186 results on '"Calixarenes pharmacology"'
Search Results
2. A spermine-responsive supramolecular chemotherapy system constructed from a water-soluble pillar[5]arene and a diphenylanthracene-containing amphiphile for precise chemotherapy.
- Author
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Yin Y, Zeng P, Duan Y, Wang J, Zhou W, Sun P, Li Z, Wang L, Liang H, and Chen S
- Subjects
- Humans, Animals, Drug Screening Assays, Antitumor, Surface-Active Agents chemistry, Surface-Active Agents pharmacology, Surface-Active Agents chemical synthesis, Cell Survival drug effects, Mice, Molecular Structure, Cell Proliferation drug effects, Particle Size, Antineoplastic Agents chemistry, Antineoplastic Agents pharmacology, Calixarenes chemistry, Calixarenes pharmacology, Water chemistry, Anthracenes chemistry, Solubility, Spermine chemistry, Spermine pharmacology, Quaternary Ammonium Compounds chemistry, Quaternary Ammonium Compounds pharmacology
- Abstract
Stimuli-responsive supramolecular chemotherapy, particularly in response to cancer biomarkers, has emerged as a promising strategy to overcome the limitations associated with traditional chemotherapy. Spermine (SPM) is known to be overexpressed in certain cancers. In this study, we introduced a novel supramolecular chemotherapy system triggered by SPM. The system featured pyridine salts of a diphenylanthracene derivative (PyEn) and a complementary water-soluble pillar[5]arene (WP5C5) with long alkyl chains. The diphenylanthracene unit of PyEn is effectively encapsulated within the long alkyl chains of WP5C5, resulting in a substantial reduction in the cytotoxicity of PyEn towards normal cells. The therapeutic effect of PyEn is selectively triggered intracellularly through SPM, leading to the endosomal release of PyEn and concurrent in situ cytotoxicity. This supramolecular chemotherapy system exhibits notable tumor inhibition against SPM-overexpressed cancers with reduced side effects on normal tissues. The supramolecular strategy for intracellular activation provides a novel tool with potential applications in chemotherapeutic interventions, offering enhanced selectivity and reduced cytotoxicity to normal cells.
- Published
- 2024
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3. NMR analysis, cytotoxic activity and theoretical study of a complex between SRPIN340 and p -sulfonic acid calix[6]arene.
- Author
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de Souza Viol LC, Liberto Silva NA, Cerceau CI, de Andrade Barros MV, Siqueira RP, Sousa Gonçalves VH, Bressan GC, Fernandes SA, Alvarenga ES, and Teixeira RR
- Subjects
- Humans, Phenols chemistry, Phenols pharmacology, Mice, Magnetic Resonance Spectroscopy, Animals, Sulfonic Acids chemistry, Sulfonic Acids antagonists & inhibitors, Sulfonic Acids pharmacology, Cell Line, Tumor, Molecular Structure, Drug Screening Assays, Antitumor, Protein Kinase Inhibitors chemistry, Protein Kinase Inhibitors pharmacology, Protein Kinase Inhibitors chemical synthesis, Cell Proliferation drug effects, Piperidines chemistry, Piperidines pharmacology, Calixarenes chemistry, Calixarenes pharmacology, Antineoplastic Agents chemistry, Antineoplastic Agents pharmacology, Antineoplastic Agents chemical synthesis, Cell Survival drug effects
- Abstract
Aim: This study aimed to enhance the aqueous dissolution of SRPK inhibitor N -(2-(piperidin-1-yl)-5-(trifluoromethyl)phenyl)isonicotinamide (SRPIN340). Materials & Methods: A complex with p -sulfonic calix[6]arene (Host) and SRPIN340 (Guest) was prepared, studied via
1 H nuclear magnetic resonance (NMR) and theoretical calculations and biologically evaluated on cancer cell lines. Results & conclusion: The 1:1 host (H)/guest (G) complex significantly enhanced the aqueous dissolution of SRPIN340, achieving 64.8% water solubility as determined by1 H NMR quantification analysis. The H/G complex reduced cell viability by 75% for HL60, ∼50% for Nalm6 and Jurkat, and ∼30% for B16F10 cells. It exhibited greater cytotoxicity than free SRPIN340 against Jurkat and B16F10 cells. Theoretical studies indicated hydrogen bond stabilization of the complex, suggesting broader applicability of SRPIN340 across diverse biological systems.- Published
- 2024
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4. Dual fluorescence response of calix[4]arene-1,8-naphthalimide derivatives towards Hg(II) /Cr(VI) and their antimicrobial studies of transparent biofilms with hyaluronic acid.
- Author
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Yildirim A, Bhatti AA, Uysal A, and Yilmaz M
- Subjects
- Chromium chemistry, Anti-Infective Agents pharmacology, Anti-Infective Agents chemistry, Microbial Sensitivity Tests, Spectrometry, Fluorescence, Anti-Bacterial Agents pharmacology, Anti-Bacterial Agents chemistry, Phenols chemistry, Phenols pharmacology, Fluorescence, Calixarenes chemistry, Calixarenes pharmacology, Hyaluronic Acid chemistry, Hyaluronic Acid pharmacology, Biofilms drug effects, Naphthalimides chemistry, Naphthalimides pharmacology, Mercury chemistry
- Abstract
In this study, 4-sulfo-1,8-naphthalimide calixarene of derivatives were prepared (3 and 4) then transparent biofilms of the Ag salts of these compounds were formed in the presence of hyaluronic acid (HA), and antimicrobial properties were investigated. In chemosensor studies, the sensing ability behavior of 3 and 4 towards some cations and anions was investigated by fluorescence spectroscopy. It was observed that the prepared chemosensors show selectivity towards Hg(II) and Cr(VI). Ligand-ion interaction occurs according to the photo-induced electron transfer (PET) mechanism. The stoichiometric ratio was calculated by using Stern-Volmer plot method and binding constant K
sv values were found as 5.2 × 107 M-1 and 5.5 × 107 M-1 for 3-Hg(II) and 4-Hg(II) complexes, respectively and 4.0 × 107 M-1 and 4.3 × 107 M-1 for 3-Cr(VI) and 4-Cr(VI) complexes. The detection limits of the complexes of 3-Hg(II) and 4-Hg(II) are 6.35 × 10-12 and 6.81 × 10-12 , while those of 3-Cr(VI) and 4-Cr(VI) are 1.41 × 10- 11 and 8.37 × 10-12 , respectively. As a result of the antimicrobial test performed with these compounds, it was observed that the most effective material was HA-3Ag, which showed a significant antibacterial effect against Sarcina lutea (S. lutea) at a minimum inhibitory concentration (MIC) value of 0.097 mg/mL., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)- Published
- 2024
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5. Calix[6]arene dismantles extracellular vesicle biogenesis and metalloproteinases that support pancreatic cancer hallmarks.
- Author
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Cordeiro HG, Azevedo-Martins JM, Faria AVS, Rocha-Brito KJP, Milani R, Peppelenbosch M, Fuhler G, de Fátima Â, and Ferreira-Halder CV
- Subjects
- Humans, Cell Line, Tumor, Gene Expression Regulation, Neoplastic drug effects, Pancreatic Neoplasms pathology, Pancreatic Neoplasms metabolism, Pancreatic Neoplasms drug therapy, Calixarenes pharmacology, Extracellular Vesicles metabolism, Phenols pharmacology, MicroRNAs metabolism, MicroRNAs genetics
- Abstract
Many challenges are faced in pancreatic cancer treatment due to late diagnosis and poor prognosis because of high recurrence and metastasis. Extracellular vesicles (EVs) and matrix metalloproteinases (MMPs), besides acting in intercellular communication, are key players in the cancer cell plasticity responsible for initiating metastasis. Therefore, these entities provide valuable targets for the development of better treatments. In this context, this study aimed to evaluate the potential of calix[6]arene to disturb the release of EVs and the activity of MMPs in pancreatic cancer cells. We found a correlation between the endocytic-associated mediators and the prognosis of pancreatic cancer patients. We observed a more active EV machinery in the pancreatic cancer cell line PANC-1, which was reduced three-fold by treatment with calix[6]arene at subtoxic concentration (5 μM; p 〈0,001). We observed the modulation of 186 microRNAs (164 miRNAs upregulated and 22 miRNAs downregulated) upon calix[6]arene treatment. Interestingly, some of them as miR-4443 and miR-3909, regulates genes HIF1A e KIF13A that are well known to play a role in transport of vesicles. Furthermore, Calix[6]arene downmodulated matrix metalloproteinases (MMPs) -2 and - 9 and disturbed the viability of pancreatic organoids which recapitulate the cellular heterogeneity, structure, and functions of primary tissues. Our findings shed new insights on calix[6]arene's antitumor mechanism, including its intracellular effects on vesicle production and trafficking, as well as MMP activity, which may harm the tumor microenvironment and contribute to a reduction in cancer cell dissemination, which is one of the challenges associated with high mortality in pancreatic cancer., Competing Interests: Declaration of competing interest The authors declare no conflicts of interest., (Copyright © 2023. Published by Elsevier Inc.)
- Published
- 2024
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6. Substitution of bridge carbons for sulphur in calix[4]arene-bis-α-hydroxymethylphosphonic acid transformed mobile carrier into ionic channel accompanied with evoked muscle contraction and impaired neurotransmission powered by membrane action of resulting thiocalix[4]arene-bis-α-hydroxymethylphosphonic acid.
- Author
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Shatursky OY, Krisanova NV, Pozdnyakova N, Pastukhov AO, Dudarenko M, Kalynovska L, Shkrabak AA, Veklich TO, Selikhova AI, Cherenok SO, Borisova TA, Kalchenko VI, and Kosterin SO
- Subjects
- Animals, Muscle Contraction drug effects, Ion Channels metabolism, Sulfur chemistry, Rats, Female, Organophosphonates chemistry, Male, Phenols chemistry, Rats, Wistar, Calixarenes chemistry, Calixarenes pharmacology, Synaptic Transmission drug effects, Lipid Bilayers chemistry
- Abstract
The action of calix[4]arenes C-424, C-425 and C-1193 has been investigated on suspended cholesterol/egg phosphatidylcholine lipid bilayer in a voltage-clamp mode. Comparative analysis with the membrane action by calix[4]arene-bis-α-hydroxymethylphosphonic acid (C-99) has shown that the substitution of bridge carbons for sulphur and addition of another methyl group to two alkyl tales in the lower rim of former dipropoxycalix[4]arene C-99 transformed mobile carrier that C-99 created in lipid bilayer (Shatursky et al., 2014) into a transmembrane pore as exposure of the bilayer membrane to sulphur-containing derivative dibutoxythiocalix[4]arene C-1193 resulted in microscopic transmembrane current patterns indicative of a channel-like mode of facilitated diffusion. Within all calix[4]arenes tested a net steady-state voltage-dependent transmembrane current was readily achieved only after addition of calix[4]-arene C-1193. In comparison with the membrane action of C-99 the current induced by calix[4]-arene C-1193 exhibited a much weakened anion selectivity passing slightly more current at positive potentials applied from the side of bilayer membrane to which the calix[4]-arene was added. Testing C-1193 for the membrane action against smooth muscle cells of rat uterus or swine myometrium and synaptosomes of rat brain nerve terminals revealed an increase in intracellular concentration of Ca
2+ with reduction of the effective hydrodynamic diameter of the smooth muscle cells and enhanced basal extracellular level of neurotransmitters (glutamate and γ-aminobutyric acid) after C-1193-induced depolarization of the nerve terminals., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)- Published
- 2024
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7. Thiacalixarene Carboxylic Acid Derivatives as Inhibitors of Lysozyme Fibrillation.
