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Multidrug resistant bacteria have been a global health threat currently and frontline clinical treatments for these infections are very limited. To develop potent antibacterial agents with new bactericidal mechanisms is thus needed urgently to address this critical antibiotic resistance challenge. Natural products are a treasure of small molecules with high bioactive and low toxicity. In the present study, we demonstrated that a natural compound, honokiol, showed potent antibacterial activity against a number of Gram-positive bacteria including MRSA and VRE. Moreover, honokiol in combination with clinically used ß-lactam antibiotics exhibits strong synergistic antimicrobial effects against drug-resistant S. aureus strains. Biochemical studies further reveal that honokiol may disrupt the GTPase activity, FtsZ polymerization, cell division. These biological impacts induced by honokiol may ultimately cause bacterial cell death. The in vivo antibacterial activity of honokiol against S. aureus infection was also verified with a biological model of G. mellonella larvae. The in vivo results support that honokiol is low toxic against the larvae and effectively increases the survival rate of the larvae infected with S. aureus. These findings demonstrate the potential of honokiol for further structural advancement as a new class of antibacterial agents with high potency against multidrug-resistant bacteria.
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Human telomerase reverse transcriptase (hTERT) may have noncanonical functions in transcriptional regulation and metabolic reprogramming in cancer cells, but it is a challenging target. We thus developed small-molecule ligands targeting hTERT promoter G-quadruplex DNA structures (hTERT G4) to downregulate hTERT expression. Ligand 5 showed high affinity toward hTERT G4 (Kd = 1.1 µM) and potent activity against triple-negative breast cancer cells (MDA-MB-231, IC50 = 1 µM). In cell-based assays, 5 not only exerts markedly inhibitory activity on classical telomere functions including decreased telomerase activity, shortened telomere length, and cellular senescence but also induces DNA damage, acute cellular senescence, and apoptosis. This study reveals that hTERT G4-targeting ligand may cause mitochondrial dysfunction, disrupt iron metabolism and activate ferroptosis in cancer cells. The in vivo antitumor efficacy of 5 was also evaluated in an MDA-MB-231 xenograft mouse model and approximately 78.7% tumor weight reduction was achieved. No observable toxicity against the major organs was observed.
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Antineoplásicos , Regulación hacia Abajo , G-Cuádruplex , Regiones Promotoras Genéticas , Telomerasa , Neoplasias de la Mama Triple Negativas , Telomerasa/antagonistas & inhibidores , Telomerasa/metabolismo , Humanos , G-Cuádruplex/efectos de los fármacos , Neoplasias de la Mama Triple Negativas/tratamiento farmacológico , Neoplasias de la Mama Triple Negativas/patología , Animales , Ligandos , Femenino , Regulación hacia Abajo/efectos de los fármacos , Ratones , Antineoplásicos/farmacología , Antineoplásicos/química , Antineoplásicos/uso terapéutico , Línea Celular Tumoral , Bibliotecas de Moléculas Pequeñas/química , Bibliotecas de Moléculas Pequeñas/farmacología , Apoptosis/efectos de los fármacos , Ensayos Antitumor por Modelo de Xenoinjerto , Ratones Desnudos , Senescencia Celular/efectos de los fármacos , Ratones Endogámicos BALB CRESUMEN
The rapid emergence of antibiotic resistance and the scarcity of novel antibacterial agents have necessitated an urgent pursuit for the discovery and development of novel antibacterial agents against multidrug-resistant bacteria. This study involved the design and synthesis of series of novel indole-benzosulfonamide oleanolic acid (OA) derivatives, in which the indole and benzosulfonamide pharmacophores were introduced into the OA skeleton semisynthetically. These target OA derivatives show antibacterial activity against Staphylococcus strains in vitro and in vivo. Among them, derivative c17 was the most promising antibacterial agent while compared with the positive control of norfloxacin, especially against methicillin-resistant Staphylococcus aureus (MRSA) in vitro. In addition, derivative c17 also showed remarkable efficacy against MRSA-infected murine skin model, leading to a significant reduction of bacterial counts during this in vivo study. Furthermore, some preliminary studies indicated that derivative c17 could effectively inhibit and eradicate the biofilm formation, disrupt the integrity of the bacterial cell membrane. Moreover, derivative c17 showed low hemolytic activity and low toxicity to mammalian cells of NIH 3T3 and HEK 293T. These aforementioned findings strongly support the potential of novel indole-benzosulfonamide OA derivatives as anti-MRSA agents.
