RESUMEN

Introduction: Lipid-based nanoparticles (LNPs) is increasingly recognized for their potential in drug delivery, offering protection to hydrophobic drugs from degradation. Industrial synthesis of LNPs, exemplified by Pfizer-BioNTech and Moderna mRNA vaccines, utilizes flow chemistry or microfluidics, showcasing its scalability. This study explores the utilization of a novel design reactor, the vortex tube reactor, within flow chemistry for LNPs synthesis, aiming to optimize its conditions and compare them with batch synthesis. Methods: LNPs were synthesized using the vortex tube reactor, incorporating bovine serum albumin (BSA) as a model drug in the aqueous phase, alongside 1.2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) and cholesterol in the organic phase. Design of experiments (DoE), specifically Box-Behnken design, was employed to optimize parameters, including X1: the flow rate ratio (10-100 mL/min), X2: the aqueous-to-organic volumetric ratio (1:1-10:1), and X3: the number of reactor units (1-5 units). Responses evaluated encompassed physical properties and productivity. Optimized conditions were determined by minimizing particle size (Y1), polydispersity index (Y2), and zeta potential (Y3), while maximizing entrapment efficiency (Y4), drug loading (Y5), and productivity (Y5). Results: Results indicated that optimal conditions were achieved at X1 of 100 mL/min, X2 of 5.278, and X3 of 1 unit. LNPs synthesized under these conditions exhibited favorable physical properties and productivity, with uniformity maintained across batches. The vortex tube reactor demonstrated superiority over batch synthesis, yielding smaller particles (166.23 ± 0.98 nm), more uniform nanoparticles (PDI 0.17 ± 0.01), and higher entrapment (67.75 ± 1.55%) and loading capacities (36.39 ± 0.83%), indicative of enhanced productivity (313.4 ± 12.88 mg/min). Conclusion: This study elucidates the potential of flow chemistry, particularly utilizing the vortex tube reactor, for large-scale LNPs formulation, offering insights into parameter relationships and advancing nanoparticle synthesis for drug delivery applications.

Asunto(s)

Nanopartículas , Tamaño de la Partícula , Albúmina Sérica Bovina , Albúmina Sérica Bovina/química , Nanopartículas/química , Lípidos/química , 1,2-Dipalmitoilfosfatidilcolina/química , Colesterol/química , Animales , Productos Biológicos/química , Composición de Medicamentos/métodos , Sistemas de Liberación de Medicamentos/métodos , Sistemas de Liberación de Medicamentos/instrumentación

RESUMEN

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was identified as the novel coronavirus that caused a life-threatening viral illness (COVID-19) at the end of 2019. Within a short period of time, this virus spread leading to tremendous loss of life and economic damage. Medications to treat this virus are not yet established, and the process of implementing new strategies for medications is time-consuming. Recent clinical studies revealed the abandonment of the most promising candidates, who later became potential leads. Only through comprehensive study for safety and efficacy the medications, which have already received approval, be repurposed for use in different therapeutic purposes. Natural sources are being used arbitrarily as antiviral drugs and immunity boosters because there are no clear therapies on the horizon. It has long been known that most natural compounds have strong antiviral properties including SARS-CoV-2. Natural remedies have been demonstrated to have inhibitory effects on MERS-CoV and SARS-CoV infections. The non-structural proteins of the virus, such as PLPRO, MPRO, and RdRp, as well as structural proteins like the spike (S) protein, have been demonstrated to have a substantial binding affinity and an inhibitory effect by a variety of natural products, according to in silico research. The virus also demonstrates to be a legitimate target for therapeutic development since it makes use of the host cell's transmembrane ACE2 receptor. In this chapter, we highlight on the potential of alkaloids, phenolic and polyphenolic compounds, flavonoids, terpenoids, cardiac glycosides, and natural products from marine sources against the human coronavirus via different mode of actions. Most of the studied metabolites act either by inhibiting virus replication or by blocking the active site of the protein of the virus either in silico or ex vivo. This review serves as a topic for further study and to discover other secondary metabolites for COVID-19 management.