- Author
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Nazarova A, Shiabiev I, Shibaeva K, Mostovaya O, Mukhametzyanov T, Khannanov A, Evtugyn V, Zelenikhin P, Shi X, Shen M, Padnya P, and Stoikov I
- Subjects
- Humans, Animals, A549 Cells, Amyloid chemistry, Amyloid metabolism, Amyloid antagonists & inhibitors, Protein Binding, Phenols chemistry, Phenols pharmacology, Calixarenes chemistry, Calixarenes pharmacology, Sulfides, Muramidase chemistry, Carboxylic Acids chemistry, Carboxylic Acids pharmacology
- Abstract
Amyloid fibroproliferation leads to organ damage and is associated with a number of neurodegenerative diseases affecting populations worldwide. There are several ways to protect against fibril formation, including inhibition. A variety of organic compounds based on molecular recognition of amino acids within the protein have been proposed for the design of such inhibitors. However, the role of macrocyclic compounds, i.e., thiacalix[4]arenes, in inhibiting fibrillation is still almost unknown. In the present work, the use of water-soluble thiacalix[4]arene derivatives for the inhibition of hen egg-white lysozyme (HEWL) amyloid fibrillation is proposed for the first time. The binding of HEWL by the synthesized thiacalix[4]arenes (logKa = 5.05-5.13, 1:1 stoichiometry) leads to the formation of stable supramolecular systems capable of stabilizing the protein structure and protecting against fibrillation by 29-45%. The macrocycle conformation has little effect on protein binding strength, and the native HEWL secondary structure does not change via interaction. The synthesized compounds are non-toxic to the A549 cell line in the range of 0.5-250 µg/mL. The results obtained may be useful for further investigation of the anti-amyloidogenic role of thiacalix[4]arenes, and also open up future prospects for the creation of new ways to prevent neurodegenerative diseases.
- Published
- 2024
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8. Calixarene-based cryoprotectants for ice recrystallization inhibition and cell cryopreservation.
- Author
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Hu B, Li JJ, Ren YB, Zhang TX, Chen LB, Li XL, Guo DS, and Wang KR
- Subjects
- Ice, Cryopreservation methods, Cell Survival, Cryoprotective Agents pharmacology, Cryoprotective Agents chemistry, Calixarenes pharmacology
- Abstract
The development of new cryoprotectants for cryopreservation of cells has attracted considerable interest. Herein, five calixarene-based CPAs (SC4A, S-S-C4A, S-SO
2 -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.- Published
- 2023
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9. Host-Guest-Interaction Enhanced Nitric Oxide Photo-Generation within a Pillar[5]arene Cavity for Antibacterial Gas Therapy.
- Author
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Wang H, Wang Y, Xu W, Zhang H, Lv J, Wang X, Zheng Z, Zhao Y, Yu L, Yuan Q, Yu L, Zheng B, and Gao L
- Subjects
- Nitric Oxide pharmacology, Anti-Bacterial Agents pharmacology, Methicillin-Resistant Staphylococcus aureus, Calixarenes pharmacology
- Abstract
Supramolecular macrocycles with intrinsic cavities have been widely explored as containers to fabricate versatile functional materials via specific host-guest recognitions. However, relatively few studies have focused on the modulation of guest reactivity within a macrocyclic cavity. Here, we demonstrate the confinement effect of pillar[5]arene with an electron-rich and precise cavity that can dramatically enhance guest photoactivity and nitric oxide (NO) generation upon visible light irradiation. Mechanism studies reveal that it is achieved through increasing the ground state nitro-aromatic torsion angle, suppressing the intersystem crossing relaxation path of the S
1 state, and accelerating the isomerization reaction path of guest molecules. This NO-generating system displays broad-spectrum antibacterial, biofilm inhibition, and dispersal activities. Moreover, it can accelerate the healing of methicillin-resistant Staphylococcus aureus (MRSA)-infected wounds in vivo .- Published
- 2023
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10. Functionalized Calixarenes as Promising Antibacterial Drugs to Face Antimicrobial Resistance.
- Author
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Mourer M, Regnouf-de-Vains JB, and Duval RE
- Subjects
- Drug Resistance, Bacterial, Anti-Bacterial Agents pharmacology, Calixarenes pharmacology, Calixarenes chemistry
- Abstract
Since the discovery of polyphenolic resins 150 years ago, the study of polymeric compounds named calix[ n ]arene has continued to progress, and those skilled in the art perfectly know now how to modulate this phenolic ring. Consequently, calix[ n ]arenes are now used in a large range of applications and notably in therapeutic fields. In particular, the calix[4]arene exhibits multiple possibilities for regioselective polyfunctionalization on both of its rims and offers researchers the possibility of precisely tuning the geometry of their structures. Thus, in the crucial research of new antibacterial active ingredients, the design of calixarenes finds its place perfectly. This review provides an overview of the work carried out in this aim towards the development of intrinsically active prodrogues or metallic calixarene complexes. Out of all the work of the community, there are some excellent activities emerging that could potentially place these original structures in a very good position for the development of new active ingredients.
- Published
- 2023
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11. Calix[4]arene-pyrazole conjugates as potential cancer therapeutics.
- Author
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Muravev AA, Voloshina AD, Sapunova AS, Gabdrakhmanova FB, Lenina OA, Petrov KA, Shityakov S, Skorb EV, Solovieva SE, and Antipin IS
- Subjects
- Animals, Humans, Mice, HeLa Cells, Calixarenes pharmacology, Neoplasms drug therapy, Porifera, Pyrazoles pharmacology, Pyrazoles therapeutic use
- Abstract
Tumor selectivity is yet a challenge in chemotherapy-based cancer treatment. A series of calixarenes derivatized at the lower rim with 3-phenyl-1H-pyrazole units with variable upper-rim substituent and conformations of macrocyclic core, alkyl chain length between heterocycle and core, as well as phenolic monomer (5-(4-tert-butylphenyloxy)methoxy-3-phenyl-1H-pyrazole) have been synthesized and characterized in a range of therapeutically relevant cellular models (M-HeLa, MCF7, A-549, PC3, Chang liver, and Wi38) from different target organs/systems. Specific cytotoxicity for M-HeLa cells has been observed in tert-butylcalix[4]arene pyrazoles in 1,3-alternate (compound 7b) and partial cone (compound 7c) conformations with low mutagenicity and haemotoxicity and in vivo toxicity in mice. Compounds 7b,c have induced mitochondrial pathway of apoptosis of M-HeLa cells through caspase-9 activation preceded by the cell cycle arrest at G0/G1 phase. A concomitant overexpression of DNA damage markers in pyrazole-treated M-HeLa cells suggests that calixarene pyrazoles target DNA, which was supported by the presence of interactions between calixarenes and ctDNA at the air-water interface., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)
- Published
- 2023
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12. An L-arginine-functionalized pillar[5]arene-based supramolecular photosensitizer for synergistically enhanced cancer therapeutic effectiveness.
- Author
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Chao S, Shen Z, Li B, Pei Y, and Pei Z
- Subjects
- Humans, Micelles, Photosensitizing Agents pharmacology, Photosensitizing Agents therapeutic use, Quaternary Ammonium Compounds, Arginine chemistry, Calixarenes pharmacology, Neoplasms drug therapy
- Abstract
An L-arginine-functionalized pillar[5]arene-based supramolecular photosensitizer LAP5⊃NBSPD was constructed by host-guest interactions, which could self-assemble into nano-micelles to achieve effective delivery and selective release of LAP5 and NBS in cancer cells. In vitro studies revealed that LAP5⊃NBSPD NPs exhibited excellent cancer cell membrane disruption and ROS generation properties, which provides a novel route for synergistically enhanced cancer therapeutic effectiveness.
- Published
- 2023
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13. A Calixarene Assembly Strategy of Combined Anti-Neuroinflammation and Drug Delivery Functions for Traumatic Brain Injury Therapy.
- Author
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Wang C, Chang YX, Chen X, Bai L, Wang H, Pan YC, Zhang C, Guo DS, and Xue X
- Subjects
- Animals, Disease Models, Animal, Inflammation drug therapy, Inflammation pathology, Mice, Mice, Inbred C57BL, Microglia, Neuroinflammatory Diseases, Brain Injuries, Traumatic pathology, Calixarenes pharmacology, Calixarenes therapeutic use
- Abstract
Excessive inflammatory reaction aggravates brain injury and hinders the recovery of neural function in nervous system diseases. Microglia, as the major players of neuroinflammation, control the progress of the disease. There is an urgent need for effective non-invasive therapy to treat neuroinflammation mediated by microglia. However, the lack of specificity of anti-inflammatory agents and insufficient drug dose penetrating into the brain lesion area are the main problems. Here, we evaluated a series of calixarenes and found that among them the self-assembling architecture of amphiphilic sulfonatocalix[8]arene (SC8A12C) had the most potent ability to suppress neuroinflammation in vitro and in vivo. Moreover, SC8A12C assemblies were internalized into microglia through macropinocytosis. In addition, after applying the SC8A12C assemblies to the exposed brain tissue, we observed that SC8A12C assemblies penetrated into the brain parenchyma and eliminated the inflammatory factor storm, thereby restoring neurobiological functions in a mouse model of traumatic brain injury.
- Published
- 2022
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14. Utilization of pillar[5]arene-based ICT probes embedded into proteins for live-cell imaging and traceable drug delivery.
- Author
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Wang Q, Bian X, Yao H, Yuan X, Han Y, and Yan C
- Subjects
- Drug Delivery Systems, Fluorescent Dyes chemistry, Fluorescent Dyes pharmacology, Quaternary Ammonium Compounds, Calixarenes pharmacology, Nanoparticles
- Abstract
Three protein microenvironment-sensitive pillar[5]arene-based fluorescent probes (3/4/5C-B) were designed and synthesized based on intramolecular charge transfer (ICT) mechanism. Unlike the majority of micromolecular ICT probes, the aforementioned probes displayed differentiated sensitivity to multiple proteins. The 7-(diethylamino)coumarin-3-formic acid (DCCA) group in the probes was essential for their sensitivity. The presence of a pillar[5]arene group was also crucial as they benefit 3/4/5C-B form complexes with the proteins, although it changed the electron density distribution of the DCCA group. 3/4/5C-B exhibited favorable carrier ability for regorafenib (REG). 4C-B had the best spatial structure for complexation. The 3/4/5C-B-REG complexes would assemble into high drug-loading fluorescent nanoparticles in a physiological environment (pH = 7.4). Such nanoparticles exhibited pH-triggered enrichment ability, which rapidly enriched REG in the acidic environment (pH = 6.0). Moreover, the complexation between 3/4/5C-B and REG maintained the live-cell membrane imaging property of the probes and the excellent targeted anticancer activity of the drug., (Copyright © 2022 Elsevier B.V. All rights reserved.)
- Published
- 2022
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15. A Simple, Rapid, Comparative Evaluation of Multiple Products for Decontamination of Actinide-contaminated Rat Skin Ex Vivo.
