ABSTRACT
G-quadruplex (G4) sequences, which can fold into higher-order G4 structures, are abundant in the human genome and are over-represented in the promoter regions of many genes involved in human cancer initiation, progression, and metastasis. They are plausible targets for G4-binding small molecules, which would, in the case of promoter G4s, result in the transcriptional downregulation of these genes. However, structural information is currently available on only a very small number of G4s and their ligand complexes. This limitation, coupled with the currently restricted information on the G4-containing genes involved in most complex human cancers, has led to the development of a phenotypic-led approach to G4 ligand drug discovery. This approach was illustrated by the discovery of several generations of tri- and tetra-substituted naphthalene diimide (ND) ligands that were found to show potent growth inhibition in pancreatic cancer cell lines and are active in in vivo models for this hard-to-treat disease. The cycles of discovery have culminated in a highly potent tetra-substituted ND derivative, QN-302, which is currently being evaluated in a Phase 1 clinical trial. The major genes whose expression has been down-regulated by QN-302 are presented here: all contain G4 propensity and have been found to be up-regulated in human pancreatic cancer. Some of these genes are also upregulated in other human cancers, supporting the hypothesis that QN-302 is a pan-G4 drug of potential utility beyond pancreatic cancer.
Subject(s)
Antineoplastic Agents , Drug Discovery , G-Quadruplexes , G-Quadruplexes/drug effects , Humans , Drug Discovery/methods , Ligands , Antineoplastic Agents/pharmacology , Antineoplastic Agents/chemistry , Phenotype , Cell Line, Tumor , Naphthalenes/pharmacology , Naphthalenes/chemistry , Gene Expression Regulation, Neoplastic/drug effects , Animals , Imides/chemistry , Imides/pharmacology , Promoter Regions, GeneticABSTRACT
Nitrobenzoxadiazole (NBD)-incorporated naphthalene diimide derivatives were designed and synthesized as candidates of antitumor agents with cytotoxicity against human pancreatic cancer cell MIA PaCa-2. Among these, compounds 1NND and 3NND exhibited fluorescent "turn-off" property toward human telomeric G-quadruplex (G4), which allows the direct measurement of dissociation constant (Kd) of ligands against G4 by fluorescence titration method. Notably, the compound 1NND not only exhibited great cytotoxic activity against MIA PaCa-2 with a half maximal inhibitory concentration (IC50) of 77.9 nM, but also exhibited high affinity against G4 with Kd of 1.72 µM. Furthermore, the target binding properties were investigated by circular dichroism (CD) spectra and further studied by molecular docking methods.
Subject(s)
Antineoplastic Agents , Drug Design , G-Quadruplexes , Imides , Naphthalenes , Humans , Antineoplastic Agents/pharmacology , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Cell Line, Tumor , Cell Proliferation/drug effects , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , Fluorescent Dyes/chemistry , Fluorescent Dyes/chemical synthesis , Fluorescent Dyes/pharmacology , G-Quadruplexes/drug effects , Imides/chemistry , Imides/pharmacology , Imides/chemical synthesis , Ligands , Molecular Docking Simulation , Molecular Structure , Naphthalenes/chemistry , Naphthalenes/pharmacology , Naphthalenes/chemical synthesis , Structure-Activity RelationshipABSTRACT
This manuscript describes the synthesis, self-assembly, and antibacterial properties of naphthalene-diimide (NDI)-derived cationic π-amphiphiles. Three such asymmetric NDI derivatives with a nonionic hydrophilic wedge and a guanidine group in the two opposite sides of the NDI chromophore were considered. They differ by a single functional group (hydrazide, amide, and ester for NDI-1, NDI-2, and NDI-3, respectively), located in the linker between the NDI and the hydrophilic wedge. For NDI-1, the H-bonding among the hydrazides regulated unilateral stacking and a preferential direction of curvature of the resulting supramolecular polymer, producing an unsymmetric polymersome with the guanidinium groups displayed at the outer surface. NDI-3, lacking any H-bonding group, exhibits π-stacking without any preferential orientation and generates spherical particles with a relatively poor display of the guanidium groups. In sharp contrast to NDI-1, NDI-2 exhibits an entangled one-dimensional (1D) fibrillar morphology, indicating the prominent role of the H-bonding motif of the amide group and flexibility of the linker. The antibacterial activity of these assemblies was probed against Staphylococcus aureus (Gram-positive) and Escherichia coli (Gram-negative). NDI-1 showed the most promising antibacterial activity with a minimum inhibitory concentration (MIC) of â¼7.8 µg/mL against S. aureus and moderate activity (MIC â¼ 125 µg/mL) against E. coli. In sharp contrast, NDI-3 did not show any significant activity against the bacteria, suggesting a strong impact of the H-bonding-regulated directional assembly. NDI-2, forming a fibrillar network, showed moderate activity against S. aureus and negligible activity against E. coli, highlighting a significant impact of the morphology. All of these three molecules were found to be compatible with mammalian cells from the 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl-tetrazolium bromide (MTT) and hemolysis assay. The mechanistic investigation by membrane polarization assay, live/dead fluorescence assay, and microscopy studies confirmed the membrane disruption mechanism of cell killing for the lead candidate NDI-1.