Asunto(s)

Antivirales , Productos Biológicos , Tratamiento Farmacológico de COVID-19 , COVID-19 , SARS-CoV-2 , Humanos , Antivirales/uso terapéutico , Antivirales/farmacología , SARS-CoV-2/efectos de los fármacos , Productos Biológicos/uso terapéutico , Productos Biológicos/farmacología , Productos Biológicos/química , COVID-19/virología , Reposicionamiento de Medicamentos

RESUMEN

The Veratrum alkaloids are a class of highly intricate natural products renowned for their complex structural and stereochemical characteristics, which underlie a diverse array of pharmacological activities ranging from anti-hypertensive properties to antimicrobial effects. These properties have generated substantial interest among both synthetic chemists and biologists. While numerous advancements have been made in the synthesis of jervanine and veratramine subtypes over the past 50 years, the total synthesis of highly oxidized cevanine subtypes has remained relatively scarce. Building on the efficiency of our previously developed strategy for constructing the hexacyclic carbon skeleton of the Veratrum alkaloid family via a stereoselective intramolecular Diels-Alder reaction and radical cyclization, here we show the development of a unified synthetic approach to access highly oxidized Veratrum alkaloids. This includes the total synthesis of (-)-zygadenine, (-)-germine, (-)-protoverine and the alkamine of veramadine A, by capitalizing on a meticulously designed sequence of redox manipulations and a late-stage neighboring-group participation strategy.

Asunto(s)

Alcaloides de Veratrum , Estereoisomerismo , Alcaloides de Veratrum/síntesis química , Alcaloides de Veratrum/química , Alcaloides de Veratrum/farmacología , Oxidación-Reducción , Ciclización , Reacción de Cicloadición , Productos Biológicos/síntesis química , Productos Biológicos/química , Productos Biológicos/farmacología , Estructura Molecular

RESUMEN

Obesity is acknowledged as a significant risk factor for various metabolic diseases, and the inhibition of human pancreatic lipase (hPL) can impede lipid digestion and absorption, thereby offering potential benefits for obesity treatment. Anthraquinones is a kind of natural and synthetic compounds with wide application. In this study, the inhibitory effects of 31 anthraquinones on hPL were evaluated. The data shows that AQ7, AQ26, and AQ27 demonstrated significant inhibitory activity against hPL, and exhibited selectivity towards other known serine hydrolases. Then the structure-activity relationship between anthraquinones and hPL was further analysed. AQ7 was found to be a mixed inhibition of hPL through inhibition kinetics, while AQ26 and AQ27 were effective non-competitive inhibition of hPL. Molecular docking data revealed that AQ7, AQ26, and AQ27 all could associate with the site of hPL. Developing hPL inhibitors for obesity prevention and treatment could be simplified with this novel and promising lead compound.

Asunto(s)

Antraquinonas , Relación Dosis-Respuesta a Droga , Descubrimiento de Drogas , Inhibidores Enzimáticos , Lipasa , Páncreas , Relación Estructura-Actividad , Antraquinonas/farmacología , Antraquinonas/química , Antraquinonas/síntesis química , Lipasa/antagonistas & inhibidores , Lipasa/metabolismo , Humanos , Inhibidores Enzimáticos/farmacología , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/síntesis química , Estructura Molecular , Páncreas/enzimología , Simulación del Acoplamiento Molecular , Productos Biológicos/farmacología , Productos Biológicos/química , Productos Biológicos/síntesis química

RESUMEN

Natural products containing the carboxy-2H-azirine moiety are an exciting target for investigation due to their broad-spectrum antimicrobial activity and new chemical space they afford for novel therapeutic development. The carboxy-2H-azirine moiety, including those appended to well-characterized chemical scaffolds, is understudied, which creates a challenge for understanding potential modes of inhibition. In particular, some known natural product carboxy-2H-azirines have long hydrophobic tails, which could implicate them in membrane-associated processes. In this study, we examined a small set of carboxy-2H-azirine natural products with varied structural features that could alter membrane partitioning. We compared the predicted membrane partitioning and alignment of these compounds to those of established membrane embedders with similar chemical scaffolds. To accomplish this, we developed parameters within the framework of the CHARMM36 force field for the 2H-azirine functional group and performed metadynamics simulations of the partitioning into a model bacterial membrane from aqueous solution. We determined that the carboxy-2H-azirine functional group is strongly hydrophilic, imbuing the long-chain natural products with amphipathicity similar to the known membrane-embedding molecules to which they were compared. For the long-chain analogs, the carboxy-2H-azirine head group stays within 1 nm of the phosphate layer, while the hydrophobic tail sits within the membrane. The carboxy-2H-azirine lacking the long alkyl chain instead partitions completely into aqueous solution.