- Author
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Griffiths NM, Devilliers K, Laroche P, and Van der Meeren A
- Subjects
- Animals, Chelating Agents pharmacology, Decontamination methods, Rats, Skin, Actinoid Series Elements, Calixarenes chemistry, Calixarenes pharmacology
- Abstract
Abstract: Decontamination of skin is an important medical countermeasure in order to limit potential internal contamination by radionuclides such as actinides. Minimizing skin surface contamination will ultimately prevent internal contamination and subsequent committed effective dose as well as contamination spreading. The decontamination agents tested on a rat skin ex vivo model ranged from water to hydrogel wound dressings. A surfactant-containing cleansing gel and calixarene nanoemulsion with chelation properties demonstrated marked decontamination efficacies as compared with water or the chelator DTPA. Based on efficacy to remove different actinide physicochemical forms from skin, the results demonstrate that all products can remove the more soluble forms, but a further component of emulsifying or tensioactive action is required for less soluble forms. This indicates that for practical purposes, successful decontamination will depend on identification of the actinide element, the physicochemical form, and possibly the solvent. This study offers a simple, quick, cheap, reproducible screening method for efficacy evaluation of multiple products for removal of a variety of contaminants., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the Health Physics Society.)
- Published
- 2022
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16. Dual-responsive drug release and fluorescence imaging based on disulfide-pillar[4]arene aggregate in cancer cells.
- Author
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Tang M, Liu YH, Xu XM, Zhang YM, and Liu Y
- Subjects
- Antibiotics, Antineoplastic chemistry, Calixarenes chemistry, Cell Line, Cell Proliferation drug effects, Disulfides chemistry, Dose-Response Relationship, Drug, Doxorubicin chemistry, Drug Liberation, Drug Screening Assays, Antitumor, Humans, Molecular Structure, Structure-Activity Relationship, Antibiotics, Antineoplastic pharmacology, Calixarenes pharmacology, Disulfides pharmacology, Doxorubicin pharmacology, Optical Imaging
- Abstract
The construction of multistimuli-responsive nanoaggregate has become one of the increasingly significant research topics in supramolecular chemistry. We herein reported the pH- and glutathione dual-responsive supramolecular assemblies fabricated by the disulfide-containing pillar[4]arene and tetraphenylethylene derivatives possessing different alkyl chains in length. Morphological characterization experiments showed the binary supramolecular assemblies formed well-defined nanoparticles, which could facilitate their endocytosis in cells. More remarkably, due to the compact nanostructures and the existence of acidifiable carboxyl group and bioreducible disulfide linkage in pillar[4]arene, the obtained nanoaggregates presented high drug-loading efficiency and sustained drug release behaviors, as well as the targeted fluorescence imaging ability in cancer cells. Thus, it can be envisioned that such microenvironment-adaptable supramolecular nanoassemblies featuring dual stimuli-responsiveness and fluorescence-imaging abilities may be developed as more appealing nanosystems for the therapy of refractory disease., (Copyright © 2022 Elsevier Ltd. All rights reserved.)
- Published
- 2022
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17. Design of a Metallacycle-Based Supramolecular Photosensitizer for In Vivo Image-Guided Photodynamic Inactivation of Bacteria.
- Author
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Xu Y, Tuo W, Yang L, Sun Y, Li C, Chen X, Yang W, Yang G, Stang PJ, and Sun Y
- Subjects
- Reactive Oxygen Species chemistry, Staphylococcus aureus drug effects, Models, Molecular, Molecular Conformation, Escherichia coli drug effects, Animals, Mice, Anti-Bacterial Agents chemical synthesis, Anti-Bacterial Agents chemistry, Anti-Bacterial Agents pharmacology, Drug Design, Calixarenes chemical synthesis, Calixarenes chemistry, Calixarenes pharmacology, Photosensitizing Agents chemical synthesis, Photosensitizing Agents chemistry, Photosensitizing Agents pharmacology, Pyridinium Compounds chemical synthesis, Pyridinium Compounds chemistry, Pyridinium Compounds pharmacology
- Abstract
Bacterial infection is one of the greatest threats to public health. In vivo real-time monitoring and effective treatment of infected sites through non-invasive techniques, remain a challenge. Herein, we designed a Pt
II metallacycle-based supramolecular photosensitizer through the host-guest interaction between a pillar[5]arene-modified metallacycle and 1-butyl-4-[4-(diphenylamino)styryl]pyridinium. Leveraging the aggregation-induced emission supramolecular photosensitizer, we improved fluorescence performance and antimicrobial photodynamic inactivation. In vivo studies revealed that it displayed precise fluorescence tracking of S. aureus-infected sites, and in situ performed image-guided efficient PDI of S. aureus without noticeable side effects. These results demonstrated that metallacycle combined with host-guest chemistry could provide a paradigm for the development of powerful photosensitizers for biomedicine., (© 2021 Wiley-VCH GmbH.)- Published
- 2022
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18. Targeting Colorectal Cancer Cells with a Functionalised Calix[4]arene Receptor: Biophysical Studies.
- Author
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Danil de Namor AF, Al Hakawati N, and Farhat SY
- Subjects
- Antineoplastic Agents chemistry, Caco-2 Cells, Carbonic Anhydrase II chemistry, Cell Proliferation, Cell Survival, Colorectal Neoplasms pathology, Humans, Antineoplastic Agents pharmacology, Calixarenes chemistry, Calixarenes pharmacology, Carbonic Anhydrase II physiology, Colorectal Neoplasms drug therapy, Phenols chemistry, Phenols pharmacology
- Abstract
Colorectal cancer (CRC) is a disease which is causing a high degree of mortality around the world. The present study reports the antiproliferative impact of the thioacetamide calix[4]arene, CAII receptor on a highly differentiated Caco-2 cell line. This statement is corroborated by the MTT assay results which revealed a reduction in the cell viability with an IC50 value of 19.02 ± 0.04 µM. Microscopic results indicated that at the starting amount of 10 µM of CAII, a decrease in cells confluency can already be observed in addition to changes in cells morphology. Cell metabolic pathway changes were also investigated.
1 H NMR findings showed downregulation in lactate, pyruvate, phosphocholine, lipids, and hydroxybutyrate with the upregulation of succinate, indicating a decline in the cells proliferation. Some biochemical alterations in the cells as a result of the CAII treatment were found by Raman spectroscopy.- Published
- 2022
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19. An application of p-sulfonatocalix[6]arenes to attenuate cardiotoxicity of mitoxantrone in vitro: preparation, characterization and evaluation.
- Author
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Yu X, Wang M, Wang H, Ren X, Jiang M, Zhu Y, and Zhang D
- Subjects
- Antineoplastic Agents pharmacology, Apoptosis drug effects, Calorimetry, Differential Scanning methods, Cell Proliferation drug effects, Cell Survival drug effects, Drug Carriers pharmacology, Drug Delivery Systems, Hep G2 Cells, Humans, Spectroscopy, Fourier Transform Infrared methods, Calixarenes pharmacology, Cardiotoxicity etiology, Cardiotoxicity prevention & control, Drug Stability, Mitoxantrone pharmacology, Mitoxantrone toxicity, Phenols pharmacology
- Abstract
Objectives: In this study, p-sulfonatocalix[6]arenes (SCA6) was proposed to construct a host-guest complexation to carry mitoxantrone (MIT) to maintain its anti-proliferation effect on HepG2 cells as well as to attenuate cardiotoxicity on H9C2 cells as a nano-size drug delivery system., Methods: SCA6 binding to MIT evidenced through competitive fluorescence titration method. The complex was characterized using UV-visible, Fourier transform infrared, and proton nuclear magnetic resonance (1H-NMR) spectroscopies and differential scanning calorimetry analysis. The cytotoxicity was examined by a cell counting kit-8 assay on six cells. High content analysis, cell apoptosis and cell cycle experiments were measured to investigate the mechanism of detoxification in H9C2., Key Findings: The host-guest complexation was formed with a stoichiometry ratio of 1:1. Cytotoxicity study demonstrated that MIT/SCA6 complex could improve the cell viability on H9C2, MCF-7, A549, Hek293 and L02 cells and remained cytotoxicity effect on HepG2 cells. High content analysis showed that MIT/SCA6 complex could enhance the cell viability, mitochondrial mass and mitochondrial membrane potential and ameliorate the nuclear swelling on H9C2 cells. Moreover, the complex were arrested in G0/G1 phase of the cell cycle and same with MIT, while the detoxication was attributed to reducing early apoptosis., Conclusions: The host-guest complexation between SCA6 and MIT had the ability to attenuate cardiotoxicity and provided a potential strategy for the application of soluble calixarenes in chemotherapy., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Royal Pharmaceutical Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)
- Published
- 2022
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20. Coassembly of hypoxia-sensitive macrocyclic amphiphiles and extracellular vesicles for targeted kidney injury imaging and therapy.
- Author
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Cheng YQ, Yue YX, Cao HM, Geng WC, Wang LX, Hu XY, Li HB, Bian Q, Kong XL, Liu JF, Kong DL, Guo DS, and Wang YB
- Subjects
- Acute Kidney Injury metabolism, Acute Kidney Injury pathology, Animals, Calixarenes chemistry, Calixarenes metabolism, Calixarenes pharmacology, Calixarenes therapeutic use, Cell Line, Epithelial Cells drug effects, Epithelial Cells metabolism, Extracellular Vesicles metabolism, Humans, Hypoxia-Inducible Factor 1, alpha Subunit metabolism, Indoles chemistry, Indoles metabolism, Indoles pharmacology, Indoles therapeutic use, Inflammation, Integrins metabolism, Macrocyclic Compounds metabolism, Macrocyclic Compounds pharmacology, Macrocyclic Compounds therapeutic use, Macrophages drug effects, Macrophages metabolism, Mice, NF-kappa B metabolism, Organometallic Compounds chemistry, Organometallic Compounds metabolism, Organometallic Compounds pharmacology, Organometallic Compounds therapeutic use, Signal Transduction drug effects, Surface-Active Agents metabolism, Surface-Active Agents pharmacology, Surface-Active Agents therapeutic use, Acute Kidney Injury diagnostic imaging, Acute Kidney Injury drug therapy, Cell Hypoxia drug effects, Extracellular Vesicles chemistry, Macrocyclic Compounds chemistry, Surface-Active Agents chemistry
- Abstract
Background: Hypoxia is a major contributor to global kidney diseases. Targeting hypoxia is a promising therapeutic option against both acute kidney injury and chronic kidney disease; however, an effective strategy that can achieve simultaneous targeted kidney hypoxia imaging and therapy has yet to be established. Herein, we fabricated a unique nano-sized hypoxia-sensitive coassembly (Pc/C5A@EVs) via molecular recognition and self-assembly, which is composed of the macrocyclic amphiphile C5A, the commercial dye sulfonated aluminum phthalocyanine (Pc) and mesenchymal stem cell-excreted extracellular vesicles (MSC-EVs)., Results: In murine models of unilateral or bilateral ischemia/reperfusion injury, MSC-EVs protected the Pc/C5A complex from immune metabolism, prolonged the circulation time of the complex, and specifically led Pc/C5A to hypoxic kidneys via surface integrin receptor α
4 β1 and αL β2 , where Pc/C5A released the near-infrared fluorescence of Pc and achieved enhanced hypoxia-sensitive imaging. Meanwhile, the coassembly significantly recovered kidney function by attenuating cell apoptosis, inhibiting the progression of renal fibrosis and reducing tubulointerstitial inflammation. Mechanistically, the Pc/C5A coassembly induced M1-to-M2 macrophage transition by inhibiting the HIF-1α expression in hypoxic renal tubular epithelial cells (TECs) and downstream NF-κB signaling pathway to exert their regenerative effects., Conclusion: This synergetic nanoscale coassembly with great translational potential provides a novel strategy for precise kidney hypoxia diagnosis and efficient kidney injury treatment. Furthermore, our strategy of coassembling exogenous macrocyclic receptors with endogenous cell-derived membranous structures may offer a functional platform to address multiple clinical needs., (© 2021. The Author(s).)- Published
- 2021
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21. Photoactivated Osmium Arene Anticancer Complexes.