Subject(s)
Anti-Bacterial Agents , Escherichia coli , Hydrogen Bonding , Staphylococcus aureus , Anti-Bacterial Agents/pharmacology , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/chemical synthesis , Staphylococcus aureus/drug effects , Escherichia coli/drug effects , Microbial Sensitivity Tests , Naphthalenes/chemistry , Naphthalenes/pharmacology , Imides/chemistry , Imides/pharmacology , Cations/chemistry , Cations/pharmacology , HumansABSTRACT
Several G-quadruplex nucleic acid (G4s) ligands have been developed seeking target selectivity in the past decade. Naphthalene diimide (NDI)-based compounds are particularly promising due to their biological activity and red-fluorescence emission. Previously, we demonstrated the existence of G4s in the promoter region of parasite genomes, assessing the effectiveness of NDI-derivatives against them. Here, we explored the biological activity of a small library of G4-DNA ligands, exploiting the NDI pharmacophore, against both Trypanosoma brucei and Leishmania major parasites. Biophysical and biological assays were conducted. Among the various families analyzed, core-extended NDIs exhibited the most promising results concerning the selectivity and antiparasitic effects. NDI 16 emerged as the most potent, with an IC50 of 0.011 nM against T. brucei and remarkable selectivity vs MRC-5 cells (3454-fold). Fascinating, 16 is 480-fold more potent than the standard drug pentamidine (IC50 = 5.3 nM). Cellular uptake and parasite localization were verified by exploiting core-extended NDI red-fluorescent emission.
Subject(s)
G-Quadruplexes , Imides , Leishmania major , Naphthalenes , Trypanocidal Agents , Trypanosoma brucei brucei , G-Quadruplexes/drug effects , Structure-Activity Relationship , Naphthalenes/pharmacology , Naphthalenes/chemistry , Imides/chemistry , Imides/pharmacology , Ligands , Trypanosoma brucei brucei/drug effects , Trypanocidal Agents/pharmacology , Trypanocidal Agents/chemistry , Trypanocidal Agents/chemical synthesis , Humans , Leishmania major/drug effects , Cell LineABSTRACT
Using nicofluprole as the lead compound, we designed and synthesized a series of new phenylpyrazole analogues through substituting the methyl group on the nitrogen atom of the amide with an acyl group. Bioassay results showed that compounds A12-A17 with a 1-cyanocyclopropimide group exhibited outstanding insecticidal activity. The LC50 values for compounds A12-A17 against Tetranychus cinnabarinus ranged from 0.58 to 0.91 mg/L. Compound A15 showed an LC50 value of 0.29 and 3.10 mg/L against Plutella xylostella and Myzus persicae, respectively. Molecular docking indicated the potential binding interactions of compound A15 with a gamma-aminobutyric acid receptor. Additionally, density functional theory calculations implied that the 1-cyanocyclopropimide structure might be essential for its biological activity. Phenylpyrazole derivatives, containing a 1-cyanocyclopropimide fragment, have the potential for further development as potential insecticides.