Asunto(s)

Azirinas , Productos Biológicos , Simulación de Dinámica Molecular , Productos Biológicos/química , Productos Biológicos/farmacología , Azirinas/química , Interacciones Hidrofóbicas e Hidrofílicas , Membrana Celular/química , Termodinámica , Estructura Molecular

RESUMEN

Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer, and STAT3 has emerged as an effective drug target for TNBC treatment. Herein, we employed a scaffold-hopping strategy of natural products to develop a series of naphthoquinone-furopiperidine derivatives as novel STAT3 inhibitors. The in vitro assay showed that compound 10g possessed higher antiproliferative activity than Cryptotanshinone and Napabucasin against TNBC cell lines, along with lower toxicity and potent antitumor activity in a TNBC xenograft model. Mechanistically, 10g could inhibit the phosphorylation of STAT3 and the binding affinity was determined by the SPR assay (KD = 8.30 µM). Molecule docking studies suggested a plausible binding mode between 10g and the SH2 domain, in which the piperidine fragment and the terminal hydroxy group of 10g played an important role in demonstrating the success of this evolution strategy. These findings provide a natural product-inspired novel STAT3 inhibitor for TNBC treatment.

Asunto(s)

Antineoplásicos , Productos Biológicos , Proliferación Celular , Simulación del Acoplamiento Molecular , Naftoquinonas , Piperidinas , Factor de Transcripción STAT3 , Neoplasias de la Mama Triple Negativas , Factor de Transcripción STAT3/antagonistas & inhibidores , Factor de Transcripción STAT3/metabolismo , Humanos , Neoplasias de la Mama Triple Negativas/tratamiento farmacológico , Neoplasias de la Mama Triple Negativas/patología , Naftoquinonas/farmacología , Naftoquinonas/química , Naftoquinonas/síntesis química , Naftoquinonas/uso terapéutico , Productos Biológicos/farmacología , Productos Biológicos/química , Productos Biológicos/síntesis química , Piperidinas/farmacología , Piperidinas/química , Piperidinas/síntesis química , Piperidinas/uso terapéutico , Animales , Femenino , Antineoplásicos/farmacología , Antineoplásicos/química , Antineoplásicos/síntesis química , Antineoplásicos/uso terapéutico , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Ratones , Relación Estructura-Actividad , Ratones Desnudos , Ensayos Antitumor por Modelo de Xenoinjerto , Descubrimiento de Drogas , Ratones Endogámicos BALB C , Ensayos de Selección de Medicamentos Antitumorales

RESUMEN

The epidermal growth factor (EGF) receptor (EGFR) is activated by the binding of one of seven EGF-like ligands to its ectodomain. Ligand binding results in EGFR dimerization and stabilization of the active receptor conformation subsequently leading to activation of downstream signaling. Aberrant activation of EGFR contributes to cancer progression through EGFR overexpression/amplification, modulation of its positive and negative regulators, and/or activating mutations within EGFR. EGFR targeted therapeutic antibodies prevent dimerization and interaction with endogenous ligands by binding the ectodomain of EGFR. However, these antibodies have had limited success in the clinic, partially due to EGFR ectodomain resistance mutations, and are only applicable to a subset of patients with EGFR-driven cancers. These limitations suggest that alternative EGFR targeted biologics need to be explored for EGFR-driven cancer therapy. To this end, we analyze the EGFR interfaces of known inhibitory biologics with determined structures in the context of endogenous ligands, using the Rosetta macromolecular modeling software to highlight the most important interactions on a per-residue basis. We use this analysis to identify the structural determinants of EGFR targeted biologics. We suggest that commonly observed binding motifs serve as the basis for rational design of new EGFR targeted biologics, such as peptides, antibodies, and nanobodies.