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Xue X, Fu Y, He L, Salassa L, He LF, Hao YY, Koh MJ, Soulié C, Needham RJ, Habtemariam A, Garino C, Lomachenko KA, Su Z, Qian Y, Paterson MJ, Mao ZW, Liu HK, and Sadler PJ
- Subjects
- A549 Cells, Antineoplastic Agents chemical synthesis, Antineoplastic Agents chemistry, Apoptosis drug effects, Calixarenes chemistry, Cell Proliferation drug effects, Cell Survival drug effects, Coordination Complexes chemical synthesis, Coordination Complexes chemistry, DNA Damage, Dose-Response Relationship, Drug, Drug Screening Assays, Antitumor, Humans, Molecular Structure, Osmium chemistry, Photochemical Processes, Antineoplastic Agents pharmacology, Calixarenes pharmacology, Coordination Complexes pharmacology, Osmium pharmacology
- Abstract
Half-sandwich Os-arene complexes exhibit promising anticancer activity, but their photochemistry has hardly been explored. To exploit the photocytotoxicity and photochemistry of Os-arenes, O,O -chelated complexes [Os(η
6 - p -cymene)(Curc)Cl] ( OsCUR-1 , Curc = curcumin) and [Os(η6 -biphenyl)(Curc)Cl] ( OsCUR-2 ), and N,N -chelated complexes [Os(η6 -biphenyl)(dpq)I]PF6 ( OsDPQ-2 , dpq = pyrazino[2,3- f ][1,10]phenanthroline) and [Os(η6 -biphenyl)(bpy)I]PF6 ( OsBPY-2 , bpy = 2,2'-bipyridine), have been investigated. The Os-arene curcumin complexes showed remarkable photocytotoxicity toward a range of cancer cell lines (blue light IC50 : 2.6-5.8 μM, photocytotoxicity index PI = 23-34), especially toward cisplatin-resistant cancer cells, but were nontoxic to normal cells. They localized mainly in mitochondria in the dark but translocated to the nucleus upon photoirradiation, generating DNA and mitochondrial damage, which might contribute toward overcoming cisplatin resistance. Mitochondrial damage, apoptosis, ROS generation, DNA damage, angiogenesis inhibition, and colony formation were observed when A549 lung cancer cells were treated with OsCUR-2 . The photochemistry of these Os-arene complexes was investigated by a combination of NMR, HPLC-MS, high energy resolution fluorescence detected (HERFD), X-ray adsorption near edge structure (XANES) spectroscopy, total fluorescence yield (TFY) XANES spectra, and theoretical computation. Selective photodissociation of the arene ligand and oxidation of Os(II) to Os(III) occurred under blue light or UVA excitation. This new approach to the design of novel Os-arene complexes as phototherapeutic agents suggests that the novel curcumin complex OsCUR-2 , in particular, is a potential candidate for further development as a photosensitizer for anticancer photoactivated chemotherapy (PACT).- Published
- 2021
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22. Structurally screening calixarenes as peptide transport activators.
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Zhang DY, Zheng Z, Zhao H, Wang HY, Ding F, Li HB, Pan YC, and Guo DS
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- Biological Transport drug effects, Calixarenes chemistry, Drug Evaluation, Preclinical, Humans, Molecular Structure, Calixarenes pharmacology, Peptides metabolism
- Abstract
Calixarenes are reportedly excellent activators that can remarkably improve the transport efficiencies of cell penetrating peptides. We employed eight calixarenes to systematically study the influence of structure on activation efficiency, which revealed that the scaffold, head group, and alkyl chain are all significant factors for activation efficiency by affecting affinities with the peptide and membrane.
- Published
- 2021
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23. Calix[ n ]arene-based immunogens: A new non-proteic strategy for anti-cocaine vaccine.
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da Silva Neto L, da Silva Maia AF, Godin AM, de Almeida Augusto PS, Pereira RLG, Caligiorne SM, Alves RB, Fernandes SOA, Cardoso VN, Goulart GAC, Martins FT, das Neves MCL, Garcia FD, and de Fátima Â
- Subjects
- Animals, Haptens, Tissue Distribution, Calixarenes chemistry, Calixarenes pharmacology, Cocaine, Vaccines
- Abstract
Introduction: Cocaine use disorder is a significant public health issue without a current specific approved treatment. Among different approaches to this disorder, it is possible to highlight a promising immunologic strategy in which an immunogenic agent may reduce the reinforcing effects of the drug if they are able to yield sufficient specific antibodies capable to bind cocaine and/or its psychoactive metabolites before entering into the brain. Several carriers have been investigated in the anti-cocaine vaccine development; however, they generally present a very complex chemical structure, which potentially hampers the proper assessment of the coupling efficiency between the hapten units and the protein structure., Objectives: The present study reports the design, synthesis and preclinical evaluation of two novel calix[ n ]arene-based anti-cocaine immunogens (herein named as V4N2 and V8N2 ) by the tethering of the hydrolysis-tolerant hapten GNE ( 15 ) on calix[4]arene and calix[8]arene moieties., Methods: The preclinical assessment corresponded to the immunogenicity and dose-response evaluation of V4N2 and V8N2 . The potential of the produced antibodies to reduce the passage of cocaine analogue through the blood-brain-barrier (BBB), modifying its biodistribution was also investigated., Results: Both calix[ n ]arene-based immunogens elicited high titers of cocaine antibodies that modified the biodistribution of a cocaine radiolabeled analogue (
99m Tc-TRODAT-1) and decreased cocaine-induced behavior, according to an animal model., Conclusion: The present results demonstrate the potential of V4N2 and V8N2 as immunogens for the treatment of cocaine use disorder., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2022 The Authors. Published by Elsevier B.V. on behalf of Cairo University.)- Published
- 2021
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24. Transcriptional control of brain tumor stem cells by a carbohydrate binding protein.
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Sharanek A, Burban A, Hernandez-Corchado A, Madrigal A, Fatakdawala I, Najafabadi HS, Soleimani VD, and Jahani-Asl A
- Subjects
- Aged, Animals, Antineoplastic Agents pharmacology, Brain Neoplasms genetics, Brain Neoplasms pathology, Brain Neoplasms radiotherapy, Calixarenes pharmacology, Cell Line, Tumor, Cell Proliferation, Cell Self Renewal, ErbB Receptors genetics, ErbB Receptors metabolism, Galectin 1 antagonists & inhibitors, Galectin 1 genetics, Gene Expression Regulation, Neoplastic, Glioblastoma genetics, Glioblastoma pathology, Glioblastoma radiotherapy, Homeodomain Proteins genetics, Homeodomain Proteins metabolism, Humans, Male, Mice, SCID, Middle Aged, Mutation, Neoplastic Stem Cells pathology, Neoplastic Stem Cells radiation effects, Radiation Tolerance, Radiation-Sensitizing Agents pharmacology, STAT3 Transcription Factor genetics, STAT3 Transcription Factor metabolism, Signal Transduction, Xenograft Model Antitumor Assays, Mice, Brain Neoplasms metabolism, Galectin 1 metabolism, Glioblastoma metabolism, Neoplastic Stem Cells metabolism, Transcription, Genetic
- Abstract
Brain tumor stem cells (BTSCs) and intratumoral heterogeneity represent major challenges in glioblastoma therapy. Here, we report that the LGALS1 gene, encoding the carbohydrate binding protein, galectin1, is a key regulator of BTSCs and glioblastoma resistance to therapy. Genetic deletion of LGALS1 alters BTSC gene expression profiles and results in downregulation of gene sets associated with the mesenchymal subtype of glioblastoma. Using a combination of pharmacological and genetic approaches, we establish that inhibition of LGALS1 signaling in BTSCs impairs self-renewal, suppresses tumorigenesis, prolongs lifespan, and improves glioblastoma response to ionizing radiation in preclinical animal models. Mechanistically, we show that LGALS1 is a direct transcriptional target of STAT3 with its expression robustly regulated by the ligand OSM. Importantly, we establish that galectin1 forms a complex with the transcription factor HOXA5 to reprogram the BTSC transcriptional landscape. Our data unravel an oncogenic signaling pathway by which the galectin1/HOXA5 complex maintains BTSCs and promotes glioblastoma., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)
- Published
- 2021
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25. Pillar[5]arene-based supramolecular photosensitizer for enhanced hypoxic-tumor therapeutic effectiveness.
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Chao S, Shen Z, Pei Y, Lv Y, Chen X, Ren J, Yang K, and Pei Z
- Subjects
- Humans, Photochemotherapy, Quaternary Ammonium Compounds chemistry, Quaternary Ammonium Compounds pharmacology, Calixarenes chemistry, Calixarenes pharmacology, Reactive Oxygen Species metabolism, Cell Line, Tumor, Cell Survival drug effects, Drug Screening Assays, Antitumor, Antineoplastic Agents pharmacology, Antineoplastic Agents chemistry, Antineoplastic Agents chemical synthesis, Photosensitizing Agents chemistry, Photosensitizing Agents pharmacology, Photosensitizing Agents chemical synthesis, Doxorubicin pharmacology, Doxorubicin chemistry
- Abstract
A galactose-targeting supramolecular photosensitizer system DOX@GP5⊃NBSPD was constructed based on a host-guest inclusion complex. The supramolecular system could achieve efficient delivery of DOX/NBS and selective release under GSH stimulation. In vitro studies revealed that this supramolecular DOX/NBS co-delivery system exhibited high ROS production and excellent cancer cell damage capability in a hypoxic environment. This strategy can therefore achieve enhanced hypoxic-tumor therapeutic effectiveness by chemo-photodynamic combination.
- Published
- 2021
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26. Cascade catalytic nanoplatform constructed by laterally-functionalized pillar[5]arenes for antibacterial chemodynamic therapy.
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Li F, Zang M, Hou J, Luo Q, Yu S, Sun H, Xu J, and Liu J
- Subjects
- Animals, Anti-Bacterial Agents chemical synthesis, Anti-Bacterial Agents chemistry, Calixarenes chemical synthesis, Calixarenes chemistry, Catalysis, Mice, Microbial Sensitivity Tests, Molecular Structure, NIH 3T3 Cells, Photosensitizing Agents chemical synthesis, Photosensitizing Agents chemistry, Anti-Bacterial Agents pharmacology, Calixarenes pharmacology, Escherichia coli drug effects, Magnetite Nanoparticles chemistry, Photochemotherapy, Photosensitizing Agents pharmacology
- Abstract
Chemodynamic therapy (CDT) is an emerging approach to overcome bacterial infections that can efficiently convert hydrogen peroxide (H2O2) to generate highly toxic hydroxyl radicals (˙OH). How to develop safe and effective CDT-based strategies is in high demand but challenging. Herein, a cascade catalytic nanoplatform (GOx-NCs/Fe3O4) was designed by absorbing glucose oxidase (GOx) onto the surface of covalent-assembled polymer capsules (NCs) encapsulating Fe3O4 nanoparticles. With the presence of glucose, GOx could effectively catalyze it to produce H2O2 and result in a decrease in pH value, both of which would assist the subsequent Fenton reaction. Encapsulated Fe3O4 nanoparticles would subsequently trigger H2O2 to produce ˙OH, which could make antibacterial CDT come true. More importantly, the polymer capsules exhibited little to no cytotoxicity towards mammalian cells, which might provide more opportunities and potential to apply in other fields.