Subject(s)
Acaricides , Drug Design , Insecticides , Molecular Docking Simulation , Pyrazoles , Animals , Pyrazoles/chemistry , Pyrazoles/pharmacology , Pyrazoles/chemical synthesis , Acaricides/chemistry , Acaricides/pharmacology , Acaricides/chemical synthesis , Insecticides/chemistry , Insecticides/pharmacology , Insecticides/chemical synthesis , Structure-Activity Relationship , Imides/chemistry , Imides/pharmacology , Imides/chemical synthesis , Aphids/drug effects , Moths/drug effects , Tetranychidae/drug effects , Molecular StructureABSTRACT
A nano-immunomodulator (R-NPT NP) comprising a tumor microenvironment (TME) activable resiquimod (R848) and a π-extended NIR-absorbing naphthophenanthrolinetetraone (NPT) has been engineered for spatiotemporal controlled photothermal immunotherapy. R-NPT NP demonstrated excellent photostability, while R848 promoted synergistic immunity as a toll-like receptor 7/8 (TLR7/8) agonist. Upon accumulation at the tumor site, R-NPT NP released R848 in response to redox metabolite glutathione (GSH), triggering dendritic cell (DC) activation. The photothermal effect endowed by R-NPT NP can ablate tumors directly and trigger immunogenic cell death to augment immunity after photoirradiation. The synergistic effect of GSH-liable TLR7/8 agonist and released immunogenic factors leads to a robust evocation of systematic immunity through promoted DC maturation and T cell infiltration. Thus, R-NPT NP with photoirradiation achieved 99.3 % and 98.2 % growth inhibition against primary and distal tumors, respectively.
Subject(s)
Imides , Immunologic Factors , Immunotherapy , Naphthalenes , Immunologic Factors/chemistry , Immunologic Factors/pharmacology , Humans , Naphthalenes/chemistry , Naphthalenes/pharmacology , Imides/chemistry , Imides/pharmacology , Animals , Nanoparticles/chemistry , Mice , Tumor Microenvironment/drug effects , Photothermal Therapy , Imidazoles/chemistry , Imidazoles/pharmacology , Dendritic Cells/drug effects , Dendritic Cells/immunology , Cell Line, TumorABSTRACT
Human immunodeficiency virus 1 (HIV-1) therapeutic regimens consist of three or more drugs targeting different steps of the viral life cycle to limit the emergence of viral resistance. In line with the multitargeting strategy, here we conjugated a naphthalene diimide (NDI) moiety with a tetraazacycloalkane to obtain novel naphthalene diimide (NDI)-tetraazacycloalkane conjugates. The NDI inhibits the HIV-1 promoter activity by binding to LTR G-quadruplexes, and the tetraazacycloalkane mimics AMD3100, which blocks HIV entry into cells by interfering with the CXCR4 coreceptor. We synthesized, purified, and tested the metal-free NDI-tetraazacycloalkane conjugate and the two derived metal-organic complexes (MOCs) that incorporate Cu2+ and Zn2+. The NDI-MOCs showed enhanced binding to LTR G4s as assessed by FRET and CD assays in vitro. They also showed enhanced activity in cells where they dose-dependently reduced LTR promoter activity and inhibited viral entry only of the HIV-1 strain that exploited the CXCR4 coreceptor. The time of addition assay confirmed the dual targeting at the different HIV-1 steps. Our results indicate that the NDI-MOC conjugates can simultaneously inhibit viral entry, by targeting the CXCR4 coreceptor, and LTR promoter activity, by stabilizing the LTR G-quadruplexes. The approach of combining multiple targets in a single compound may streamline treatment regimens and improve the overall patient outcomes.