Asunto(s)

Receptores ErbB , Receptores ErbB/química , Receptores ErbB/antagonistas & inhibidores , Receptores ErbB/metabolismo , Receptores ErbB/genética , Humanos , Productos Biológicos/química , Productos Biológicos/farmacología , Productos Biológicos/metabolismo , Modelos Moleculares , Unión Proteica , Sitios de Unión , Diseño de Fármacos , Ligandos

RESUMEN

Chalcones have been utilized for centuries as foods and medicines across various cultures and traditions worldwide. This paper concisely overviews their biosynthesis as specialized metabolites in plants and their significance, potential, efficacy, and possibility as future medicines. This is followed by a more in-depth exploration of naturally occurring chalcones and their corresponding mechanisms of action in human bodies. Based on their mechanisms of action, chalcones exhibit many pharmacological properties, including antioxidant, anti-inflammatory, anticancer, antimalarial, antiviral, and antibacterial properties. Novel naturally occurring chalcones are also recognized as potential antidiabetic drugs, and their effect on the GLUT-4 transporter is investigated. In addition, they are examined for their anti-inflammatory effects, focusing on chalcones used for future pharmaceutical utilization. Chalcones also bind to specific receptors and toxins that prevent bacterial and viral infections. Chalcones exhibit physiological protective effects on the biological degradation of different systems, including demyelinating neurodegenerative diseases and preventing hypertension or hyperlipidemia. Chalcones that are/were in clinical trials have been included as a separate section. By revealing the many biological roles of chalcones and their impact on medicine, this paper underlines the significance of naturally occurring chalcones and their extension to patient care, providing the audience with an index of topic-relevant information.

Asunto(s)

Chalconas , Chalconas/farmacología , Chalconas/química , Humanos , Ensayos Clínicos como Asunto , Animales , Antiinflamatorios/farmacología , Antiinflamatorios/química , Antiinflamatorios/uso terapéutico , Antioxidantes/farmacología , Antioxidantes/química , Hipoglucemiantes/farmacología , Hipoglucemiantes/química , Hipoglucemiantes/uso terapéutico , Productos Biológicos/farmacología , Productos Biológicos/química , Productos Biológicos/uso terapéutico

RESUMEN

Lamellarins are natural products with a [3,4]-fused pyrrolocoumarin skeleton possessing interesting biological properties. More than 70 members have been isolated from diverse marine organisms, such as sponges, ascidians, mollusks, and tunicates. There is a continuous interest in the synthesis of these compounds. In this review, the synthetic strategies for the synthesis of the title compounds are presented along with their biological properties. Three routes are followed for the synthesis of lamellarins. Initially, pyrrole derivatives are the starting or intermediate compounds, and then they are fused to isoquinoline or a coumarin moiety. Second, isoquinoline is the starting compound fused to an indole moiety. In the last route, coumarins are the starting compounds, which are fused to a pyrrole moiety and an isoquinoline scaffold. The synthesis of isolamellarins, azacoumestans, isoazacoumestans, and analogues is also described. The above synthesis is achieved via metal-catalyzed cross-coupling, [3 + 2] cycloaddition, substitution, and lactonization reactions. The title compounds exhibit cytotoxic, multidrug resistance (MDR), topoisomerase I-targeted antitumor, anti-HIV, antiproliferative, anti-neurodegenerative disease, and anti-inflammatory activities.