- Published
- 2021
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27. Scandium calix[ n ]arenes ( n = 4, 6, 8): structural, cytotoxicity and ring opening polymerization studies.
- Author
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Alshamrani AFA, Santoro O, Prior TJ, Alamri MA, Stasiuk GJ, Elsegood MRJ, and Redshaw C
- Subjects
- Antineoplastic Agents chemistry, Antineoplastic Agents pharmacology, Antineoplastic Agents toxicity, Calixarenes pharmacology, Calixarenes toxicity, Cell Survival drug effects, HCT116 Cells, HT29 Cells, Humans, Models, Molecular, Polymerization, Scandium pharmacology, Scandium toxicity, Calixarenes chemistry, Scandium chemistry
- Abstract
Interaction of [Sc(OR)3] (R = iPr or triflate) with p-tert-butylcalix[n]arenes, where n = 4, 6, or 8, affords a number of intriguing structural motifs, which are relatively non-toxic (cytotoxicity evaluated against cell lines HCT116 and HT-29) and a number were capable of the ring opening polymerization (ROP) of cyclohexene oxide.
- Published
- 2021
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28. New Treatment Strategy Targeting Galectin-1 against Thyroid Cancer.
- Author
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Gheysen L, Soumoy L, Trelcat A, Verset L, Journe F, and Saussez S
- Subjects
- Animals, Antineoplastic Agents pharmacology, Calixarenes pharmacology, Cell Line, Tumor, Cell Proliferation, Focal Adhesion Kinase 2 metabolism, Galectin 1 antagonists & inhibitors, Heat-Shock Proteins metabolism, Humans, Male, Mice, Molecular Chaperones metabolism, Nitric Oxide Synthase Type III metabolism, Thyroid Neoplasms metabolism, Antineoplastic Agents therapeutic use, Calixarenes therapeutic use, Galectin 1 metabolism, Thyroid Neoplasms drug therapy
- Abstract
Although the overall survival rate of papillary or follicular thyroid cancers is good, anaplastic carcinomas and radio iodine refractory cancers remain a significant therapeutic challenge. Galectin-1 (Gal-1) is overexpressed in tumor cells and tumor-associated endothelial cells, and is broadly implicated in angiogenesis, cancer cell motility and invasion, and immune system escape. Our team has previously demonstrated a higher serum level of Gal-1 in patients with differentiated thyroid cancers versus healthy patients, and explored, by a knockdown strategy, the effect of Gal-1 silencing on cell proliferation and invasion in vitro, and on tumor and metastasis development in vivo. OTX008 is a calixarene derivative designed to bind the Gal-1 amphipathic β-sheet conformation and has previously demonstrated anti-proliferative and anti-invasive properties in several cancer cell lines including colon, breast, head and neck, and prostate cancer lines. In the current work, the impacts of OTX008 were evaluated in six thyroid cancer cell lines, and significant inhibitions of proliferation, migration, and invasion were observed in all lines expressing high Gal-1 levels. In addition, the signaling pathways affected by this drug were examined using RPPA (reverse phase protein array) and phosphoprotein expression assays, and opposite regulation of eNos, PYK2, and HSP27 by OTX008 was detected by comparing the two anaplastic lines 8505c and CAL 62. Finally, the sensitive 8505c line was xenografted in nude mice, and 3 weeks of OTX008 treatment (5 mg/kg/day) demonstrated a significant reduction in tumor and lung metastasize sizes without side effects. Overall, OXT008 showed significant anti-cancer effects both in vitro and in vivo in thyroid cancer lines expressing Gal-1, supporting further investigation of the molecular mechanisms of the drug and future clinical trials in patients with anaplastic thyroid cancer.
- Published
- 2021
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29. Calix[4]API-s: fully functionalized calix[4]arene-based facial active pharmaceutical ingredients.
- Author
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Pur FN
- Subjects
- Animals, Humans, Anti-Infective Agents chemistry, Anti-Infective Agents pharmacology, Antineoplastic Agents chemistry, Antineoplastic Agents pharmacology, Calixarenes chemistry, Calixarenes pharmacology, Phenols chemistry, Phenols pharmacology
- Abstract
This mini-review covers 25 fully functionalized facial calix[4]arene-based symmetrical and conical cyclic tetramers with significant (comparable to established therapeutic agents) anticancer and anti-infective activities. The main role of the calixarene scaffold in these calix[4]arene-based active pharmaceutical ingredients (calix[4]API-s) is to replicate embedded phenolic units in the cyclic tetramers. So, probably owing to the multivalency, facial, conical structures of calix[4]API-s and synergistic effect of their four replicated units, they can be considered as effective bioactive agents.
- Published
- 2021
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30. A supramolecular complex of hydrazide-pillar[5]arene and bisdemethoxycurcumin with potential anti-cancer activity.
- Author
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Guo F, Xia T, Xiao P, Wang Q, Deng Z, Zhang W, and Diao G
- Subjects
- Antineoplastic Agents chemical synthesis, Antineoplastic Agents pharmacology, Cell Movement drug effects, Cell Survival drug effects, Drug Design, Drug Liberation, HEK293 Cells, Hep G2 Cells, Humans, Calixarenes chemistry, Calixarenes pharmacology, Diarylheptanoids chemistry, Diarylheptanoids pharmacology, Macromolecular Substances chemical synthesis, Macromolecular Substances pharmacology
- Abstract
Pillar[5]arene complexes of the naturally occurring compound bisdemethoxycurcumin (BDMC) were acquired for improving the water solubility and stability of BDMC. As a family member of curcuminoid compounds, BDMC has many interesting therapeutic properties. However, its low aqueous solubility and stability resulted in poor availability and restricted the clinical efficacy. Pillar[5]arenes with hydrophilic ends and a hydrophobic cavity could include with BDMC based on size matching. The synthesized hydrazide-pillar[5]arene (HP5A) and BDMC had a strong host-guest interaction with a 1:1 binding stoichiometry. Furthermore, the HP5A ⊃ BDMC complex could self-assemble into well-defined fibers in water/ethanol solution. This supramolecular complex worked well in vitro for inhibiting the proliferation of hepatoma carcinoma cells HepG2. Remarkably, this method of complexation with pillar[5]arenes visibly reduced the undesirable side effects on normal cells without weakening the anti-cancer activity of the drugs. We expected that the obtained host-guest complex and fibrous assembly would provide a promising platform for delivering drugs with low water solubility., (Copyright © 2021 Elsevier Inc. All rights reserved.)
- Published
- 2021
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31. Grafting Dendrons onto Pillar[5]Arene Scaffolds.
- Author
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Nierengarten I, Holler M, Rémy M, Hahn U, Billot A, Deschenaux R, and Nierengarten JF
- Subjects
- Calixarenes pharmacology, Dendrimers pharmacology, Genetic Vectors genetics, Humans, Models, Molecular, Tissue Scaffolds chemistry, Calixarenes chemistry, Dendrimers chemistry, Genetic Vectors chemistry, Nanostructures chemistry
- Abstract
With their ten peripheral substituents, pillar[5]arenes are attractive compact scaffolds for the construction of nanomaterials with a controlled number of functional groups distributed around the macrocyclic core. This review paper is focused on the functionalization of pillar[5]arene derivatives with small dendrons to generate dendrimer-like nanomaterials and bioactive compounds. Examples include non-viral gene vectors, bioactive glycoclusters, and liquid-crystalline materials.
- Published
- 2021
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32. Difunctionalized pillar[5]arene-based polymer nanosheets for photodynamic therapy of Staphylococcus aureus infection.
- Author
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Li F, Zang M, Liu S, Li X, Jiang X, Tian R, Luo Q, Hou C, Xu J, and Liu J
- Subjects
- Animals, Cell Line, Photochemotherapy, Reactive Oxygen Species metabolism, Staphylococcus aureus metabolism, Anti-Bacterial Agents chemistry, Anti-Bacterial Agents pharmacology, Calixarenes chemistry, Calixarenes pharmacology, Nanostructures chemistry, Staphylococcus aureus drug effects, Staphylococcus aureus radiation effects
- Abstract
Bacterial infections pose severe threats to global public health security. Developing antibacterial agents with both high efficiency and safety to handle this problem has become a top priority. Here, highly stable and effective polymer nanosheets have been constructed by the covalent co-assembly of a pillar[5]arene derivative and metalloporphyrin for photodynamic antibacterial therapy (PDAT). The monolayer nanosheets are strongly positively charged and thus capable of binding with Staphylococcus aureus (SA) through electrostatic interactions. Additionally, the nanosheets can be activated to generate reactive oxygen species (ROS) under white-light irradiation, and exhibit satisfactory antibacterial performance towards SA. More importantly, cell viability assays demonstrate that the nanosheets show little to no cytotoxicity impact on mammalian cells even when the concentrations are much higher than those employed in the antibacterial studies. The above results suggest that the polymer nanosheets could be an effective antibacterial agent to overcome bacterial infections and hold a broad range of potential applications in real life.
- Published
- 2021
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33. Targeting the CRD F-face of Human Galectin-3 and Allosterically Modulating Glycan Binding by Angiostatic PTX008 and a Structurally Optimized Derivative.
- Author
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Miller MC, Zheng Y, Suylen D, Ippel H, Cañada FJ, Berbís MA, Jiménez-Barbero J, Tai G, Gabius HJ, and Mayo KH
- Subjects
- Binding Sites, Blood Proteins metabolism, Calixarenes chemistry, Dose-Response Relationship, Drug, Galectins metabolism, Humans, Magnetic Resonance Spectroscopy, Molecular Structure, Phenols chemistry, Polysaccharides chemistry, Structure-Activity Relationship, Blood Proteins antagonists & inhibitors, Calixarenes pharmacology, Galectins antagonists & inhibitors, Phenols pharmacology, Polysaccharides pharmacology
- Abstract
Calix[4]arene PTX008 is an angiostatic agent that inhibits tumor growth in mice by binding to galectin-1, a β-galactoside-binding lectin. To assess the affinity profile of PTX008 for galectins, we used
15 N,1 H HSQC NMR spectroscopy to show that PTX008 also binds to galectin-3 (Gal-3), albeit more weakly. We identified the contact site for PTX008 on the F-face of the Gal-3 carbohydrate recognition domain. STD NMR revealed that the hydrophobic phenyl ring crown of the calixarene is the binding epitope. With this information, we performed molecular modeling of the complex to assist in improving the rather low affinity of PTX008 for Gal-3. By removing the N-dimethyl alkyl chain amide groups, we produced PTX013 whose reduced alkyl chain length and polar character led to an approximately eightfold stronger binding than PTX008. PTX013 also binds Gal-1 more strongly than PTX008, whereas neither interacts strongly, if at all, with Gal-7. In addition, PTX013, like PTX008, is an allosteric inhibitor of galectin binding to the canonical ligand lactose. This study broadens the scope for galectin targeting by calixarene-based compounds and opens the perspective for selective galectin blocking., (© 2020 Wiley-VCH GmbH.)- Published
- 2021
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34. Biomedical Applications of Calixarenes: State of the Art and Perspectives.