Subject(s)
G-Quadruplexes , HIV-1 , Humans , HIV-1/genetics , Imides/pharmacology , Imides/chemistry , Imides/metabolism , Naphthalenes/pharmacology , Naphthalenes/chemistryABSTRACT
The limitations associated with the in vivo use of the thrombin binding aptamer (TBA or TBA15) have dramatically stimulated the search of suitable chemically modified analogues in order to discover effective and reversible inhibitors of thrombin activity. In this context, we previously proposed cyclic and pseudo-cyclic TBA analogues with improved stability that proved to be more active than the parent aptamer. Herein, we have investigated a novel library of TBA derivatives carrying naphthalene diimide (NDI) moieties at the 3'- or 5'-end. In a subset of the investigated oligonucleotides, additional 3-hydroxypropylphosphate (HPP) groups were introduced at one or both ends of the TBA sequence. Evaluation of the G-quadruplex thermal stability, serum nuclease resistance and in vitro anticoagulant activity of the new TBA analogues allowed rationalizing the effect of these appendages on the activity of the aptamer on the basis of their relative position. Notably, most of the different TBA analogues tested were more potent thrombin inhibitors than unmodified TBA. Particularly, the analogue carrying an NDI group at the 5'-end and an HPP group at the 3'-end, named N-TBA-p, exhibited enhanced G-quadruplex thermal stability (ΔTm + 14° C) and ca. 10-fold improved nuclease resistance in serum compared to the native aptamer. N-TBA-p also induced prolonged and dose-dependent clotting times, showing a ca. 11-fold higher anticoagulant activity compared to unmodified TBA, as determined by spectroscopic methods. Overall, N-TBA-p proved to be in vitro a more efficient thrombin inhibitor than all the best ones previously investigated in our group. Its interesting features, associated with its easy preparation, make it a very promising candidate for future in vivo studies.
Subject(s)
Aptamers, Nucleotide , G-Quadruplexes , Thrombin/metabolism , Anticoagulants/chemistry , Imides/pharmacology , Naphthalenes/pharmacology , Aptamers, Nucleotide/chemistryABSTRACT
We report a supramolecular naphthalene diimide (NDI) radical anion with efficient NIR-II photothermal conversion for E.â coli-responsive photothermal therapy. The supramolecular radical anion (NDI-2CB[7])â - , which is obtained from the E.â coli-induced in situ reduction of NDI-2CB[7] neutral complex, formed by the host-guest interaction between an NDI derivative and cucurbit[7]uril (CB[7]), exhibits unexpectedly strong NIR-II absorption and remarkable photothermal conversion capacity in aqueous solution. The NIR-II absorption is caused by the self-assembly of NDI radical anions to form supramolecular dimer radicals in aqueous solution, which is supported by theoretically predicted spectra. The (NDI-2CB[7])â - demonstrates excellent NIR-II photothermal antimicrobial activity (>99 %). This work provides a new approach for constructing NIR-II photothermal agents and non-contact treatments for bacterial infections.
Subject(s)
Escherichia coli , Photothermal Therapy , Anions , Imides/pharmacologyABSTRACT
In this work, four naphthalene diimide (NDI)-functionalized half-sandwich Ru(II) complexes Ru1-Ru4 bearing the general formula [(η6-arene)RuII(N^N)Cl]PF6, where arene = benzene (bn), p-cymene (p-cym), 1,3,5-trimethylbenzene (tmb), and hexamethylbenzene (hmb), have been synthesized and characterized. By introducing the NDI unit into the N,N-chelating ligand of these half-sandwich complexes, the poor luminescent half-sandwich complexes are endowed with excellent emission performance. Besides, modification on the arene ligand of arene-Ru(II) complexes can influence the electron density of the metal center, resulting in great changes in the kinetic properties, catalytic activities in the oxidative conversion of NADH to NAD+, and biological activities of these compounds. Particularly, Ru4 exhibits the highest reactivity and the strongest inhibitory activity against the growth of three tested cancer cell lines. Further study revealed that Ru4 can enter cells quickly in an energy-dependent manner and preferentially accumulate in the mitochondria of MDA-MB-231 cells, inducing cell apoptosis via reactive oxygen species overproduction and mitochondrial dysfunction. Significantly, Ru4 can effectively inhibit the cell migration and invasion. Overall, the complexation with NDI and modification on the arene ligand endowed the half-sandwich Ru(II) complexes with improved spectroscopic properties and anticancer activities, highlighting their potential applications for cancer treatment.