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Antibacterianos , Diseño de Fármacos , Indoles , Staphylococcus aureus Resistente a Meticilina , Pruebas de Sensibilidad Microbiana , Ácido Oleanólico , Sulfonamidas , Staphylococcus aureus Resistente a Meticilina/efectos de los fármacos , Antibacterianos/farmacología , Antibacterianos/síntesis química , Antibacterianos/química , Ratones , Humanos , Animales , Relación Estructura-Actividad , Ácido Oleanólico/farmacología , Ácido Oleanólico/química , Ácido Oleanólico/síntesis química , Indoles/química , Indoles/farmacología , Indoles/síntesis química , Sulfonamidas/farmacología , Sulfonamidas/química , Sulfonamidas/síntesis química , Estructura Molecular , Células HEK293 , Células 3T3 NIH , Biopelículas/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Infecciones Estafilocócicas/tratamiento farmacológicoRESUMEN
Addressing the global challenge of bacterial resistance demands innovative approaches, among which multitargeting is a widely used strategy. Current strategies of multitargeting, typically achieved through drug combinations or single agents inherently aiming at multiple targets, face challenges such as stringent pharmacokinetic and pharmacodynamic requirements and cytotoxicity concerns. In this report, we propose a bacterial-specific global disruption approach as a vastly expanded multitargeting strategy that effectively disrupts bacterial subcellular organization. This effect is achieved through a pioneering chemical design of ligand-receptor interaction-induced aggregation of small molecules, i.e., DNA-induced aggregation of a diarginine peptidomimetic within bacterial cells. These intracellular aggregates display affinity toward various proteins and thus substantially interfere with essential bacterial functions and rupture bacterial cell membranes in an "inside-out" manner, leading to robust antibacterial activities and suppression of drug resistance. Additionally, biochemical analysis of macromolecule binding affinity, cytoplasmic localization patterns, and bacterial stress responses suggests that this bacterial-specific intracellular aggregation mechanism is fundamentally different from nonselective classic DNA or membrane binding mechanisms. These mechanistic distinctions, along with the peptidomimetic's selective permeation of bacterial membranes, contribute to its favorable biocompatibility and pharmacokinetic properties, enabling its in vivo antimicrobial efficacy in several animal models, including mice-based superficial wound models, subcutaneous abscess models, and septicemia infection models. These results highlight the great promise of ligand-receptor interaction-induced intracellular aggregation in achieving a globally disruptive multitargeting effect, thereby offering potential applications in the treatment of malignant cells, including pathogens, tumor cells, and infected tissues.
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Antibacterianos , Ligandos , Animales , Antibacterianos/farmacología , Antibacterianos/química , Ratones , Pruebas de Sensibilidad Microbiana , Farmacorresistencia Bacteriana/efectos de los fármacos , Peptidomiméticos/farmacología , Peptidomiméticos/química , Separación de FasesRESUMEN
Amid rising antibiotic resistance, the quest for advanced antibacterial agents to surpass microbial adaptation is paramount. This study introduces Pyrgos[n]cages (n = 1 to 4), pioneering multidecker cationic covalent organic cages engineered to combat drug-resistant bacteria via a dual-targeting approach. Synthesized through successive photocatalytic bromination and cage-forming reactions, these architectures stand out for their dense positive charge distribution, exceptional stability, and substantial rigidity. Pyrgos[n]cages exhibit potent bactericidal activity by disrupting bacterial membrane potential and binding to DNA. Notably, these structures show unparalleled success in eradicating both extracellular and intracellular drug-resistant pathogens in diverse infection scenarios, with antibacterial efficiency markedly increasing over 100-fold as the decker number rises from 1 to 3. This study provides an advance in antibacterial tactics and underscores the transformative potential of covalent organic cages in devising enduring countermeasures against antibiotic-resistant microbial threats.