- Author
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Pan YC, Hu XY, and Guo DS
- Subjects
- Anti-Infective Agents chemistry, Anti-Infective Agents pharmacology, Bacteria drug effects, Biomarkers analysis, Calixarenes pharmacology, Gene Transfer Techniques, Humans, Nanoparticles chemistry, Biosensing Techniques methods, Calixarenes chemistry, Drug Carriers chemistry, Optical Imaging methods
- Abstract
Calixarenes (CAs), representing the third generation of supramolecular hosts and one of the most widely studied macrocyclic scaffolds, offer (almost) unlimited structure and application possibilities due to their ease of modification, which allows one to establish a large molecular library as a material basis for diverse biomedical applications. Moreover, CAs and their derivatives engage in various noncovalent interactions for the facile recognition of guests including bioactive molecules and are also important building blocks for the fabrication of supramolecular architectures. In view of their molecular recognition and self-assembly properties, CAs are extensively applied in biosensing, bioimaging, and drug/gene delivery. Additionally, some CA derivatives exhibit biological activities and can therefore be used as new therapeutic agents. Herein, we summarize the diverse biomedical applications of CAs including in vitro diagnosis (biosensing), in vivo diagnosis (bioimaging), and therapy., (© 2020 Wiley-VCH GmbH.)
- Published
- 2021
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35. Design, synthesis and evaluation of calix[4]arene-based carbonyl amide derivatives with antitumor activities.
- Author
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An L, Wang C, Zheng YG, Liu JD, and Huang TH
- Subjects
- Amides chemistry, Antineoplastic Agents chemical synthesis, Antineoplastic Agents chemistry, Calixarenes chemical synthesis, Calixarenes chemistry, Cell Cycle drug effects, Cell Proliferation drug effects, Cell Survival drug effects, Cells, Cultured, Dose-Response Relationship, Drug, Drug Screening Assays, Antitumor, Humans, Molecular Structure, Phenols chemical synthesis, Phenols chemistry, Structure-Activity Relationship, Wound Healing drug effects, Amides pharmacology, Antineoplastic Agents pharmacology, Calixarenes pharmacology, Drug Design, Phenols pharmacology
- Abstract
Calixarenes, with potential functionalization on the upper and lower rim, have been explored in recent years for the design and construction of anticancer agents in the field of drugs and pharmaceuticals. Herein, optimization of bis [N-(2-hydroxyethyl) aminocarbonylmethoxyl substituted calix [4] arene (CLX-4) using structure-based drug design and traditional medicinal chemistry led to the discovery of series of calix [4]arene carbonyl amide derivatives 5a-5t. Evaluation of the cytotoxicity of 5a-5t employing MTT assay in MCF-7, MDA-MB-231 (human breast cancer cells), HT29 (human colon carcinoma cells), HepG2 (human hepatocellular carcinoma cells), A549 (human lung adenocarcinoma cells) and HUVEC (Human Umbilical Vein Endothelial) cells demonstrated that the most promising compound 5h displayed the most superior inhibitory effect against A549 and MDA-MB-231 cells, which were 3.2 times and 6.8 times of CLX-4, respectively. In addition, the cell inhibition rate (at 10 μM) against normal HUVEC cells in vitro was only 9.6%, indicating the safty of compound 5h. Moreover, compound 5h could inhibit the migration of MDA-MB-231 cell in wound healing assay. Further mechanism studies significantly indicated that compound 5h could block MDA-MB-231 cell cycle arrest in G0/G1 phase by down regulating cyclin D1 and CDK4, and induce apoptosis by up-regulation of Bax, down-regulation of Caspase-3, PARP and Bcl-2 proteins, resulting in the reduction of DNA synthesis and cell division arrest. This work provides worthy of further exploration for the promising calixarene-based anticancer drugs., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Masson SAS. All rights reserved.)
- Published
- 2021
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36. The Odd Couple(s): An Overview of Beta-Lactam Antibiotics Bearing More Than One Pharmacophoric Group.
- Author
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De Rosa M, Verdino A, Soriente A, and Marabotti A
- Subjects
- Animals, Anti-Bacterial Agents pharmacology, Azetidines pharmacology, Bacteria drug effects, Bacterial Infections drug therapy, Calixarenes chemistry, Calixarenes pharmacology, Drug Discovery, Humans, Lactams, Macrocyclic pharmacology, beta-Lactams pharmacology, Anti-Bacterial Agents chemistry, Azetidines chemistry, Lactams, Macrocyclic chemistry, beta-Lactams chemistry
- Abstract
β-lactam antibiotics are among the most important and widely used antimicrobials worldwide and are comprised of a large family of compounds, obtained by chemical modifications of the common scaffolds. Usually these modifications include the addition of active groups, but less frequently, molecules were synthesized in which either two β-lactam rings were joined to create a single bifunctional compound, or the azetidinone ring was joined to another antibiotic scaffold or another molecule with a different activity, in order to create a molecule bearing two different pharmacophoric functions. In this review, we report some examples of these derivatives, highlighting their biological properties and discussing how this strategy can lead to the development of innovative antibiotics that can represent either novel weapons against the rampant increase of antimicrobial resistance, or molecules with a broader spectrum of action.
- Published
- 2021
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37. Thiacalixarene based quaternary ammonium salts as promising antibacterial agents.
- Author
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Padnya PL, Terenteva OS, Akhmedov AA, Iksanova AG, Shtyrlin NV, Nikitina EV, Krylova ES, Shtyrlin YG, and Stoikov II
- Subjects
- Anti-Bacterial Agents pharmacology, Bacillus subtilis drug effects, Benzalkonium Compounds pharmacology, Calixarenes pharmacology, Chlorhexidine pharmacology, Drug Design, Drug Resistance, Microbial, Humans, Microbial Sensitivity Tests, Molecular Conformation, Staphylococcus aureus drug effects, Staphylococcus epidermidis drug effects, Structure-Activity Relationship, Anti-Bacterial Agents chemical synthesis, Calixarenes chemical synthesis, Quaternary Ammonium Compounds chemistry
- Abstract
The search for new antibacterial and antiseptic drugs is an urgent problem due to the resistance of microorganisms to existing drugs. In this work, for the first time, the design of antibacterial and bactericidal agents based on quaternary ammonium compounds on thiacalixarene macrocyclic platform was proposed and implemented. A series of tetrasubstituted quaternary ammonium salts with different nature and length of the substituent (-N
+ (CH3 )2 R, R = CH2 Ph, Cn H2n+1 , n = 1, 4, 8, 10) based on p-tert-butylthiacalix[4]arene in cone and 1,3-alternate conformations was obtained with excellent yields. The obtained compounds have a high antibacterial effect against Gram-positive (S. aureus, S. epidermidis, B. subtilis) bacteria comparable with commercial antiseptics chlorhexidine, miramistin and benzalkonium chloride. It was found that quaternary ammonium derivatives of thiacalix[4]arene in 1,3-alternate conformation more effectively inhibit the growth of the tested bacterial strains in comparison with compounds in cone conformation. Cytotoxicity studies on human skin fibroblast (HSF) cells demonstrated that all compounds were less toxic compared to reference drugs. The different type of interaction of the studied compounds with model DPPC lipid membranes explains different antibacterial activity and cytotoxicity of compounds. The compounds in cone conformation are adsorbed on the DPPC vesicles membrane surface, while the incorporation of lipophilic alkyl fragments of macrocycles in 1,3-alternate conformation into the membrane leads to "clumping" of DPPC vesicles. It was shown the saving of antibacterial activity of thiacalixarene derivatives in 1,3-alternate conformation on Gram-positive clinical strains. The obtained results allow viewing the described thiacalixarene based quaternary ammonium compounds as promising molecules in the development of the new antibacterial agents., (Copyright © 2020 Elsevier Ltd. All rights reserved.)- Published
- 2021
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38. Supraamphiphilic Systems Based on Metallosurfactant and Calix[4]resorcinol: Self-Assembly and Drug Delivery Potential.
- Author
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Kashapov R, Razuvayeva Y, Ziganshina A, Sergeeva T, Lukashenko S, Sapunova A, Voloshina A, Kashapova N, Nizameev I, Salnikov V, Ziganshina S, Gareev B, and Zakharova L
- Subjects
- Antineoplastic Agents chemistry, Antineoplastic Agents pharmacology, Calixarenes chemistry, Cisplatin chemistry, Cisplatin pharmacology, Drug Delivery Systems, HeLa Cells, Hepatocytes, Humans, Inhibitory Concentration 50, Microscopy, Atomic Force, Microscopy, Electron, Transmission, Molecular Structure, Resorcinols chemistry, Surface-Active Agents, Calixarenes pharmacology, Organometallic Compounds chemistry, Resorcinols pharmacology
- Abstract
Metallic amphiphiles are used as building blocks in the construction of nanoscale superstructures, where the hydrophobic effects induce the self-assembly of the nanoparticles of interest. However, the influence of synergizing multiple chemical interactions on an effective design of these structures mostly remains an open question. In this regard, supraamphiphilic systems based on flexible surfactant molecules and rigid macrocycles are being actively developed, but there are few works on the interaction between metallosurfactants and macrocycles. In the present work, the self-assembly and biological properties of a metallosurfactant with calixarene were studied for the first time. The metallosurfactant, a complex between lanthanum nitrate and two 4-aza-1-hexadecylazoniabicyclo[2.2.2]octane bromide units, and calix[4]resorcinol containing sulfonate groups on the upper rim were used to form a novel supraamphiphilic composition. The system formed was studied using a variety of physicochemical methods, including spectrophotometry, NMR, XRF, and dynamic and electrophoretic light scattering. It was found that the most optimal tetraanionic calix[4]resorcinol to dicationic metallosurfactant molar ratio, leading to mixed aggregation upon ion pair complexation, is 2:3. The mixed aggregates formed in the pentamolar concentration range were able to encapsulate hydrophilic substrates, including the anticancer drug cisplatin, the pure form of which is more cytotoxic toward healthy cells than toward diseased cells. Interestingly, the drug loaded into the macrocycle-metallosurfactant particles was less cytotoxic to a healthy Chang liver cell line and more cytotoxic to tumor M-HeLa cells. This selectivity depends on the amount of cisplatin added. The more drug is added to the macrocycle-metallosurfactant composition, the greater the biological activity against cancer cells. Taking into account that the appearance of resistance of cancer cells to drugs, especially to cisplatin, is one of the most important problems in treatment, the results of this work envisage the potential application of a mixed macrocycle-metallosurfactant system for the design of therapeutic cisplatin compositions.
- Published
- 2020
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39. Effect of charge status on the ion transport and antimicrobial activity of synthetic channels.
