ABSTRACT
Nucleolus was an important cellular organelle. The abnormal morphology and number of the nucleolus have been considered as diagnostic biomarkers for some human diseases. However, the imaging agent based on nucleolus was limited. In this manuscript, a series of nucleolar fluorescent probes based on naphthalimide derivatives (NI-1 â¼ NI-5) had been designed and synthesized. NI-1 â¼ NI-5 could penetrate cell membranes and nuclear membranes, achieve clear nucleolar staining in living cells. These results suggested that the presence of amino groups on the side chains of naphthalimide backbone could enhance the targeting to the cell nucleolus. In addition, the molecular docking results showed that NI-1 â¼ NI-5 formed hydrogen bonds and hydrophobic interactions with RNA, and exhibited enhanced fluorescence upon binding with RNA. These results will provide favorable support for the diagnosis and treatment of nucleolus-related diseases in the future.
Subject(s)
Cell Nucleolus , Naphthalimides , Humans , Cell Nucleolus/metabolism , Molecular Docking Simulation , RNA/metabolismABSTRACT
Synthetic glycoconjugates as chemical probes have been widely developed for the detection of glycosidase enzymes. However, the binding interactions between iminosugar derivatives and glycosidases were limited, especially for the binding interactions between multivalent glycosidase inhibitors and α-glycosidases. In this paper, three naphthalimide-DNJ conjugates were synthesized. Furthermore, the binding interactions and glycosidase inhibition effects of them were investigated. It was found that the strong binding interactions of multivalent glycosidase inhibitors with enzymes were related to the efficient inhibitory activity against glycosidase. Moreover, the lengths of the chain between DNJ moieties and the triazole ring for the naphthalimide-DNJ conjugates influenced the self-assembly properties, binding interactions and glycosidase inhibition activities with multisource glycosidases. Compound 13 with six carbons between the DNJ moiety and triazole ring showed the stronger binding interactions and better glycosidase inhibition activities against α-mannosidase (jack bean) and α-glucosidase (aspergillus niger). In addition, compound 13 showed an effective PBG inhibition effect in mice with 51.18 % decrease in blood glucose at 30 min. This result opens a way for detection of multivalent glycosidase inhibition effect by a fluorescent sensing method.
Subject(s)
Enzyme Inhibitors , Glycoside Hydrolases , Mice , Animals , Enzyme Inhibitors/chemistry , Glycoside Hydrolases/metabolism , Naphthalimides/pharmacology , Fluorescence , alpha-MannosidaseABSTRACT
This study aims to explore the mechanism of Yanghe Decoction(YHD) against subcutaneous tumor in pulmonary metastasis from breast cancer, which is expected to lay a basis for the treatment of breast carcinoma with YHD. The chemical components of medicinals in YHD, and the targets of the components were retrieved from Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform(TCMSP) and SwissTargetPrediction. The disease-related targets were searched from GeneCards and Online Mendelian Inheritance in Man(OMIM). Excel was employed to screen the common targets and plot the Venn diagram. The protein-protein interaction network was constructed. R language was used for Gene Ontology(GO) term enrichment and Kyoto Encyclopedia of Genes and Genomes(KEGG) pathway enrichment. A total of 53 female SPF Bablc/6 mice were randomized into normal group(same volume of normal saline, ig), model group(same volume of normal saline, ig), and low-dose and high-dose YHD groups(YHD, ig, 30 days), with 8 mice in normal group and 15 mice in each of the other groups. Body weight and tumor size was measured every day. Curves for body weight variation and growth of tumor in situ were plotted. In the end, the subcutaneous tumor sample was collected and observed based on hematoxylin and eosin(HE) staining. The mRNA and protein levels of hypoxia inducible factor-1α(HIF-1α), pyruvate kinase M2(PKM2), lactate dehydrogenase A(LDHA), and glucose transporter type 1(GLUT1) were detected by PCR and Western blot. A total of 213 active components of YHD and 185 targets against the disease were screened out. The hypothesis that YHD may regulate glycolysis through HIF-1α signaling pathway to intervene in breast cancer was proposed. Animal experiment confirmed that the mRNA and protein levels of HIF-1α, PKM2, LDHA, and GLUT1 in the high-and low-dose YHD groups were lower than those in the model group. YHD has certain inhibitory effect on subcutaneous tumor in pulmonary metastasis from breast cancer in the early stage, which may intervene pulmonary metastasis from breast cancer by regulating glycolysis through HIF-1α signaling pathway.