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Antibacterianos , Pruebas de Sensibilidad Microbiana , Antibacterianos/farmacología , Antibacterianos/química , Farmacorresistencia Bacteriana/efectos de los fármacos , Humanos , Bacterias/efectos de los fármacosRESUMEN
Mitochondria are important drug targets for anticancer and other disease therapies. Certain human mitochondrial DNA sequences capable of forming G-quadruplex structures (G4s) are emerging drug targets of small molecules. Despite some mitochondria-selective ligands being reported for drug delivery against cancers, the ligand design is mostly limited to the triphenylphosphonium scaffold. The ligand designed with lipophilic small-sized scaffolds bearing multipositive charges targeting the unique feature of high mitochondrial membrane potential (MMP) is lacking and most mitochondria-selective ligands are not G4-targeting. Herein, we report a new small-sized dicationic lipophilic ligand to target MMP and mitochondrial DNA G4s to enhance drug delivery for anticancer. The ligand showed marked alteration of mitochondrial gene expression and substantial induction of ROS production, mitochondrial dysfunction, DNA damage, cellular senescence, and apoptosis. The ligand also exhibited high anticancer activity against HCT116 cancer cells (IC50, 3.4 µM) and high antitumor efficacy in the HCT116 tumor xenograft mouse model (â¼70% tumor weight reduction).
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Antineoplásicos , Neoplasias Colorrectales , G-Cuádruplex , Mitocondrias , Humanos , G-Cuádruplex/efectos de los fármacos , Ligandos , Animales , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo , Antineoplásicos/farmacología , Antineoplásicos/química , Antineoplásicos/síntesis química , Antineoplásicos/uso terapéutico , Ratones , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/patología , Neoplasias Colorrectales/metabolismo , Apoptosis/efectos de los fármacos , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Especies Reactivas de Oxígeno/metabolismo , Ratones Desnudos , Bibliotecas de Moléculas Pequeñas/química , Bibliotecas de Moléculas Pequeñas/farmacología , Bibliotecas de Moléculas Pequeñas/síntesis química , Ensayos Antitumor por Modelo de Xenoinjerto , Células HCT116 , ADN Mitocondrial/metabolismoRESUMEN
Twenty-seven rosmarinic acid derivatives were synthesized, among which compound RA-N8 exhibited the most potent antibacterial ability. The minimum inhibition concentration of RA-N8 against both S. aureus (ATCC 29213) and MRSA (ATCC BAA41 and ATCC 43300) was found to be 6 µg/mL, and RA-N8 killed E. coli (ATCC 25922) at 3 µg/mL in the presence of polymyxin B nonapeptide (PMBN) which increased the permeability of E. coli. RA-N8 exhibited a weak hemolytic effect at the minimum inhibitory concentration. SYTOX Green assay, SEM, and LIVE/DEAD fluorescence staining assay proved that the mode of action of RA-N8 is targeting bacterial cell membranes. Furthermore, no resistance in wildtype S. aureus developed after incubation with RA-N8 for 20 passages. Cytotoxicity studies further demonstrated that RA-N8 is non-toxic to the human normal cell line (HFF1). RA-N8 also exerted potent inhibitory ability against biofilm formation of S. aureus and even collapsed the shaped biofilm.
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Antibacterianos , Staphylococcus aureus Resistente a Meticilina , Humanos , Antibacterianos/química , Staphylococcus aureus , Ácido Rosmarínico , Escherichia coli , Relación Estructura-Actividad , Pruebas de Sensibilidad Microbiana , BiopelículasRESUMEN
rRNAs are prevalent in living organisms. They are produced in nucleolus and mitochondria and play essential cellular functions. In addition to the primary biofunction in protein synthesis, rRNAs have been recognized as the emerging signaling molecule and drug target for studies on nucleolus morphology, mitochondrial autophagy, and tumor cell malignancy. Currently, only a few rRNA-selective probes have been developed, and most of them encounter the drawbacks of low water solubility, poor nuclear membrane permeability, short emission wavelength, low stability against photobleaching, and high cytotoxicity. These unfavorable properties of rRNA probes limit their potential applications. In the present study, we reported a new rRNA-selective and near-infrared fluorescent turn-on probe, 4MPS-TO, capable of tracking rRNA in live human cancer cells. The real-time monitoring performance in nucleolus morphology and mitochondrial autophagy is demonstrated in HeLa cells. The probe shows great application potential for being used as a rRNA-selective, sensitive, and photostable imaging tool in chemical biology study and drug screening.