Asunto(s)

Cumarinas , Cumarinas/química , Cumarinas/síntesis química , Cumarinas/farmacología , Humanos , Animales , Productos Biológicos/química , Productos Biológicos/síntesis química , Productos Biológicos/farmacología , Isoquinolinas/química , Isoquinolinas/síntesis química , Isoquinolinas/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/farmacología , Antineoplásicos/química , Pirroles/química , Pirroles/síntesis química , Pirroles/farmacología , Estructura Molecular , Compuestos Heterocíclicos de 4 o más Anillos

RESUMEN

Molecularly Imprinted Microspheres (MIMs) or Microsphere Molecularly Imprinted Polymers represent an innovative design for the selective extraction of active compounds from natural products, showcasing effectiveness and cost-efficiency. MIMs, crosslinked polymers with specific binding sites for template molecules, overcome irregularities observed in traditional Molecularly Imprinted Polymers (MIPs). Their adaptability to the shape and size of target molecules allows for the capture of compounds from complex mixtures. This review article delves into exploring the potential practical applications of MIMs, particularly in the extraction of active compounds from natural products. Additionally, it provides insights into the broader development of MIM technology for the purification of active compounds. The synthesis of MIMs encompasses various methods, including precipitation polymerization, suspension polymerization, Pickering emulsion polymerization, and Controlled/Living Radical Precipitation Polymerization. These methods enable the formation of MIPs with controlled particle sizes suitable for diverse analytical applications. Control over the template-to-monomer ratio, solvent type, reaction temperature, and polymerization time is crucial to ensure the successful synthesis of MIPs effective in isolating active compounds from natural products. MIMs have been utilized to isolate various active compounds from natural products, such as aristolochic acids from Aristolochia manshuriensis and flavonoids from Rhododendron species, among others. Based on the review, suspension polymerization deposition, which is one of the techniques used in creating MIPs, can be classified under the MIM method. This is due to its ability to produce polymers that are more homogeneous and exhibit better selectivity compared to traditional MIP techniques. Additionally, this method can achieve recovery rates ranging from 94.91% to 113.53% and purities between 86.3% and 122%. The suspension polymerization process is relatively straightforward, allowing for the effective control of viscosity and temperature. Moreover, it is cost-effective as it utilizes water as the solvent.

Asunto(s)

Productos Biológicos , Microesferas , Impresión Molecular , Polímeros Impresos Molecularmente , Polimerizacion , Productos Biológicos/química , Impresión Molecular/métodos , Polímeros Impresos Molecularmente/química , Polímeros/química

RESUMEN

Two new sulfur glycosides, bursapastoris A-B (3-4), were extracted and isolated from shepherd's purse seed, along with two new natural products, 11-(methylsulfinyl)undecanoic acid (2) and 10-(methylsulfinyl)decanoic acid (1). Their structures were determined though infrared spectroscopy, one-dimensional nuclear magnetic resonance (1H and 13C), and electrospray ionization mass spectrometry. Additionally, the structures of 3-4 were further identified by two-dimensional nuclear magnetic resonance (HMBC, HSQC, 1H-1H COSY, and NOESY). Compounds 1-4 showed relatively favorable docking to NF-κB. Unfortunately, we only discovered that compound 1-4 had weak anti-radiation activity at present. Therefore, further research regarding the biological activity of these organosulfur compounds is required at a later stage.

Asunto(s)

Productos Biológicos , Glicósidos , Fitoquímicos , Semillas , Semillas/química , Glicósidos/química , Glicósidos/farmacología , Fitoquímicos/química , Fitoquímicos/farmacología , Productos Biológicos/química , Productos Biológicos/farmacología , Estructura Molecular , Azufre/química , Simulación del Acoplamiento Molecular , Espectroscopía de Resonancia Magnética , Extractos Vegetales/química , Extractos Vegetales/farmacología

RESUMEN

Galanthamine derivatives are known for their AChE inhibitory activity. Among them, galanthamine has been approved for treatment of Alzheimer's disease. N-Acetylnorgalanthamine (narcisine) and N-(2'-methyl)allylnorgalanthamine (the most potent natural AChE inhibitor of galanthamine type) were synthetized using N-norgalanthamine as a precursor. The NMR data described previously for narcisine were revised by two-dimensional 1H-1H and 1H-13C chemical shift correlation experiments. AChE inhibitory assays showed that N-acetylnorgalanthamine and N-formylnorgalanthamine (with previously unknown activity) are 4- and 43-times, respectively, less potent than galanthamine. In vitro (AChE inhibitory) and in silico (docking, ADME) assays and comparison of N-(2'-methyl)allylnorgalanthamine with galanthamine prove that this molecule is a very promising natural AChE inhibitor (33-times more potent than galanthamine) which further in vivo studies would provide better estimation about its applicability as a drug.