Subject(s)
Animal Experimentation , Drugs, Chinese Herbal , Neoplasms , Female , Mice , Animals , Glucose Transporter Type 1/genetics , Network Pharmacology , Saline Solution , Drugs, Chinese Herbal/pharmacology , Drugs, Chinese Herbal/therapeutic use , Medicine, Chinese Traditional , Signal Transduction , Glycolysis , RNA, Messenger , Neoplasms/drug therapy , Molecular Docking SimulationABSTRACT
Organelles possess critical biological effects in cellular processes. However, the relationship between organelle targeting and antitumour activity is a challenging issue. In this paper, a number of amide/acylhydrazine modified naphthalimide derivatives were designed and synthesized. Interestingly, amide modified naphthalimide derivatives NI-A-NH and NI-C-NH with (R)-piperdine and (S)-pyrrolidine functionalization exhibited enhanced cytotoxicity compared with acylhydrazine modified derivatives NI-A-2NH and NI-C-2NH. However, acylhydrazine modified derivatives NI-B-2NH and NI-D-2NH with (S)-piperdine and achiral piperdine conjugates possessed better cytotoxicity than NI-B-NH and NI-D-NH with amide modifications. Fluorescence imaging, DNA binding interactions and cell cycle analyses were further completed to clarify that the nucleus-targeting effects showed enhanced cytotoxic activity, strong DNA binding and the blocking of cells in S phase. These results provide a preliminary theoretical basis for the further design of organelle-targeting antitumour drugs.
Subject(s)
Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Cell Nucleus/drug effects , Naphthalimides/chemistry , Naphthalimides/pharmacology , Antineoplastic Agents/analysis , Cell Cycle/drug effects , Cell Line, Tumor , Cell Nucleus/metabolism , Cell Nucleus/pathology , HeLa Cells , Humans , Naphthalimides/analysis , Neoplasms/drug therapy , Neoplasms/metabolism , Neoplasms/pathology , Optical ImagingABSTRACT
Stroke is one of the most serious problems that seriously affect people's health and brings huge economic burden to society. The development of new nanocarriers with desired degradability and targeted ability is of great significance for efficient drug delivery. In recent years, nano drug delivery system has developed rapidly and applied to treat ischemic stroke. Here, we report the synthesis and functionalization of monodisperse hollow structured MnO2 (H-MnO2). The highly monodisperse H-MnO2 with uniform morphology was obtained by in situ growing MnO2 on solid silica nanoparticles and subsequently removing the silica core. After successive modification of poly ethylene glycol(PEG), we further verified their protective effect on ischemic stroke in our study.
Subject(s)
Infarction, Middle Cerebral Artery/drug therapy , Manganese Compounds/chemistry , Nanoparticle Drug Delivery System/chemistry , Oxides/chemistry , Polyethylene Glycols/chemistry , Silicon Dioxide/chemistry , Animals , Apoptosis/drug effects , Behavior, Animal , Disease Models, Animal , Drug Liberation , Humans , Male , Morris Water Maze Test , Nanoparticle Drug Delivery System/administration & dosage , Nanoparticle Drug Delivery System/adverse effects , Rats , Rats, Sprague-Dawley , Surface PropertiesABSTRACT
A series of novel N,N-bis(3-aminopropyl)methylamine bridged bis-naphthalimide derivatives NI1-NI8 containing saturated nitrogenous heterocycles were designed and synthesized, their cytotoxic activities against Hela, MCF-7, A549 and MGC-803 cells were investigated, Compounds NI1-NI4 modified with piperidine and piperazine exhibited good and selective cytotoxic activity, for instance, compounds NI1 and NI4 showed potent cytotoxic activity against Hela cells and MGC-803 cells with the IC50 values of 2.89, 060, 2.73 and 1.60⯵M, respectively, better than the control drug (Amonafide). However, compounds NI5-NI8 conjugated with pyrrole derivatives showed weak cytotoxic activities against the all tested cell lines. Furthermore, their DNA binding properties, fluorescence imaging and cell cycle were investigated. Interestingly, compounds NI1 and NI4 showed fluorescence enhancement because of the strong binding with Ct-DNA, and exhibited fluorescence imaging with Hela cells on the lysosomes.