- Author
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Xin P, Zhao L, Mao L, Xu L, Hou S, Kong H, Fang H, Zhu H, Jiang T, and Chen CP
- Subjects
- Animals, Anti-Bacterial Agents chemistry, Calixarenes chemistry, Dose-Response Relationship, Drug, Erythrocytes drug effects, Gramicidin chemistry, Ion Channels metabolism, Ion Transport drug effects, Microbial Sensitivity Tests, Molecular Structure, Rats, Anti-Bacterial Agents pharmacology, Bacillus subtilis drug effects, Calixarenes pharmacology, Gramicidin pharmacology, Ion Channels antagonists & inhibitors, Staphylococcus aureus drug effects
- Abstract
A class of unimolecular channels formed by pillararene-gramicidin hybrid molecules are presented. The charge status of the peptide domain in these channels has a significant impact on their ion transport and antimicrobial activity. These channels exhibited different membrane-association abilities between microbial cells and mammalian cells. One of the channels displayed a higher antimicrobial activity towards S. aureus (IC
50 = 0.55 μM) and negligible hemolytic toxicity, showing potential to serve as a systemic antibiotic.- Published
- 2020
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40. Antimicrobial Activity of Calixarenes and Related Macrocycles.
- Author
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Shurpik DN, Padnya PL, Stoikov II, and Cragg PJ
- Subjects
- Amino Acid Motifs, Animals, Calixarenes chemistry, Drug Delivery Systems, Glycosylation, Humans, Lectins chemistry, Metals chemistry, Nanoparticles chemistry, Oxazoles chemistry, Phenylalanine analogs & derivatives, Phenylalanine chemistry, Solubility, Thiadiazoles chemistry, Thiazoles chemistry, Vancomycin chemistry, Water chemistry, Anti-Infective Agents pharmacology, Biofilms, Calixarenes pharmacology, Prodrugs pharmacology, Sulfonamides chemistry
- Abstract
Calixarenes and related macrocycles have been shown to have antimicrobial effects since the 1950s. This review highlights the antimicrobial properties of almost 200 calixarenes, resorcinarenes, and pillararenes acting as prodrugs, drug delivery agents, and inhibitors of biofilm formation. A particularly important development in recent years has been the use of macrocycles with substituents terminating in sugars as biofilm inhibitors through their interactions with lectins. Although many examples exist where calixarenes encapsulate, or incorporate, antimicrobial drugs, one of the main factors to emerge is the ability of functionalized macrocycles to engage in multivalent interactions with proteins, and thus inhibit cellular aggregation.
- Published
- 2020
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41. Pillar[5]arene-Based Switched Supramolecular Photosensitizer for Self-Amplified and pH-Activated Photodynamic Therapy.
- Author
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Huang B, Wang P, Ouyang Y, Pang R, Liu S, Hong C, Ma S, Gao Y, Tian J, and Zhang W
- Subjects
- Animals, Antineoplastic Agents chemistry, Breast Neoplasms metabolism, Breast Neoplasms pathology, Calixarenes chemistry, Cell Line, Tumor, Cell Proliferation drug effects, Cell Survival drug effects, Drug Screening Assays, Antitumor, Fluorescence Resonance Energy Transfer, Hydrogen-Ion Concentration, Macromolecular Substances chemistry, Macromolecular Substances pharmacology, Mice, Mitochondria drug effects, Mitochondria metabolism, Particle Size, Photosensitizing Agents chemistry, Surface Properties, Antineoplastic Agents pharmacology, Breast Neoplasms drug therapy, Calixarenes pharmacology, Photochemotherapy, Photosensitizing Agents pharmacology
- Abstract
Photodynamic therapy (PDT) has emerged as a promising and spatiotemporally controllable cancer treatment modality. However, serious skin photosensitization during the PDT process limits the clinical application of PDT. Thus, the construction of "smart" and multifunctional photosensitizers has attracted substantial interest. Herein, we develop a mitochondria-targeting and pH-switched hybrid supramolecular photosensitizer by the host-guest interaction. The PDT efficacy of supramolecular photosensitizers can be quenched by the Förster resonance energy transfer (FRET) effect during long circulation and activated by the dissociation of supramolecular photosensitizers in an acidic tumor microenvironment, benefitting from the dynamic feature of the host-guest interaction and pH responsiveness of the water-soluble pillar[5]arene on gold nanoparticles. The rational integration of mitochondria-targeting and reductive glutathione (GSH) elimination in the hybrid switchable supramolecular photosensitizer prolongs the lifetime of reactive oxygen species generated in the PDT near mitochondria and further amplifies the PDT efficacy. Thus, the facile and versatile construction of switchable supramolecular photosensitizer offers not only the targeted and precise phototherapy but also high therapeutic efficacy, which would provide a new path for the clinic application of PDT.
- Published
- 2020
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42. Formation of the inclusion complex of water soluble fluorescent calix[4]arene and naringenin: solubility, cytotoxic effect and molecular modeling studies.
- Author
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Oguz M, Bhatti AA, Dogan B, Karakurt S, Durdagi S, and Yilmaz M
- Subjects
- Flavanones, Humans, Phenols, Solubility, Calixarenes pharmacology, Water
- Abstract
Naringenin is considered as an important flavonoid in phytochemistry because of its important effect on cancer chemoprevention. Unfortunately its poor solubility has restricted its therapeutic applications. In this study, an efficient water-soluble fluorescent calix[4]arene (compound 5 ) was synthesized as host macromolecule to increase solubility and cytotoxicity in cancer cells of water-insoluble naringenin as well as to clarify localization of naringenin into the cells. Complex formed by host-guest interaction between compound 5 and naringenin was analyzed with UV-visible, fluorescence, FTIR spectroscopic techniques and molecular modeling studies. Stern-Volmer analysis showed binding constant value of K
sv 3.5 × 107 M-1 suggesting strong interaction between host and guest. Binding capacity shows 77% of naringenin was loaded on compound 5 . Anticarcinogenic effects of naringenin complex were evaluated on human colorectal carcinoma cells (DLD-1) and it was found that 5- naringenin complex inhibits proliferation of DLD-1 cells 3.4-fold more compared to free naringenin. Fluorescence imaging studies show 5- naringenin complex was accumulated into the cytoplasm instead of the nucleus. Increased solubility and cytotoxicity of naringenin with fluorescent calix[4]arene makes it one of the potential candidates as a therapeutic enhancer. For deep understanding of host-guest interaction mechanisms, complementary multiscale molecular modeling studies were also carried out.Communicated by Ramaswamy H. Sarma.- Published
- 2020
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43. Synthesis and anticancer activity of open-resorcinarene conjugates.
- Author
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Daniel Pedro-Hernández L, Hernández-Montalbán C, Martínez-Klimova E, Ramírez-Ápan T, and Martínez-García M
- Subjects
- Animals, Antineoplastic Agents chemical synthesis, Antineoplastic Agents chemistry, COS Cells, Calixarenes chemical synthesis, Calixarenes chemistry, Cell Line, Tumor, Cell Proliferation drug effects, Chlorocebus aethiops, Dose-Response Relationship, Drug, Drug Screening Assays, Antitumor, Humans, Molecular Structure, Phenylalanine chemical synthesis, Phenylalanine chemistry, Phenylalanine pharmacology, Structure-Activity Relationship, Antineoplastic Agents pharmacology, Calixarenes pharmacology, Phenylalanine analogs & derivatives
- Abstract
The first example of conjugation of open-resorcinarenes with chlorambucil, ibuprofen, naproxen and indomethacin are presented. The cytotoxic properties of the obtained conjugates were tested against the cancer cell lines U-251, PC-3, K-562, HCT-15, MCF-7 and SKLU-1. It was found that the conjugate with chlorambucil, naproxen or indomethacin (having 8 moieties) was toxic towards cancer cell lines U-251 and K-562, with no activity against non-cancerous COS-7 cells. The conjugates with naproxen and indomethacin showed high selectivity towards U-251 tumor cells., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Ltd. All rights reserved.)
- Published
- 2020
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44. Calix[6]arene diminishes receptor tyrosine kinase lifespan in pancreatic cancer cells and inhibits their migration and invasion efficiency.
- Author
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Rocha-Brito KJP, Fonseca EMB, Oliveira BGF, Fátima Â, and Ferreira-Halder CV
- Subjects
- Cell Line, Tumor, Cell Movement drug effects, Endocytosis drug effects, Humans, Molecular Docking Simulation, Neoplasm Invasiveness pathology, Pancreatic Neoplasms metabolism, Pancreatic Neoplasms pathology, Proteolysis drug effects, Proto-Oncogene Proteins antagonists & inhibitors, Receptor Protein-Tyrosine Kinases antagonists & inhibitors, Axl Receptor Tyrosine Kinase, Antineoplastic Agents pharmacology, Calixarenes pharmacology, Neoplasm Invasiveness prevention & control, Pancreatic Neoplasms drug therapy, Phenols pharmacology, Proto-Oncogene Proteins metabolism, Receptor Protein-Tyrosine Kinases metabolism
- Abstract
Pancreatic cancer is a challenging malignancy, mainly due to aggressive regional involvement, early systemic dissemination, high recurrence rate, and subsequent low patient survival. Scientific advances have contributed in particular by identification of molecular targets as well as the definition of the mechanism of action of the drug candidate in the cellular microenvironment. Previously, we have reported the identification of the molecular mechanisms by which calix[6]arene (CLX6) reduces the viability and proliferation of pancreatic cancer cells. Now, we show the biochemical mechanisms by which CLX6 decreases the aggressiveness of Panc-1 cells, focusing specifically on receptor tyrosine kinases (RTK). The results show that clathrin-mediated endocytosis is involved in CLX6-induced AXL receptor tyrosine kinase degradation in Panc-1 cells. This response may be related to the interaction of CLX6 with the tyrosine kinase receptor binding site (such as AXL). As a result, RTK is internalized and degraded by endocytosis, a condition that negatively impacts events dependent on its signaling. Additionally, CLX6 inhibits migration and invasion of Panc-1 cells by downregulating FAK (downstream mediator of AXL) activity and reducing expression levels of MMP2 and MMP9, directly related to the metastatic profile of these cells. It is noteworthy that according to the mechanism proposed here, CLX6 appears as a candidate to be used in therapeutic protocols of patients that display high expression of AXL and consequently, poor diagnosis., Competing Interests: Declaration of Competing Interest The authors declared that there is no conflict of interest., (Copyright © 2020 Elsevier Inc. All rights reserved.)
- Published
- 2020
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45. Injectable supramolecular nanohydrogel from a micellar self-assembling calix[4]arene derivative and curcumin for a sustained drug release.
- Author
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Granata G, Petralia S, Forte G, Conoci S, and Consoli GML
- Subjects
- Calixarenes chemistry, Computer Simulation, Curcumin chemistry, Drug Stability, Models, Molecular, Phenols chemistry, Rheology, Spectrophotometry, Ultraviolet, Viscosity, Calixarenes pharmacology, Curcumin pharmacology, Drug Liberation, Hydrogels chemistry, Injections, Micelles, Phenols pharmacology
- Abstract
In the search for soft and smart materials for nanomedicine, which is a present challenge, supramolecular nanohydrogels built on self-assembling low-molecular-weight building blocks attract interest for their structural, mechanical and functional properties. Herein, we describe a supramolecular nanohydrogel formed by a biofriendly micellar self-assembling choline-calix[4]arene derivative in the presence of curcumin, a natural and multitarget pharmacologically relevant drug. Morphology and mechanical properties of the nanohydrogel were investigated, and theoretical simulation performed to model the nanohydrogel structure. The self-healing and injectable nanohydrogel easily formed in PBS medium at physiologic pH, without using additives and organic solvents. The micellar nanohydrogel protected curcumin from rapid chemical and photochemical degradation, and slowly dissolved in curcumin-loaded micelles sustaining the drug release in a low rate. The nanohydrogel which combines the mechanical properties of a hydrogel and the benefits of a nanoscale micelle in drug delivery, appears a promising novel material for drug delivery., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier B.V. All rights reserved.)