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Mitofagia , Neoplasias , Humanos , Células HeLa , Colorantes Fluorescentes/química , Imagen Óptica/métodos , AutofagiaRESUMEN
A smart and heavy-atom-free photoinactive nano-photosensitizer capable of being activated by cysteine at the tumor site to generate highly photoactive nano-photosensitizers that show strong NIR absorption and fluorescence with a good singlet oxygen quantum yield (16.8%) for photodynamic therapy is reported.
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Neoplasias , Fotoquimioterapia , Humanos , Fármacos Fotosensibilizantes/farmacología , Cisteína , Oxígeno Singlete , Neoplasias/tratamiento farmacológicoRESUMEN
The development of effective antibacterial drugs to combat bacterial infections, particularly the biofilm-related infections, remains a challenge. There are two important features of bacterial biofilms, which are well-known critical factors causing biofilms hard-to-treat in clinical, including the dense and impermeable extracellular polymeric substances (EPS) and the metabolically repressed dormant and persistent bacterial population embedded. These characteristics largely increase the difficulty for regular antibiotic treatment due to insufficient penetration into EPS. In addition, the dormant bacteria are insensitive to the growth-inhibiting mechanism of traditional antibiotics. Herein, we explore the potential of a series of new oligopyridinium-based oligomers bearing a multi-biomacromolecule targeting function as the potent bacterial biofilm eradication agent. These oligomers were rationally designed to be "charge-on-backbone" that can offer a special alternating amphiphilicity. This novel and unique feature endows high affinity to bacterial membrane lipids, DNAs as well as proteins. Such a broad multi-targeting nature of molecules not only enables its penetration into EPS, but also plays vital roles in the bactericidal mechanism of action that is highly effective against dormant and persistent bacteria. Our in vitro, ex vivo, and in vivo studies demonstrated that OPc3, one of the most effective derivatives, was able to offer excellent antibacterial potency against a variety of bacteria and effectively eliminate biofilms in zebrafish models and mouse wound biofilm infection models.
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Infecciones Bacterianas , Pez Cebra , Animales , Ratones , Biopelículas , Bacterias , Antibacterianos/farmacología , Antibacterianos/uso terapéutico , Infecciones Bacterianas/tratamiento farmacológico , Infecciones Bacterianas/microbiologíaRESUMEN
Catabolite control protein A (CcpA), an important global regulatory protein, is extensively found in S. aureus. Many studies have reported that CcpA plays a pivotal role in regulating the tricarboxylic acid cycle and pathogenicity. Moreover, the CcpA-knockout Staphylococcus aureus (S. aureus) in diabetic mice, compared with the wild-type, showed a reduced colonization rate in the tissues and organs and decreased inflammatory factor expression. However, the effect of CcpA-knockout S. aureus on the host's energy metabolism in a high-glucose environment and its mechanism of action remain unclear. S. aureus, a common and major human pathogen, is increasingly found in patients with obesity and diabetes, as recent clinical data reveal. To address this issue, we generated CcpA-knockout S. aureus strains with different genetic backgrounds to conduct in-depth investigations. In vitro experiments with high-glucose-treated cells and an in vivo model study with type 1 diabetic mice were used to evaluate the unknown effect of CcpA-knockout strains on both the glucose and lipid metabolism phenotypes of the host. We found that the strains caused an abnormal metabolic phenotype in type 1 diabetic mice, particularly in reducing random and fasting blood glucose and increasing triglyceride and fatty acid contents in the serum. In a high-glucose environment, CcpA-knockout S. aureus may activate the hepatic STAT5/PDK4 pathway and affect pyruvate utilization. An abnormal metabolic phenotype was thus observed in diabetic mice. Our findings provide a better understanding of the molecular mechanism of glucose and lipid metabolism disorders in diabetic patients infected with S. aureus.