Subject(s)
Antineoplastic Agents/pharmacology , Fluorescent Dyes/pharmacology , Lysosomes/metabolism , Naphthalimides/pharmacology , Adenine , Animals , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Cell Line, Tumor , DNA/chemistry , Drug Screening Assays, Antitumor , Fluorescence , Fluorescent Dyes/chemical synthesis , Fluorescent Dyes/chemistry , Humans , Microscopy, Confocal , Microscopy, Fluorescence , Naphthalimides/chemical synthesis , Naphthalimides/chemistry , Nucleic Acid Conformation , Organophosphonates , Piperazines/chemical synthesis , Piperazines/chemistry , Piperazines/pharmacology , Piperidines/chemical synthesis , Piperidines/chemistry , Piperidines/pharmacology , S Phase Cell Cycle Checkpoints/drug effects , Transition Temperature , ZebrafishABSTRACT
A lactose modified pyrene derivative (Py-Lac) was synthesized, with which novel twisted supramolecular nanofibers in diameter about 20â¯nm were constructed by self-assembly. The nanofibers showed solid-state fluorescence between 400â¯nm and 650â¯nm with the maximum emission at 495â¯nm. Furthermore, its recognition reaction with PNA lectin was investigated by fluorescence spectra and turbidity assays. It is interesting found that the supramolecular assembly as multivalent glycocluster exhibited unique and selectively binding interactions with PNA lectin with the binding constant of 5.74â¯×â¯106â¯M-1. Moreover, compound Py-Lac showed two-photon fluorescence imaging with Hep G2 cells.
Subject(s)
Fluorescent Dyes/chemistry , Lactose/analogs & derivatives , Macromolecular Substances/chemistry , Nanofibers/chemistry , Pyrenes/chemistry , Arachis/chemistry , Fluorescence , Fluorescent Dyes/chemical synthesis , Fluorescent Dyes/radiation effects , Hep G2 Cells , Humans , Lactose/chemical synthesis , Lactose/radiation effects , Light , Macromolecular Substances/chemical synthesis , Macromolecular Substances/radiation effects , Microscopy, Fluorescence/methods , Nanofibers/radiation effects , Peanut Agglutinin/chemistry , Pyrenes/chemical synthesis , Pyrenes/radiation effectsABSTRACT
High excimer-state emission in the H-type aggregate of a novel asymmetric perylene bisimide derivative, 6, with triethyleneglycol chains and lactose functionalization was achieved in water. Furthermore, its application for enhancing the visualization of transfer latent fingerprints from glass slides to the poly(vinylidene fluoride) (PVDF) membrane was explored, which showed clear images of the latent fingerprint in daylight and under 365â nm ultraviolet illumination.
Subject(s)
Dermatoglyphics , Imides/chemistry , Perylene/analogs & derivatives , Fluorescence , Glass/chemistry , Humans , Perylene/chemistry , Polyvinyls/chemistryABSTRACT
A novel water-soluble fluorescent glycodendrimer based on perylene bisimides is synthesized, which exhibits high fluorescence quantum yield of 54%. While the binding interactions of PBI-Man with Concanavalin A (Con A) are studied by fluorescence spectra and CD spectra, which show strong binding affinity for Con A with the binding constant of 3.8 × 10(7) m(-1) for monomeric mannose, nearly four orders of magnitude higher affinity than the monovalent mannose ligand. Furthermore, the fluorescence imaging of macrophage cell with PBI-Man is investigated, and shows selectively binding interaction with the mannose receptor-medicated cell entry. Moreover, the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) activities of PBI-Man show that PBI-Man as a biocompatible agent is noncytotoxic to living cells.