Subject(s)
Antineoplastic Agents , Coordination Complexes , Ruthenium , Molecular Structure , Ligands , Antineoplastic Agents/pharmacology , Antineoplastic Agents/chemistry , Imides/pharmacology , Ruthenium/pharmacology , Ruthenium/chemistry , Coordination Complexes/pharmacology , Coordination Complexes/chemistry , Cell Line, TumorABSTRACT
The potential of ionic liquids (ILs) to be used as antimicrobial agents for biomedical applications has been hindered by the fact that most of them are cytotoxic toward mammalian cells. Understanding the mechanism of bacterial and mammalian cellular damage of ILs is key to their safety design. In this work, we evaluate the antimicrobial activity and mode of action of several ILs with varying anions and cations toward the clinically relevant Gram-negative Escherichia coli. Langmuir monolayer technique was used to evaluate if the IL's mode of action was related to the bacterial cell membrane interaction for an effective E. coli killing. 1-Decyl-3-methylimidazolium bis(trifluoromethylsulfonyl) imide [DMIM][TFSI] and trihexyltetradecyl phosphonium bis(trifluoromethylsulfonyl) imide [P6,6,6,14][TFSI] were surface-active and induced bacterial cell lysis, through a membrane-disruption phenomenon on bacteria, in a mechanism that was clearly related to the long alkyl chains of the cation. 1-Ethyl-3-methylimidazolium hydrogen sulfate [EMIM][HSO4] was highly antimicrobial toward E. coli and found suitable for biological applications since it was harmless to mammalian cells at most of the tested concentrations. The results suggest that the imidazolium cation of the ILs is mostly responsible not only for their antimicrobial activity but also for their cytotoxicity, and the inclusion of different anions may tailor the ILs' biocompatibility without losing the capacity to kill bacteria, as is the case of [EMIM][HSO4]. Importantly, this IL was found to be highly antimicrobial even when incorporated in a polymeric matrix.
Subject(s)
Ionic Liquids , Animals , Ionic Liquids/pharmacology , Escherichia coli , Anti-Bacterial Agents/pharmacology , Anions/pharmacology , Cations/pharmacology , Imides/pharmacology , MammalsABSTRACT
Naphthalene diimide (NDI) is a central scaffold that has been commonly used in the design of G-quadruplex (G4) ligands. Previous work revealed notable anticancer activity of a disubstituted N-methylpiperazine propyl NDI G4 ligand. Here, we explored structure-activity relationship studies around ligand bis-N,N-2,7-(3-(4-methylpiperazin-1-yl)propyl)-1,4,5,8-naphthalenetetracarboxylic diimide, maintaining the central NDI core whilst modifying the spacer and the nature of the cationic groups. We prepared new disubstituted NDI derivatives of the original compound and examined their in vitro antiproliferative and antiparasitic activity. Several N-methylpiperazine propyl NDIs showed sub-micromolar activity against Trypanosoma brucei and Leishmania major parasites with up to 30 fold selectivity versus MRC-5 cells. The best compound was a dimorpholino NDI with an IC50 of 0.17 µM against T.brucei and 40 fold selectivity versus MRC-5 cells. However, no clear correlation between G4 binding of the new NDI derivatives and antiproliferative or antiparasitic activity was observed, indicating that other mechanisms of action may be responsible for the observed biological activity.
Subject(s)
Antiparasitic Agents , G-Quadruplexes , Antiparasitic Agents/chemistry , Antiparasitic Agents/pharmacology , Imides/chemistry , Imides/pharmacology , Ligands , Naphthalenes , Structure-Activity RelationshipABSTRACT
The [ferrocene-ene-phenol] motif has been identified as the pharmacophore responsible for the anticancer activity of the family of ferrocene-based molecules coined ferrocifens, owing to its unique redox properties. The addition of imide entities to the historical ferrociphenol scaffold tremendously enhanced the cytotoxic activity of a large panel of cancer cell cultures and preliminary studies showed that the reduction of one of the carbonyl groups of the imide groups to the corresponding α-hydroxylactams only slightly affected the antiproliferative activity. As a continuation to these studies, we took advantage of the facile conversion of α-hydroxylactams to highly electrophilic N-acyliminium ions to graft various substituents to the imide motif of phthalimido ferrocidiphenol. Cell viability studies showed that the newly synthesized compounds showed diverse cytotoxic activities on two breast cancer cell lines, while only one compound was significantly less active on the non-tumorigenic cell line hTERT-RPE1.