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Intracellular bacterial pathogens, such as Staphylococcus aureus, that may hide in intracellular vacuoles represent the most significant manifestation of bacterial persistence. They are critically associated with chronic infections and antibiotic resistance, as conventional antibiotics are ineffective against such intracellular persisters due to permeability issues and mechanistic reasons. Direct subcellular targeting of S. aureus vacuoles suggests an explicit opportunity for the eradication of these persisters, but a comprehensive understanding of the chemical biology nature and significance of precise S. aureus vacuole targeting remains limited. Here, we report an oligoguanidine-based peptidomimetic that effectively targets and eradicates intracellular S. aureus persisters in the phagolysosome lumen, and this oligomer was utilized to reveal the mechanistic insights linking precise targeting to intracellular antimicrobial efficacy. The oligomer has high cellular uptake via a receptor-mediated endocytosis pathway and colocalizes with S. aureus persisters in phagolysosomes as a result of endosome-lysosome interconversion and lysosome-phagosome fusion. Moreover, the observation of a bacterium's altered susceptibility to the oligomer following a modification in its intracellular localization offers direct evidence of the critical importance of precise intracellular targeting. In addition, eradication of intracellular S. aureus persisters was achieved by the oligomer's membrane/DNA dual-targeting mechanism of action; therefore, its effectiveness is not hampered by the hibernation state of the persisters. Such precise subcellular targeting of S. aureus vacuoles also increases the agent's biocompatibility by minimizing its interaction with other organelles, endowing excellent in vivo bacterial targeting and therapeutic efficacy in animal models.
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Infecciones Estafilocócicas , Staphylococcus aureus , Animales , Antibacterianos/farmacología , Antibacterianos/uso terapéutico , Infecciones Estafilocócicas/tratamiento farmacológico , Infecciones Estafilocócicas/microbiología , Bacterias , Biología , Pruebas de Sensibilidad MicrobianaRESUMEN
Four previously undescribed hirsutinolide-type sesquiterpenoids, cyanolides A-D (1-4), along with twelve known analogues (5-16), were isolated from the aerial parts of Cyanthillium cinereum. Their structures were determined by comprehensive analysis of NMR, HRESIMS, and ECD spectra. Compound 1 is a rarely occurring hirsutinolide-type sesquiterpenoid with 1,4-ether ring ruptured and containing a chlorine atom, and compounds 13-16 were reported from this plant for the first time. All compounds were tested for their inhibiting effects on prostate cancer cells. As a result, compounds 1, 3, and 8-14 exhibited significant anti-prostate cancer activity against PC-3 and LNCaP cells with IC50 values ranging from 2.2 ± 0.4 to 8.5 ± 0.7 µM and 3.0 ± 0.7 to 10.5 ± 1.1 µM, respectively. The preliminary structure-activity relationship was discussed. Further investigation showed that compound 1 induced apoptosis in PC-3 cells.
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Asteraceae , Neoplasias de la Próstata , Sesquiterpenos , Masculino , Humanos , Estructura Molecular , Asteraceae/química , Sesquiterpenos/farmacología , Sesquiterpenos/química , Relación Estructura-Actividad , Neoplasias de la Próstata/tratamiento farmacológicoRESUMEN
RNA structures, including those formed from coding and noncoding RNAs, alternative to protein-based drug targets, could be a promising target of small molecules for drug discovery against various human diseases, particularly in anticancer, antibacterial and antivirus development. The normal cellular activity of cells is critically dependent on the function of various RNA molecules generated from DNA transcription. Moreover, many studies support that mRNA-targeting small molecules may regulate the synthesis of disease-related proteins via the non-covalent mRNA-ligand interactions that do not involve gene modification. RNA-ligand interaction is thus an attractive approach to address the challenge of "undruggable" proteins in drug discovery because the intracellular activity of these proteins is hard to be suppressed with small molecule ligands. We selectively surveyed a specific area of RNA structure-selective small molecule ligands in fluorescence live cell imaging and drug discovery because the area was currently underexplored. This state-of-the-art review thus mainly focuses on the research published within the past three years and aims to provide the most recent information on this research area; hopefully, it could be complementary to the previously reported reviews and give new insights into the future development on RNA-specific small molecule ligands for live cell imaging and drug discovery.