Asunto(s)

Acetilcolinesterasa , Inhibidores de la Colinesterasa , Galantamina , Inhibidores de la Colinesterasa/farmacología , Inhibidores de la Colinesterasa/química , Inhibidores de la Colinesterasa/síntesis química , Galantamina/farmacología , Galantamina/química , Galantamina/síntesis química , Acetilcolinesterasa/metabolismo , Relación Estructura-Actividad , Humanos , Estructura Molecular , Simulación del Acoplamiento Molecular , Productos Biológicos/química , Productos Biológicos/farmacología , Productos Biológicos/síntesis química , Relación Dosis-Respuesta a Droga

RESUMEN

A large scale of pandemic coronavirus disease (COVID-19) in the past five years motivates a great deal of endeavors donating to the exploration on therapeutic drugs against COVID-19 as well as other diseases caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Herein is an overview on the organic small molecules that are potentially employed to treat COVID-19 and other SARS-CoV-2-related diseases. These organic small molecules are accessed from both natural resources and synthetic strategies. Notably, typical natural products presented herein consist of polyphenols, lignans, alkaloids, terpenoids, and peptides, which exert an advantage for the further discovery of novel anti-COVID-19 drugs from plant herbs. On the other hand, synthetic prodrugs are composed of a series of inhibitors towards RNA-dependent RNA polymerase (RdRp), main protease (Mpro), 3-chymotrypsin-like cysteine protease (3CLpro), spike protein, papain-like protease (PLpro) of the SARS-CoV-2 as well as the angiotensin-converting enzyme 2 (ACE2) in the host cells. Synthetic strategies are worth taken into consideration because they are beneficial for designing novel anti-COVID-19 drugs in the coming investigations. Although examples collected herein are just a drop in the bucket, developments of organic small molecules against coronavirus infections are believed to pave a promising way for the discovery of multi-targeted therapeutic drugs against not only COVID-19 but also other virus-mediated diseases.

Asunto(s)

Antivirales , Productos Biológicos , Tratamiento Farmacológico de COVID-19 , SARS-CoV-2 , Productos Biológicos/química , Productos Biológicos/farmacología , Productos Biológicos/síntesis química , Humanos , Antivirales/farmacología , Antivirales/química , Antivirales/síntesis química , Antivirales/uso terapéutico , SARS-CoV-2/efectos de los fármacos , COVID-19/virología , Bibliotecas de Moléculas Pequeñas/química , Bibliotecas de Moléculas Pequeñas/farmacología , Bibliotecas de Moléculas Pequeñas/síntesis química , Profármacos/farmacología , Profármacos/química , Profármacos/síntesis química , Profármacos/uso terapéutico

RESUMEN

Natural products encompass a diverse range of compounds with high impact applications in consumer care, agriculture and most notably, therapeutics. However, despite the expansive chemical repertoire indicated in genomic information of microbes, only a small subset can be obtained under laboratory conditions. To increase accessible chemical space and realize Nature's full chemical potential, a multi-pronged genetic- and cultivation-based strategy has been employed to activate and upregulate natural product biosyntheses in native and heterologous strains. This data descriptor documents a characterized collection of 2,138 liquid chromatography-tandem mass spectrometry (LC/MS-MS) spectra of fermentation extracts from 54 native actinobacterial strains collected from soil and marine environments in Singapore, and their 459 activated mutants in 3 to 5 media. A total of 743 unique metabolites have been identified, with the activated mutants demonstrating an approximately 2-fold expansion in accessible chemical space over wild type strains. Interrogating this expanded chemical diversity with cheminformatic tools can provide direction for the discovery of novel natural products with desirable functional activity.