Subject(s)
Biocompatible Materials/chemical synthesis , Biosensing Techniques , Concanavalin A/chemistry , Dendrimers/chemical synthesis , Fluorescence , Imides/chemical synthesis , Molecular Imaging , Perylene/analogs & derivatives , Animals , Biocompatible Materials/chemistry , Cell Survival , Circular Dichroism , Dendrimers/chemistry , Imides/chemistry , Macrophages/cytology , Mice , Molecular Conformation , Molecular Structure , Perylene/chemical synthesis , Perylene/chemistry , Spectrometry, FluorescenceABSTRACT
Systemic lupus erythematosus (SLE) is a chronic autoimmune disease in which multiple organs are damaged that prevails in fertile women. Currently, glucocorticoids and immunosuppressants are widely used to treat SLE patients. However, ovarian dysfunction occurs following the use of these drugs in women with SLE. Here, we summarize recent progress in terms of understanding ovarian injury, the effects of drug application and strategies to improve ovarian function in women with SLE. This review could be helpful to precisely cure SLE in women desiring to have offspring.
ABSTRACT
Multivalent glycosidase inhibitors based on 1-deoxynojirimycin derivatives against α-glucosidases have been rapidly developed. Nonetheless, the mechanism based on self-assembled multivalent glucosidase inhibitors in living systems needs to be further studied. It remains to be determined whether the self-assembly possesses sufficient stability to endure transit through the small intestine and subsequently bind to the glycosidases located therein. In this paper, two amphiphilic compounds, 1-deoxynojirimycin and α-peptoid conjugates (LP-4DNJ-3C and LP-4DNJ-6C), were designed. Their self-assembling behaviors, multivalent α-glucosidase inhibition effect, and fluorescence imaging on living organs were studied. LP-4DNJ-6C exhibited better multivalent α-glucosidase inhibition activities in vitro. Moreover, the self-assembly of LP-4DNJ-6C could effectively form a complex with Nile red. The complex showed fluorescence quenching effect upon binding with α-glucosidases and exhibited potent fluorescence imaging in the small intestine. This result suggests that a multivalent hypoglycemic effect achieved through self-assembly in the intestine is a viable approach, enabling the rational design of multivalent hypoglycemic drugs.
Subject(s)
1-Deoxynojirimycin , Hypoglycemic Agents , Hypoglycemic Agents/pharmacology , Hypoglycemic Agents/metabolism , 1-Deoxynojirimycin/pharmacology , alpha-Glucosidases/metabolism , Enzyme Inhibitors/pharmacology , Glycoside Hydrolases , Glycoside Hydrolase Inhibitors/pharmacologyABSTRACT
A new triazatruxene-based fluorescent glycocluster has been designed, synthesized, and fully characterized by NMR spectroscopy and mass spectrometry. Furthermore, its specific and selective binding properties with concanavalin A (Con A) have been investigated by fluorescence spectroscopy, circular dichroism (CD) spectroscopy, and turbidity assay. The obtained results showed that the multivalent mannose-modified triazatruxene exhibited specific binding with Con A, but no binding to peanut agglutinin (PNA) lectin or bovine serum albumin (BSA), corresponding to a two-orders-of-magnitude higher affinity than that of monovalent mannose ligands. Most interestingly, a fluorescence enhancement of the triazatruxene-based glycocluster was observed upon binding with Con A because of hydrophobic interactions involving sites close to the triazatruxene moiety. Furthermore, the inhibitory ability of the triazatruxene-based glycocluster against ORN178-induced haemagglutination has been investigated by haemagglutination inhibition assay. The results indicated selective binding with ORN178.
Subject(s)
Carbazoles/chemistry , Concanavalin A/chemistry , Concanavalin A/chemical synthesis , Escherichia coli/chemistry , Fluorescent Dyes/chemistry , Agglutination , Binding Sites , Escherichia coli/metabolism , Hydrophobic and Hydrophilic Interactions , Ligands , Magnetic Resonance Spectroscopy , Mass SpectrometryABSTRACT
A novel glycodendrimer based on 18 peripheral α-D-mannoses functionalized perylene bisimide derivative PBI-18-Man was synthesized and its selectively binding interactions for Con A were investigated by CD spectra and turbidity assay, which exhibited strong binding affinity for Con A with the binding constant of 1.3×10(8) M(-1) (7.2×10(6) M(-1) for monomeric mannose, valency corrected), 3 orders of magnitude higher affinity than the monovalent mannose ligand. Furthermore, the inhibitory activity for Con A was studied by ELLA experiment, showed 2 times inhibitor activity than the reference compound (α-MMP).