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ARN , Bibliotecas de Moléculas Pequeñas , Humanos , ARN/metabolismo , Ligandos , Bibliotecas de Moléculas Pequeñas/química , Descubrimiento de Drogas , ARN Mensajero , ProteínasRESUMEN
A large number of studies have shown that matrine (MA) possesses various pharmacological activities and is one of the few natural, plant-derived pesticides with the highest prospects for promotion and application. Fifty-eight MA derivatives were prepared, including 10 intermediates and 48 target compounds in 3 series, to develop novel mosquitocidal agents. Compounds 4b, 4e, 4f, 4m, 4n, 6e, 6k, 6m, and 6o showed good larvicidal activity against Aedes albopictus, which is both a highly aggressive mosquito and an important viral vector that can transmit a wide range of pathogens. Dipping methods and a bottle bioassay were used for insecticidal activity evaluation. The LC50 values of 4e, 4m, and 6m reached 147.65, 140.08, and 205.79 µg/mL, respectively, whereas the LC50 value of MA was 659.34 µg/mL. Structure-activity relationship analysis demonstrated that larvicidal activity could be improved by the unsaturated heterocyclic groups introduced into the carboxyl group after opening the D ring. The MA derivatives with oxidized N-1 lost their mosquitocidal activities, indicating that the bareness of N-1 is crucial to maintain their anti-mosquito activity. However, the activity was not greatly influenced by introducing a cyan group at C-6 or a benzene sulfonyl group at N-16. Additionally, compounds 4e and 4m exhibited good inhibitory activities against acetylcholinesterase with inhibitory rates of 59.12% and 54.30%, respectively, at a concentration of 250 µg/mL, whereas the inhibitory rate of MA was 9.88%. Therefore, the structural modification and mosquitocidal activity of MA and its derivatives obtained here pave the way for those seeking strong mosquitocidal agents of plant origin.
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Aedes , Insecticidas , Animales , Matrinas , Larva , Acetilcolinesterasa , Mosquitos Vectores , Insecticidas/farmacología , Insecticidas/químicaRESUMEN
Bacterial biofilms are major causes of persistent and recurrent infections and implant failures. Biofilms are formable by most clinically important pathogens worldwide, such as Staphylococcus aureus, Pseudomonas aeruginosa, and Escherichia coli, causing recalcitrance to standard antibiotic therapy or anti-biofilm strategies due to amphiphilic impermeable extracellular polymeric substances (EPS) and the presence of resistant and persistent bacteria within the biofilm matrix. Herein, we report our design of an oligoamidine-based amphiphilic "nano-sword" with high structural compacity and rigidity. Its rigid, amphiphilic structure ensures effective penetration into EPS, and the membrane-DNA dual-targeting mechanism exerts strong bactericidal effect on the dormant bacterial persisters within biofilms. The potency of this oligoamidine is shown in two distinct modes of application: it may be used as a coating agent for polycaprolactone to fully inhibit surface biofilm growth in an implant-site mimicking micro-environment; meanwhile, it cures model mice of biofilm infections in various ex vivo and in vivo studies.