Asunto(s)

Actinobacteria , Mutación , Espectrometría de Masas en Tándem , Actinobacteria/genética , Actinobacteria/metabolismo , Cromatografía Liquida , Productos Biológicos/metabolismo , Productos Biológicos/química , Singapur , Microbiología del Suelo

RESUMEN

Xanthones are chemical substances in higher plants, marine organisms, and lower microorganisms. The most prevalent naturally occurring sources of xanthones are those belonging to the families Caryophyllaceae, Guttiferae, and Gentianaceae. Structurally, xanthones (9H xanthan-9-one) are heterocyclic compounds with oxygen and a γ-pyrone component. They are densely packed with a two-benzene ring structure. The carbons in xanthones are numbered from their nucleus and biosynthetic construct. They have mixed shikimate-acetate (higher plants) and acetate-malonate (lower organisms) biosynthetic origins, which influence their classification. Based on the level of oxidation of the C-ring, they are classified into monomers, dimers, and heterodimers. While based on the level of oxygenation or the type of ring residue, they can be categorized into mono-, di-, tri-, tetra-, penta- and hexa-oxygenated xanthones, bis-xanthones, prenylated and related xanthones, xanthonolignoids, and other miscellaneous xanthones. This structural diversity has made xanthones exhibit considerable biological properties as promising antioxidant, antifungal, antimicrobial, and anticancer agents. Structure-activity relationship studies suggest C-1, C-3, C-6, and C-8 as the key positions that influence the biological activity of xanthones. Furthermore, the presence of functional groups, such as prenyl, hydroxyl, glycosyl, furan, and pyran, at the key positions of xanthones, may contribute to their spectrum of biological activity. The unique chemical scaffolds of xanthones, their notable biological activities, and the structure-activity relationships of some lead molecules were discussed to identify lead molecules as possible drug candidates.

Asunto(s)

Xantonas , Xantonas/química , Relación Estructura-Actividad , Antioxidantes/química , Antioxidantes/farmacología , Humanos , Antiinfecciosos/química , Antiinfecciosos/farmacología , Estructura Molecular , Productos Biológicos/química , Productos Biológicos/farmacología

RESUMEN

The Jurassic relict Royal fern, Osmunda regalis L., is widely distributed across temperate zones in the Northern and Southern hemispheres. Even though this species has been utilised for centuries as a medicinal plant, its phytochemical composition mainly remains unknown. As part of our ongoing research to identify potential lead compounds for future anticancer drugs, 17 natural products were characterised from the aerial parts of Osmunda regalis L. Fifteen of these compounds were identified in this species for the first time, including the six previously undescribed compounds kaempferol 3-O-(2''-O-(2'''-α-rhamnopyranosyl)-ß-glucopyranosyl)-ß-glucopyranoside, quercetin 3-O-(2''-O-(2'''-α-rhamnopyranosyl)-ß-glucopyranosyl)-ß-glucopyranoside, kaempferol 3-O-(2''-O-(2'''-α-rhamnopyranosyl-6'''-O-(E)-caffeoyl-)-ß-glucopyranosyl)-ß-glucopyranoside, 3-methoxy-5-hydroxy-4-olide, 4-hydroxy-3-(3'-hydroxy-4'-(hydroxyethyl)-oxotetrafuranone-5-methyl tetrahydropyranone, and 4-O-(5-hydroxy-4-oxohexanoyl) osmundalactone. The molecular structures were determined by combining several 1D and 2D NMR experiments, circular dichroism spectroscopy, and HRMS. Determination of cytotoxicity against AML MOLM-13, H9c2, and NRK cell lines showed that two isolated lactones exhibited significant cytotoxic activity.

Asunto(s)

Productos Biológicos , Productos Biológicos/química , Productos Biológicos/farmacología , Humanos , Helechos/química , Antineoplásicos Fitogénicos/farmacología , Antineoplásicos Fitogénicos/química , Línea Celular Tumoral , Estructura Molecular , Extractos Vegetales/química , Extractos Vegetales/farmacología , Espectroscopía de Resonancia Magnética