Subject(s)
Antineoplastic Agents , Ferrous Compounds , Antineoplastic Agents/pharmacology , Cell Line, Tumor , Cell Proliferation , Drug Screening Assays, Antitumor , Ferrous Compounds/pharmacology , Humans , Imides/pharmacology , Metallocenes/pharmacology , Molecular Structure , Structure-Activity RelationshipABSTRACT
To find more effective anticancer agents, a series of novel dehydroabietylamine (DA) derivatives were synthesized, focusing on C-ring nitro modifications and C-18 imide introduction. Their cytotoxic activities against human tumor cell line HeLa (cervix), MCF-7 (breast), A549 (lung), HepG2 (liver), and nonmalignant cell line HUVEC (umbilical vein) in vitro were screened. The C-18 imide heterocyclic compounds 1, 2, and C-ring 14-nitro substituted 14 exhibited moderate to good cytotoxic activities and significant selectivity towards malignant cell lines. More importantly, they were significantly less cytotoxic to nonmalignant cells (HUVEC) than the parent compound and positive control doxorubicin hydrochloride (DOX). Meantime the mechanism of cytotoxicity of DA derivatives was studied. Annexin V-FITC/PI double-staining analysis suggested that cytotoxicity of compounds 2 and 14 was associated with early apoptosis induction. The interaction between compounds and DNA (herring sperm DNA) was studied using absorption spectral analysis and ethidium bromide (EB) fluorescence displacement experiments, the results exhibited that the binding of the compound to DNA was in the intercalative mode. The structure-activity relationship discussion implied that introduction of the nitro-group, especially the 14-nitro group, can significantly improve the cytotoxicity of dehydroabietylimide compounds. The relatively high cytotoxicity and significant high selectivity of compounds 2 and 14 indicated that they were particularly noteworthy. NO released amounts indicated that the amounts of NO released by the compounds bearing nitro-group were quite well associated positive correlation with their cytotoxic activity, which provide a new strategy for structure design of DA anticancer agents in the future.
Subject(s)
Antineoplastic Agents , Semen , Abietanes , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Apoptosis , Cell Line, Tumor , Cell Proliferation , DNA/pharmacology , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , Female , Humans , Imides/pharmacology , Male , Molecular Structure , Structure-Activity RelationshipABSTRACT
Stomach cancer causes the third-highest cancer-related deaths worldwide. Limited availability of anticancer measures with higher efficiency and low unwanted toxicities necessitates the development of better cancer chemotherapeutics. Naphthalene diimide (NDI) derivatives have gained significant attention owing to their excellent anticancer potential. We evaluated the anticancer properties of NDI derivatives, 1a and 2a in cancer cell lines and found that 1a showed higher efficacy as compared to 2a exhibiting a remarkable difference in activity upon single atom substitution of C with N. Particularly, NDI 1a showed potent inhibitory activity against gastric cancer cell line AGS with IC50 of 2.0 µM. NDI 1a induced remarkable morphological changes and reduced clonogenicity as well as the migratory ability of AGS cells. The reduction in AGS cell migration was mediated through inhibition of Tyr397 p-FAK dephosphorylation at focal adhesion points leading to enhanced attachment of cells at contact points. NDI 1a caused extensive DNA double-strand-breaks (DSBs) leading to activation of p53 and its transcriptional target p21. Reduced nuclear BRCA1 but enhanced nuclear p53BP1 foci formation upon 1a treatment suggests that DNA DSB repair is mediated through error-prone NHEJ which led to the accumulation of extensive DNA damage. Combinatorial effects mediated by interactions of 1a with double-stranded DNA through minor groove binding as well as induction of intracellular ROS exacerbated the loss of genomic integrity induced by 1a. NDI 1a mediated DNA damage-induced S phase arrest; however, cells experiencing extensive and irreparable DNA damage underwent mitochondrial apoptosis through downregulation of anti-apoptotic protein p21. Furthermore, proliferation inhibitory activity of 1a is also attributed to inhibition of ß-catenin/c-Myc axis in AGS cells with constitutively active ß-catenin pathway. In vivo toxicity analysis of 1a revealed minimal systemic toxicity suggesting that compound 1a is a safe and potential candidate for the development of gastric cancer chemotherapeutics.
