/farmacología , Estrés Oxidativo , Xantonas/farmacología , Xantonas/uso terapéutico , Xantonas/química , Accidente Cerebrovascular/tratamiento farmacológicoRESUMEN
Efficient biosynthesis of microbial bioactive natural products (NPs) is beneficial for the survival of producers, while self-protection is necessary to avoid self-harm resulting from over-accumulation of NPs. The underlying mechanisms for the effective but tolerable production of bioactive NPs are not well understood. Herein, in the biosynthesis of two fungal polyketide mycotoxins aurovertinâ E (1) and asteltoxin, we show that the cyclases in the gene clusters promote the release of the polyketide backbone, and reveal that a signal peptide is crucial for their subcellular localization and full activity. Meanwhile, the fungus adopts enzymatic acetylation as the major detoxification pathway of 1. If intermediates are over-produced, the non-enzymatic shunt pathways work as salvage pathways to avoid excessive accumulation of the toxic metabolites for self-protection. These findings provided new insight into the interplay of efficient backbone release and multiple detoxification strategies for the production of fungal bioactive NPs.
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Micotoxinas , Policétidos , Policétidos/metabolismo , Sintasas Poliquetidas/genética , Sintasas Poliquetidas/metabolismo , Procesamiento Proteico-Postraduccional , Familia de MultigenesRESUMEN
Covering: 2013 to 2021As the characteristic metabolites of Euphorbia plants, Euphorbia diterpenoids have always been a hot topic in related science communities due to their intriguing structures and broad bioactivities. In this review, we intent to provide an in-depth and extensive coverage of Euphorbia diterpenoids reported from 2013 to the end of 2021, including 997 new Euphorbia diterpenoids and 78 known ones with latest progress. Multiple aspects will be summarized, including their occurrences, chemical structures, bioactivities, and syntheses, in which the structure-activity relationship and biosynthesis of this class will be discussed for the first time.
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Diterpenos , Euphorbia , Euphorbia/química , Diterpenos/farmacología , Diterpenos/química , Relación Estructura-Actividad , Estructura MolecularRESUMEN
A serial jatrophane-type diterpenoids, comprised with three undescribed compounds kanesulones C-E (1-3) and four known ones (4-7), were obtained from the roots of Euphorbia kansui. The structures of compounds 1-3 were elucidated by detailed interpretation of their spectroscopic data, especially 2D-NMR and HR-ESI-MS, the absolute configuration of 1 was revealed by single crystal X-ray diffraction. These isolates were assayed for their multidrug resistance reversing activities on human breast adenocarcinoma cell line MCF-7/ADR. Compound 1 possessed potential as low toxic MDR modulator that could promote the efficacy of anticancer drug adriamycin ca. 85-fold at 5â µM, as 12â times stronger than the positive drug verapamil.
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Diterpenos , Euphorbia , Humanos , Euphorbia/química , Estructura Molecular , Diterpenos/farmacología , Diterpenos/química , Resistencia a Múltiples MedicamentosRESUMEN
α-Glucosidase (AGS) is a therapeutic target for Type 2 diabetes mellitus (T2DM) that tends to complicate with other diseases. Some medications for the treatment of T2DM complications have the risk of inducing severe adverse reactions such as diarrhea via the metabolism of intestinal bacterial ß-glucuronidase (BGUS). The development of new AGS and/or BGUS inhibitors may improve the therapeutic effects of T2DM and its complications. The present work focused on the isolation and characterization of AGS and/or BGUS inhibitors from the medicinal plant Schisandra sphaerandra. A total of eight compounds were isolated and identified. Sphaerandralide A (1) was obtained as a previously undescribed triterpenoid, which may have chemotaxonomy significance in the authentication of the genus Schisandra and Kadsura. 2'-acetyl-4',4-dimethoxybiphenyl-2-carbaldehyde (8) was obtained from a plant source for the first time, while compounds 2-7 were isolated from S. sphaerandra for the first time. In the in vitro assay, compounds 1-5 showed potent to moderate activity against AGS. Interestingly, compound 3 also exhibited significant BGUS inhibitory activity, demonstrating the potential of being developed as a bifunctional inhibitor that may find application in the therapy of T2DM and/or the diarrhea induced by medications for the treatment of T2DM complications.
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This is the first phytochemical investigation of Schisandra tomentella A. C. Smith. 11 lignans and 8 sesquiterpenoids, were isolated from the stems of S. tomentella, including two undescribed lignans, tomentaschinins A-B (1-2), and two new sesquiterpenoids, tomentaschinnes A-B (3-4). Their structures were elucidated based on the interpretation of their spectroscopic data. Cytotoxicity and MDR reversal effect of these compounds were screened on multidrug resistance cancer cell line MCF-7/ADR, and results showed gomisin M2 (7) could promote the efficacy of adriamycin against MCF-7/ADR.