- Published
- 2020
- Full Text
- View/download PDF
46. (Thia)calixarenephosphonic Acids as Potent Inhibitors of the Nucleic Acid Chaperone Activity of the HIV-1 Nucleocapsid Protein with a New Binding Mode and Multitarget Antiviral Activity.
- Author
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Humbert N, Kovalenko L, Saladini F, Giannini A, Pires M, Botzanowski T, Cherenok S, Boudier C, Sharma KK, Real E, Zaporozhets OA, Cianférani S, Seguin-Devaux C, Poggialini F, Botta M, Zazzi M, Kalchenko VI, Mori M, and Mély Y
- Subjects
- Animals, Calixarenes classification, HIV-1 drug effects, Inhibitory Concentration 50, Mice, Mice, Transgenic, Molecular Dynamics Simulation, Protein Binding, Anti-HIV Agents pharmacology, Calixarenes pharmacology, HIV-1 chemistry, Molecular Chaperones antagonists & inhibitors, Nucleocapsid Proteins antagonists & inhibitors, Organophosphonates pharmacology
- Abstract
The nucleocapsid protein (NC) is a highly conserved protein that plays key roles in HIV-1 replication through its nucleic acid chaperone properties mediated by its two zinc fingers and basic residues. NC is a promising target for antiviral therapy, particularly to control viral strains resistant to currently available drugs. Since calixarenes with antiviral properties have been described, we explored the ability of calixarene hydroxymethylphosphonic or sulfonic acids to inhibit NC chaperone properties and exhibit antiviral activity. By using fluorescence-based assays, we selected four calixarenes inhibiting NC chaperone activity with submicromolar IC
50 values. These compounds were further shown by mass spectrometry, isothermal titration calorimetry, and fluorescence anisotropy to bind NC with no zinc ejection and to compete with nucleic acids for the binding to NC. Molecular dynamic simulations further indicated that these compounds interact via their phosphonate or sulfonate groups with the basic surface of NC but not with the hydrophobic plateau at the top of the folded fingers. Cellular studies showed that the most soluble compound CIP201 inhibited the infectivity of wild-type and drug-resistant HIV-1 strains at low micromolar concentrations, primarily targeting the early steps of HIV-1 replication. Moreover, CIP201 was also found to inhibit the flipping and polymerization activity of reverse transcriptase. Calixarenes thus form a class of noncovalent NC inhibitors, endowed with a new binding mode and multitarget antiviral activity.- Published
- 2020
- Full Text
- View/download PDF
47. Evaluation of Anticancer Activities of Novel Facile Synthesized Calix[n]arene Sulfonamide Analogs.
- Author
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Yilmaz B, Bayrac AT, and Bayrakci M
- Subjects
- Cell Survival drug effects, Dose-Response Relationship, Drug, Drug Screening Assays, Antitumor, HEK293 Cells, Humans, Inhibitory Concentration 50, MCF-7 Cells, Magnetic Resonance Spectroscopy, Spectroscopy, Fourier Transform Infrared, Spheroids, Cellular, Sulfones chemistry, Trifluoroacetic Acid chemistry, Antineoplastic Agents pharmacology, Calixarenes pharmacology, Sulfonamides pharmacology
- Abstract
Here, new calixarene sulfonamide analogs were synthesized from the reaction of chlorosulfonated calix[n]arene (n: 4, 6, and 8) with N,N'-dimethylethylenediamine or ethylenediamine for the first time and an excellent calixarene sulfonamide analog showing potent and selective cytotoxic activity on some cancer cell lines were discovered. Cytotoxicity of the prepared calix[n]arene sulfonamide analogs towards both cancer and healthy cell lines was assessed by performing cell growth inhibition assays. In cytotoxicity assay results, it was observed that while sulfonamide analog based calix[4]arene (9) was not affecting the growth of epithelial cell lines (HEK), and it was especially effective on inhibiting the growth of some human cancer cell lines (MCF-7 and MIA PaCa-2). These results highlight that sulfonamide analog-based calix [4] arene (9) can be further studied as a potential anticancer agent.
- Published
- 2020
- Full Text
- View/download PDF
48. The antibacterial activity of p-tert-butylcalix[6]arene and its effect on a membrane model: molecular dynamics and Langmuir film studies.
- Author
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Wrobel EC, de Lara LS, do Carmo TAS, Castellen P, Lazzarotto M, de Lázaro SR, Camilo A Jr, Caseli L, Schmidt R, DeWolf CE, and Wohnrath K
- Subjects
- Thermodynamics, Anti-Bacterial Agents chemistry, Anti-Bacterial Agents pharmacology, Calixarenes chemistry, Calixarenes pharmacology, Cell Membrane drug effects, Membranes, Artificial, Molecular Dynamics Simulation
- Abstract
The antibacterial activity of a calixarene derivative, p-tert-butylcalix[6]arene (Calix6), was assessed and was shown not to inhibit the growth of E. coli, S. aureus and B. subtilis bacteria. With the aim of gaining more insights into the absence of antibacterial activity of Calix6, the interaction of this derivative with DPPG, a bacterial cell membrane lipid, was studied. Langmuir monolayers were used as the model membrane. Pure DPPG and pure Calix6 monolayers, as well as binary DPPG:Calix6 mixtures were studied using surface pressure measurements, compressional modulus, Brewster angle and fluorescence microscopies, ellipsometry, polarization-modulation infrared reflection absorption spectroscopy and molecular dynamics simulations. Thermodynamic properties of the mixed monolayers were additionally calculated using thermodynamic parameters. The analysis of isotherms showed that Calix6 significantly affects the DPPG monolayers, modifying the isotherm profile and increasing the molecular area, in agreement with the molecular dynamics simulations. The presence of Calix6 in the mixed monolayers decreased the interfacial elasticity, indicating that calixarene disrupts the strong intermolecular interactions of DPPG hindering its organization into a compact arrangement. At low molar ratios of Calix6, the DPPG:Calix6 interactions are preferentially attractive, due to the interactions between the hydrophobic tails of DPPG and the tert-butyl groups of Calix6. Increasing the proportion of calixarene generates repulsive interactions. Calix6 significantly affects the hydrophobic tail organization, which was confirmed by PM-IRRAS measurements. Calix6 appears to be expelled from the mixed films at a biologically relevant surface pressure, π = 30 mN m-1, indicating a low interaction with the cell membrane model related to the absence of antibacterial activity.
- Published
- 2020
- Full Text
- View/download PDF
49. Para-sulfonatocalix[n]arene-based biomaterials: Recent progress in pharmaceutical and biological applications.
- Author
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Bahojb Noruzi E, Molaparast M, Zarei M, Shaabani B, Kariminezhad Z, Ebadi B, Shafiei-Irannejad V, Rahimi M, and Pietrasik J
- Subjects
- Animals, Anti-Infective Agents chemistry, Anti-Infective Agents pharmacology, Biocompatible Materials chemistry, Biosensing Techniques, Calixarenes chemistry, Cell Line, Tumor, Drug Carriers chemistry, Drug Carriers pharmacology, Fluorescent Dyes chemistry, Fluorescent Dyes pharmacology, Humans, Optical Imaging, Sulfonic Acids chemistry, Biocompatible Materials pharmacology, Calixarenes pharmacology, Sulfonic Acids pharmacology
- Abstract
The history, properties, and characteristics of para-sulfonato-calixarenes are described. On the one hand, the inherent antibacterial and antifungal properties against microorganisms, and on the other hand non-toxicity of these supramolecules toward human organs are analyzed. The resulting biocompatibility of para-sulfonato-calixarenes makes them potential candidates for diverse life sciences and pharmaceutical applications without significant side effects. The interactions with different drugs, the capability of drug encapsulation, delivery, and release, the formation of host-quest assemblies and inclusion complexation between para-sulfonato-calixarenes and drugs were also investigated in detail. Besides, their function in cancer treatment and their toxicity against different cancer cell lines were fully reviewed and summarized. Afterward, the capability of these macrocyclic compounds for biosensing of organic compounds, peptides and enzymes activity was highlighted. In this review, we also take a brief look at recent reports on the applications of para-sulfonato-calixarenes in fluorescence imaging and their usage as highly stable and bright probes for in vivo and in vitro imaging and sensing., Competing Interests: Declaration of competing interest The authors report no conflicts of interest., (Copyright © 2020. Published by Elsevier Masson SAS.)
- Published
- 2020
- Full Text
- View/download PDF
50. Synthesis, Crystal Structure, and Biological Activity of a Multidentate Calix[4]arene Ligand Doubly Functionalized by 2-Hydroxybenzeledene-Thiosemicarbazone.
- Author
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Bahojb Noruzi E, Shaabani B, Geremia S, Hickey N, Nitti P, and Kafil HS
- Subjects
- Anti-Infective Agents chemistry, Anti-Infective Agents pharmacology, Calixarenes chemical synthesis, Cell Line, Tumor, Coordination Complexes chemistry, Crystallography, X-Ray, Dose-Response Relationship, Drug, Hemolysis, Humans, Ligands, Phenols chemical synthesis, Spectrum Analysis, Structure-Activity Relationship, Antineoplastic Agents chemistry, Antineoplastic Agents pharmacology, Calixarenes chemistry, Calixarenes pharmacology, Chemistry Techniques, Synthetic, Models, Molecular, Phenols chemistry, Phenols pharmacology, Thiosemicarbazones chemistry
- Abstract
The design and synthesis of a novel tert-butyl-calix[4]arene functionalized at 1, 3 positions of the lower rim with two terminal 2-hydroxybenzeledene-thiosemicarbazone moieties is reported. The new ligand with multi-dentate chelating properties was fully characterized by several techniques: ESI-Mass spectroscopy, FT-IR, 1H-NMR, and single crystal X-ray diffraction. The solid state structure confirms that the calix[4]arene macrocycle has the expected open cone conformation, with two opposite phenyl rings inclined outwards with large angles. The conformation of the two alkoxythiosemicarbazone arms produces a molecule with a C2 point group symmetry. An interesting chiral helicity is observed, with the two thiosemicarbazone groups oriented in opposite directions like a two-blade propeller. A water molecule is encapsulated in the center of the two-blade propeller through multiple H-bond coordinations. The antibacterial, antifungal, anticancer, and cytotoxic activities of the calix[4]arene-thiosemicarbazone ligand and its metal derivatives (Co2+, Ni2+, Cu2+, and Zn2+) were investigated. A considerable antibacterial activity (in particular against E. coli , MIC, and MBC = 31.25 μg/mL) was observed for the ligand and its metal derivatives. Significant antifungal activities against yeast ( C. albicans ) were also observed for the ligand (MIC = 31.25 μg/mL and MBC = 125 μg/mL) and for its Co
2+ derivative (MIC = 62.5 μg/mL). All compounds show cytotoxicity against the tested cancerous cells. For the Saos-2 cell line, the promising anticancer activity of ligand L (IC50 < 25 μg/mL) is higher than its metal derivatives. The microscopic analysis of DAPI-stained cells shows that the treated cells change in morphology, with deformation and fragmentation of the nuclei. The hemo-compatibility study demonstrated that this class of compounds are suitable candidates for further in vivo investigations.- Published
- 2020
- Full Text
- View/download PDF
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