Subject(s)
Apoptosis , Cell Cycle , DNA Damage , Imides , Naphthalenes , Stomach Neoplasms , Apoptosis/drug effects , Cell Cycle/drug effects , Cell Line, Tumor , Humans , Imides/pharmacology , Naphthalenes/pharmacology , Stomach Neoplasms/genetics , Stomach Neoplasms/pathology , beta CateninABSTRACT
Glycosyl conjugation to drugs is a strategy being used to take advantage of glucose transporters (GLUT) overexpression in cancer cells in comparison with non-cancerous cells. Its extension to the conjugation of drugs to thiosugars tries to exploit their higher biostability when compared to O-glycosides. Here, we have synthesized a series of thiosugar naphthalene diimide conjugates as G-quadruplex ligands and have explored modifications of the amino sidechain comparing dimethyl amino and morpholino groups. Then, we studied their antiproliferative activity in colon cancer cells, and their antiparasitic activity in T. brucei and L. major parasites, together with their ability to bind quadruplexes and their cellular uptake and location. We observed higher toxicity for the sugar-NDI-NMe2 derivatives than for the sugar-NDI-morph compounds, both in mammalian cells and in parasites. Our experiments indicate that a less efficient binding to quadruplexes and a worse cellular uptake of the carb-NDI-morph derivatives could be the reasons for these differences. We found small variations in cytotoxicity between O-carb-NDIs and S-carb-NDIs, except against non-cancerous human fibroblasts MRC-5, where thiosugar-NDIs tend to be less toxic. This leads to a notable selectivity for ß-thiomaltosyl-NDI-NMe212 (9.8 fold), with an IC50 of 0.3 µM against HT-29 cells. Finally, the antiparasitic activity observed for the carb-NDI-NMe2 derivatives against T. brucei was in the nanomolar range with a good selectivity index in the range of 30- to 69- fold.
Subject(s)
G-Quadruplexes , Thiosugars , Animals , Antiparasitic Agents/pharmacology , Humans , Imides/chemistry , Imides/pharmacology , Ligands , NaphthalenesABSTRACT
The applicability of ionic liquids (ILs) has increased over the last years, and even new opportunities are becoming a reality, i.e. mixtures of pure IL and inorganic salt as electrolytes for smart electrochemical devices, yet the effects on the environment are almost unknown. In this work, the ecotoxicity of two pure protic ILs (Ethylammonium nitrate and Ethylimidazolium nitrate) and two pure aprotic ILs (butylmethylpyrrolidinium bis(trifluoromethylsulfonyl)imide and butyldimethylimidazolium bis(trifluoromethylsulfonyl)imide) and that of their binary mixtures with inorganic salts with common cation was tested towards changes in the bioluminescence of the bacteria Aliivibrio fischeri, using the Microtox® standard toxicity test. EC50 of these mixtures was determined over three standard periods of time and compared with the corresponding values to pure ILs. Results indicate that the aprotic ILs are more toxic than protic and that aromatic are more toxic than non-aromatic. The addition of inorganic mono (LiNO3), di (Ca(NO3)2·4H2O, Mg(NO3)2·6H2O) and trivalent (Al(NO3)3·9H2O) salts in binary mixtures with EAN was analysed first. The latter was found to induce an important increase in toxicity. Finally, mixtures of IL-inorganic lithium salt (LiNO3, for the protic ILs and LiTFSI for the aprotic ILs) toxicity was also studied, which showed toxicity levels strongly dependent on the IL of the mixture.