RESUMEN

Natural compounds are important precursors for the synthesis of new drugs. The development of novel molecules that are useful for various diseases is the main goal of researchers, especially for the diagnosis and treatment of many diseases. Some pathologies need to be treated with radiopharmaceuticals, and, for this reason, radiopharmaceuticals that use the radiolabeling of natural derivates molecules are arousing more and more interest. Radiopharmaceuticals can be used for both diagnostic and therapeutic purposes depending on the radionuclide. ß+- and gamma-emitting radionuclides are used for diagnostic use for PET or SPECT imaging techniques, while α- and ß--emitting radionuclides are used for in metabolic radiotherapy. Based on these assumptions, the purpose of this review is to highlight the studies carried out in the last ten years, to search for potentially useful radiopharmaceuticals for nuclear medicine that use molecules of natural origin as lead structures. In this context, the main radiolabeled compounds containing natural products as scaffolds are analyzed, in particular curcumin, stilbene, chalcone, and benzofuran. Studies on structural and chemical modifications are emphasized in order to obtain a collection of potential radiopharmaceuticals that exploit the biological properties of molecules of natural origin. The radionuclides used to label these compounds are 68Ga, 44Sc, 18F, 64Cu, 99mTc, and 125I for diagnostic imaging.

Asunto(s)

Productos Biológicos , Medicina Nuclear , Radiofármacos , Radiofármacos/química , Productos Biológicos/química , Humanos , Medicina Nuclear/métodos , Tomografía de Emisión de Positrones/métodos , Radioisótopos/química , Animales , Marcaje Isotópico/métodos , Tomografía Computarizada de Emisión de Fotón Único/métodos

RESUMEN

MOTIVATION: This study aims to investigate non-covalent and non-peptide inhibitors of Mpro, a crucial protein target, by employing a comprehensive approach that integrates molecular docking, molecular dynamics simulations, and top-hits activity predictions. The focus is on elucidating the non-covalent and non-peptide binding modes of potential inhibitors with Mpro. METHODS: We employed a semi-flexible molecular docking methodology, binding score and ADME screening, which are based on structure, to screen compounds from CMNPD and HERB in silico. These methodologies allowed us to find potential candidates depending on their binding values and interactions with the binding site of main protease. To further evaluate the stability of these interactions, we conducted molecular dynamics simulations and calculated binding energies. Ultimately, a top-hits activity prediction method was employed to prioritize compounds based on their predicted inhibitory potential. RESULTS: Through a combination of binding energy calculations and activity predictions, we identified six potential inhibitor molecules exhibiting promising activity against Mpro. These compounds demonstrated favorable binding interactions and stability profiles, making them attractive candidates for further experimental validation and drug development efforts targeting Mpro.

Asunto(s)

Productos Biológicos , Simulación del Acoplamiento Molecular , Simulación de Dinámica Molecular , Productos Biológicos/química , Productos Biológicos/farmacología , Productos Biológicos/metabolismo , Humanos , Unión Proteica

RESUMEN

Cyclic acid anhydride is a not very widespread structure in nature, but with a determining role in natural products possessing this functionality in their skeleton. To the best of our knowledge, no revision of terpenes containing cyclic anhydrides has been previously reported. The result was that more than 100 terpenic cyclic anhydrides and related compounds were found to be in need of being reported. This review has been systematically organized by terpene skeletons, from the smallest to largest, describing their sources and bioactivities. In addition, different biosynthetic pathways for their final oxidations, namely, routes A, B and C, leading to the formation of these heterocyclic natural products, have been proposed. We have also included the most plausible precursors of these natural products, which mostly happened to be present in the same natural source. Some molecules derived from terpene cyclic anhydrides, such as their natural imide derivatives, have also been described due to their significant biological activity. In this sense, special attention has been paid to cantharidin because of its historical relevance and its broad bioactivity. A plausible biosynthesis of cantharidin has been proposed for the first time. Finally, cyclic anhydride structures that were firstly assigned as anhydrides and later corrected have been also described.

Asunto(s)

Anhídridos , Productos Biológicos , Terpenos , Terpenos/química , Terpenos/metabolismo , Anhídridos/química , Productos Biológicos/química , Productos Biológicos/metabolismo , Vías Biosintéticas , Humanos , Animales

RESUMEN

The potential of marine natural compounds for drug design is difficult to overestimate [...].

Asunto(s)

Organismos Acuáticos , Productos Biológicos , Productos Biológicos/farmacología , Productos Biológicos/química , Organismos Acuáticos/química , Animales , Humanos