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Biopelículas , Infecciones Estafilocócicas , Ratones , Animales , Matriz Extracelular de Sustancias Poliméricas , Staphylococcus aureus , Infecciones Estafilocócicas/tratamiento farmacológico , Antibacterianos/farmacología , Bacterias , Escherichia coli , Pseudomonas aeruginosaRESUMEN
The design and synthesis of multifunctional chitosan hydrogels based on polymerized ionic liquid and a near-infrared (NIR) fluorescent probe (PIL-CS) is a promising strategy, which not only prevents the transition from acute to chronic wounds, but also provides prompt measures regarding microenvironmental alterations in chronic wounds. PIL-CS hydrogel can real-time visualize wound pH through in vivo NIR fluorescent imaging and also feature the pH-responsive sustained drug release, such as antioxidant, to eliminate reactive oxygen species (ROS) and to boost diabetic wound healing. PIL-CS hydrogel is specific, sensitive, stable, and reversible in response to pH changes at the wound site. It, therefore, enables real-time monitoring for a dynamic pH change in the microenvironment of irregular wounds. PIL-CS hydrogel is also designed to possess many merits including high water containment and swelling rate, good biocompatibility, electrical conductivity, antifreeze, tissue adhesion, hemostatic performance, and efficient antibacterial activity against MRSA. In vivo studies showed that PIL-CS hydrogel provided fast diabetic wound healing support, promoted vascular endothelial growth factor (VEGF) production, and reduced ROS and tumor necrosis factor (TNF-α) generation. The results support that the hydrogels coupled with NIR fluorescent probes can be an excellent diabetic wound dressing for enhancing and real-time monitoring skin restoration and regeneration.
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Diabetes Mellitus , Hidrogeles , Hidrogeles/farmacología , Especies Reactivas de Oxígeno , Factor A de Crecimiento Endotelial Vascular , Vendajes , Cicatrización de Heridas , Colorantes Fluorescentes , Antibacterianos/farmacología , Concentración de Iones de HidrógenoRESUMEN
Two series of novel sophoridine derivatives were designed, synthesized, and evaluated for their anti-mosquito activity. SOP-2g, SOP-2q, and SOP-2r exhibited potential larvicidal activity against Aedes albopictus larva with LC50 values of 330.98, 430.53, and 411.09 ppm, respectively. Analysis of structure-activity relationships indicated that the oxime ester group was beneficial for improving the larvicidal biological activity, whereas the long-chain aliphatic group and fused-ring group were introduced. Furthermore, the larvicidal mechanism was also investigated based on the inhibition assay of acetylcholinesterase (AChE) and the morphological observation of dead larva treated with derivatives. Results indicated that the AChE inhibitory activity of the preferred three derivatives were 63.16%, 46.67%, and 35.11%, respectively, at 250 ppm concentration. Additionally, morphological evidence demonstrated that SOP-2q and SOP-2r induced changes in the larva's intestinal cavity, caudal gill, and tail, thereby displaying larvicidal action against Ae. albopictus together with AChE inhibition. Therefore, this study implied that sophoridine and its novel derivatives could be used to control the population of mosquito larva, which may also be effective alkaloids to reduce the mosquito population density.
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Fluorinated molecules are widely used in pharmaceutical and agrochemical industries. Herein we report the synthesis of 2-(3,3-difluoro-4-(silyloxy)but-1-en-1-yl)benzamides from the unprecedented rhodium(III)-catalyzed alkenylation of various benzamides with difluorohomoallylic silyl ethers. The practicability of this protocol is demonstrated by its broad substrate compatibility, good functional group tolerance, ready scalability and high regioselectivity. The oxygen in difluorohomoallylic silyl ethers makes ß-H elimination feasible, which suppresses both the ß-F elimination and dialkenylation of benzamides. This redox-neutral reaction proceeds efficiently via N-O bond cleavage without external oxidants and thus provides new opportunities for the synthesis of elaborate difluorinated compounds from readily available fluorinated synthons.
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The development of site-specific, target-selective and biocompatible small molecule ligands as a fluorescent tool for real-time study of cellular functions of RNA G-quadruplexes (G4s), which are associated with human cancers, is of significance in cancer biology. We report a fluorescent ligand that is a cytoplasm-specific and RNA G4-selective fluorescent biosensor in live HeLa cells. The inâ vitro results show that the ligand is highly selective targeting RNA G4s including VEGF, NRAS, BCL2 and TERRA. These G4s are recognized as human cancer hallmarks. Moreover, intracellular competition studies with BRACO19 and PDS, and the colocalization study with G4-specific antibody (BG4) in HeLa cells may support that the ligand selectively binds to G4s in cellulo. Furthermore, the ligand was demonstrated for the first time in the visualization and monitoring of dynamic resolving process of RNA G4s by the overexpressed RFP-tagged DHX36 helicase in live HeLa cells.