Subject(s)
Ionic Liquids , Aliivibrio fischeri , Cations , Imides/pharmacology , Ionic Liquids/toxicity , SaltsABSTRACT
Positively charged amphiphiles hold great significance in supramolecular chemistry due to their good solubility, and physiochemical and molecular recognition properties. Herein, we report the synthesis, characterization and molecular recognition properties of the dicationic amphiphile based on perylene diimide-tyrosine alkyl amide amine (PDI 3). PDI 3 showed the formation of a nanoring architecture in the self-assembled aggregated state (90% H2O-DMSO mixture) as observed by SEM and TEM studies. The diameter of the nanoring is around 30-50 nm with a height varying from 1 to 2 nm. The self-assembled aggregates of PDI 3 are very sensitive towards nucleoside triphosphates. Upon addition of ATP, PDI 3 showed a decrease in the absorbance and emission intensity at 535 and 580 nm (due to the monomer state), respectively. The lowest detection limit for ATP is 10.8 nM (UV) and 3.06 nM (FI). Upon interaction of ATP with PDI 3, the nanoring morphology transformed into a spherical structure. These changes could be attributed to the formation of ionic self-assembled aggregates between dicationic PDI 3 and negatively charged ATP via electrostatic and H-bonding interactions. The complexation mechanism of PDI 3 and ATP was confirmed by optical, NMR, Job's plot, DLS, SEM and AFM studies. PDI 3 displays low cytotoxicity toward MG-63 cells and can be successfully used for the detection of exogenous and endogenous ATP. The resulting PDI 3 + ATP complex is successfully used as a 'turn-on' biochemical assay for monitoring phosphorylation of glucose.
Subject(s)
Adenosine Triphosphate/analysis , Biocompatible Materials/chemistry , Glucose/analysis , Imides/chemistry , Nanoparticles/chemistry , Perylene/analogs & derivatives , Biocompatible Materials/chemical synthesis , Biocompatible Materials/pharmacology , Cell Survival/drug effects , Glucose/metabolism , Humans , Imides/chemical synthesis , Imides/pharmacology , Materials Testing , Particle Size , Perylene/chemical synthesis , Perylene/chemistry , Perylene/pharmacology , Phosphorylation , Tumor Cells, CulturedABSTRACT
A series of thionated perylenediimides with modulating phototheranostic modalities have been synthesized by a one-pot method for multiple anti-cancer applications. Compared to the initial and 4-tert-butyl phenol-substituted fluorescent perylenediimide, the obtained monothionated perylenediimide became photodynamic. With the increase of thionation degree, tetrathionated perylenediimide changed into an optimal photothermal agent.
Subject(s)
Antineoplastic Agents/pharmacology , Breast Neoplasms/drug therapy , Fluorescence , Imides/pharmacology , Perylene/analogs & derivatives , Photochemotherapy , Photosensitizing Agents/pharmacology , Sulfhydryl Compounds/pharmacology , Animals , Antineoplastic Agents/chemistry , Breast Neoplasms/pathology , Cell Line, Tumor , Cell Survival/drug effects , Drug Screening Assays, Antitumor , Female , Imides/chemistry , Mice , Molecular Structure , Perylene/chemistry , Perylene/pharmacology , Photosensitizing Agents/chemistry , Sulfhydryl Compounds/chemistryABSTRACT
G-quadruplex existence was proved in cells by using both antibodies and small molecule fluorescent probes. However, the G-quadruplex probes designed thus far are structure- but not conformation-specific. Recently, a core-extended naphthalene diimide (cex-NDI) was designed and found to provide fluorescent signals of markedly different intensities when bound to G-quadruplexes of different conformations or duplexes. Aiming at evaluating how the fluorescence behaviour of this compound is associated with specific binding modes to the different DNA targets, cex-NDI was here studied in its interaction with hybrid G-quadruplex, parallel G-quadruplex, and B-DNA duplex models by biophysical techniques, molecular docking, and biological assays. cex-NDI showed different binding modes associated with different amounts of stacking interactions with the three DNA targets. The preferential binding sites were the groove, outer quartet, or intercalative site of the hybrid G-quadruplex, parallel G-quadruplex, and B-DNA duplex, respectively. Interestingly, our data show that the fluorescence intensity of DNA-bound cex-NDI correlates with the amount of stacking interactions formed by the ligand with each DNA target, thus providing the rationale behind the conformation-sensitive properties of cex-NDI and supporting its use as a fluorescent probe of G-quadruplex structures. Notably, biological assays proved that cex-NDI mainly localizes in the G-quadruplex-rich nuclei of cancer cells.