Subject(s)
Concanavalin A/metabolism , Imides/chemistry , Imides/chemical synthesis , Perylene/analogs & derivatives , Biological Assay , Circular Dichroism , Concanavalin A/chemistry , Dendrimers , Imides/metabolism , Molecular Structure , Perylene/chemical synthesis , Perylene/chemistry , Perylene/metabolism , Perylene/pharmacology , Protein BindingABSTRACT
Water-soluble perylene bisimide derivative 7 modified with six mannoses was synthesized and its self-assembled properties were studied by UV-Vis and CD spectroscopy, which revealed an interesting self-assembly with a solvent-tuning chiral conformation in H(2)O-DMSO solution. As H(2)O was added to the DMSO solution until a 60% (or 70%) v/v proportion was achieved, the self-assembly of the mannose functionalized compound 7 exhibited a left-handed helical conformation. More interestingly, when the volume of H(2)O constituted beyond 85% of the solution, the conformation of the self-assembly turned out to be a right-handed helical conformation. Furthermore, the binding interactions between the self-assembly of compound 7 and Con A were investigated by turbidity assay, CD spectra, TEM and SEM images, and ELLA experiment, which indicated that the self-assembly of compound 7 as multivalent glycoclusters exhibited specific binding to Con A with an IC(50) value of 24 µM (144 µM, valency corrected), 10 times stronger than the reference compound (α-MMP).
Subject(s)
Imides/chemistry , Mannose/chemistry , Perylene/analogs & derivatives , Circular Dichroism , Concanavalin A/chemistry , Microscopy, Electron, Transmission , Models, Molecular , Perylene/chemistry , StereoisomerismABSTRACT
The development of new cryoprotectants for cryopreservation of cells has attracted considerable interest. Herein, five calixarene-based CPAs (SC4A, S-S-C4A, S-SO2-C4A, SBAC4A, and CAC4A) were developed, and their IRI activity, DIS property and cryoprotective effect were studied. SBAC4A with a sulphobetaine zwitterion and SC4A with sulfo group modification possessed better cryoprotective effects than the other calixarene-based CPAs, especially for SBAC4A with the enhanced cell viabilities of 16.16 ± 1.78%, 12.60 ± 1.15% and 14.90 ± 1.66% against MCF-7, hucMSCs and A549 cells, respectively. This result provides a supramolecular principle for developing novel CPAs with consideration of the factors of hydrogen bonding, the macromolecular crowding principle and the three-dimensional (3D) structure.
Subject(s)
Calixarenes , Cryoprotective Agents , Cryoprotective Agents/pharmacology , Cryoprotective Agents/chemistry , Ice , Calixarenes/pharmacology , Cryopreservation/methods , Cell SurvivalABSTRACT
Renal-clearable nanomedicines are considered the next generation of nanomedicines, and show potential application for future clinical translations. However, it is important to determine whether self-assembly can form large aggregates that accrue in tumors and then tailor the size of these assemblies to be excreted renally. In this paper, a renal-clearable nanomedicine based on quanterrylene bisimide-mannose conjugates (QDI-Man) was developed. QDI-Man showed a high renal clearance efficiency of 80.31 ± 2.85% in mice. We confirmed that the self-assembly of QDI-Man exhibited a dynamic adjustment process through the renal filtration thresholds, that is, "aggregation â self-regulating the aggregate size through the renal filtration thresholds â reaggregating into aggregates". Benefiting from the modification of mannose-based glycoclusters, QDI-Man showed selective photothermal therapy because of the mannose receptors overexpressed in breast cancer cells, and showed good photothermal therapy in mice. This paper developed a dynamic adjustment theory for effective renal clearance based on organic self-assembly.
Subject(s)
Neoplasms , Photothermal Therapy , Animals , Humans , Kidney , Mannose/therapeutic use , Mice , Nanomedicine , Neoplasms/drug therapyABSTRACT
Cyclodextrin-based cryoprotectants were developed. α-TMCD, which can be easily put into large-scale production, showed enhanced cell viabilities of 19.97 ± 0.78%, 13.93 ± 4.46% and 19.10 ± 0.95% against GES-1, hucMSCs and A549 cells. Moreover, the viable cells observed by light microscope imaging showed that the enhanced hucMSC cell number percentage of α-TMCD was 103.2%. An α-TMCD-DMSO-based CPA exhibited an enhanced cryoprotective effect by a mechanism of DMSO-enhanced cell penetrating effect and α-TMCD-DMSO synergistically enhanced IMA ability. α-TMCD exhibited potential for the discovery of macrocycle-molecule-based cryoprotectants.
Subject(s)
Cryoprotective Agents , Cyclodextrins , Amides , Cryopreservation/methods , Cryoprotective Agents/chemistry , Cryoprotective Agents/pharmacology , Cyclopropanes , Dimethyl Sulfoxide , IceABSTRACT
Although multivalent glucosidase inhibitors based on iminosugars have shown enhanced inhibition activity, an effective way to improve their hypoglycemic effect in vivo, is still in infancy and needs further development. In this paper, PBI-5DNJ and PBI-6DNJ, with three or four DNJ moieties respectively conjugated at the bay position were synthesized. PBI-6DNJ evidenced stronger π-π stacking interactions and, when self-assembled, a smaller size than that of PBI-5DNJ. It was found that PBI-6DNJ exhibited superior α-glucosidases (from mice) inhibition activity (Ki = 0.14 ± 0.007 µM) in vitro than that (Ki = 0.31 ± 0.01) of PBI-5DNJ and in vivo hypoglycemic effects in mice models. PBI-6DNJ possessed good hypoglycemic effects with the percentages of PBG levels of 40.40 ± 3.33% and 39.23 ± 4.84% at a dose of 2.0 mg/kg after 15 min and 30 min of administration, respectively. In terms of measuring percentage decrease of PBG level per DNJ unit, PBI-6DNJ displayed a 2.1-fold enhancement than miglitol, demonstrating a consistency between in vitro and in vivo experiments. This paves the way to the connection between in vivo hypoglycemic potency and in vitro glucosidase inhibition assay, leading to reliable and simplified assessment of hypoglycemic potency determination, and opening a basic understanding of the design of multivalent glucosidase inhibitors.
Subject(s)
Imides , Perylene , Animals , Enzyme Inhibitors/pharmacology , Hypoglycemic Agents/pharmacology , Mice , Perylene/analogs & derivatives , alpha-GlucosidasesABSTRACT
In the title compound, C(6)H(9)N(3)O(3), the 3-diazo-2-oxopropan-amide section of the mol-ecule is nearly planar, with a maximum deviation of 0.025â (1)â Å from the mean plane of its constituent atoms. The diazo C=N=N angle is 178.0â (3)°. In the crystal, pairs of inter-molecular O-Hâ¯O and N-Hâ¯O hydrogen bonds link the mol-ecules into infinite double chains along the [100] direction. The double chains are additionally stabilized by weak C-Hâ¯O contacts with Câ¯O distances of 3.039â (3)â Å. Neighboring double chains in turn inter-act with each other through π-π stacking inter-actions [centroid-centroid distance of the 3-diazo-2-oxopropanamide units = 3.66â (6)â Å] to form infinite stacks along the b axis. Mol-ecules from neighboring stacks inter-digitate with each other in the c-axis direction, thus leading to an inter-woven three-dimensional network held together by O-Hâ¯O, N-Hâ¯O and C-Hâ¯O inter-actions and π-π stacking.
ABSTRACT
Correction for 'Synthesis, self-aggregation and cryopreservation effects of perylene bisimide-glycopeptide conjugates' by Xu He et al., Chem. Commun., 2021, DOI: 10.1039/d1cc03835d.