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A series of water-soluble chiral cyclen-based chelators with chemical handles for selective targeting have been synthesized (cyclen = 1,4,7,10-Tetraazacyclododecane). Optical studies, relaxivity measurements, and competitive titrations were performed to show the versatility of these chiral chelators. The complexations of L3, L4, and L5 with Lu3+, Y3+, Sc3+, and Cu2+ were successfully demonstrated in around 90% to 100% yields. Efficient and rapid radiolabeling of L5 with 177Lu was achieved under mild conditions with 96% yield. The chelators exhibit near quantitative labeling efficiencies with a wide range of radiometal ions, which are promising for the development of targeting specific radiopharmaceutical and molecular magnetic resonance imaging contrast agents.
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BACKGROUND/AIM: 18 kDa Translocator protein (TSPO) is a mitochondrial protein up-regulated in colorectal carcinoma (CRC). Our purpose was to develop a TSPO-targeted doxorubicin prodrug (Dox-TSPO) which can be loaded onto drug-eluting beads for transarterial chemoembolization. Furthermore, we evaluated its loading and release kinetics and effects on cell viability. MATERIALS AND METHODS: N-Fmoc-DOX-14-O-hemiglutarate was coupled with a TSPO ligand, 6-TSPOmbb732, using classical N,N,N',N'-tetramethyl-O-(1H-benzotriazol-1-yl)uranium hexafluorophosphate coupling to produce Dox-TSPO. Loading and elution studies were performed using DC beads™. Cell viability studies were performed using CellTiter-Glo® Luminescent Cell Viability Assay. RESULTS: Dox-TSPO was successfully synthesized and readily loaded onto and eluted from DC beads™, albeit at a slower rate than free doxorubicin. CRC cell lines expressing TSPO were 2- to 4- fold more sensitive to Dox-TSPO compared to free doxorubicin at 72 h. CONCLUSION: Dox-TSPO is a promising candidate for targeted and directed cancer treatment of CRC liver metastases.
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Neoplasias Colorretais/tratamento farmacológico , Doxorrubicina/farmacologia , Pró-Fármacos/farmacologia , Receptores de GABA/genética , Proteínas de Transporte/química , Proteínas de Transporte/farmacologia , Linhagem Celular Tumoral , Quimioembolização Terapêutica/métodos , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Doxorrubicina/química , Sistemas de Liberação de Medicamentos , Humanos , Pró-Fármacos/química , Receptores de GABA/químicaRESUMO
PURPOSE: Prostate-specific membrane antigen (PSMA) continues to be the hallmark biomarker for prostate cancer as it is expressed on nearly all prostatic tumors. In addition, increased PSMA expression correlates with castration resistance and progression to the metastatic stage of the disease. Recently, we combined both an albumin-binding motif and an irreversible PSMA inhibitor to develop the novel PSMA-targeted radiotherapeutic agent, CTT1403. This molecule was novel in the field of PSMA-targeted agents as its key motifs resulted in extended blood circulation time and tumor uptake, rapid and extensive internalization into PSMA+ cells, and promising therapeutic efficacy. The objective of this study was to perform IND-enabling translational studies on CTT1403 in rodent models. PROCEDURES: A dose optimization study was performed in PC3-PIP (PSMA+) tumor-bearing mice. Treatment groups were randomly selected to receive one to three 14-MBq injections of CTT1403. Control groups included (1) saline, (2) non-radioactive [175Lu]CTT1403, or (3) two injections of 14 MBq CTT1751, a Lu-177-labeled non-targeted albumin-binding moiety. Tumor growth was monitored up to 120 days. Small-animal single photon emission tomography/X-ray computed tomography imaging was performed with CTT1403 and CTT1751 in PC3-PIP tumor-bearing mice to visualize infiltration of the Lu-177-labeled agent into the tumor. In preparation for a first-in-human study, human absorbed doses were estimated based on rat biodistribution out to 5 weeks to determine a safe CTT1403 therapy dose in humans. RESULTS: Two to 3 injections of 14 MBq CTT1403 yielded significant tumor growth inhibition and increased survival compared with all control groups and mice receiving 1 injection of 14 MBq CTT1403. Five of 12 mice receiving 2 or 3 injections of CTT1403 survived to the 120-day post-treatment study endpoint. Dosimetry identified the kidneys as the dose-limiting organ, with an equivalent dose of 5.18 mSv/MBq, resulting in a planned maximum dose of 4.4 GBq for phase 1 clinical trials. CONCLUSIONS: The preclinical efficacy and dosimetry of CTT1403 suggest that this agent has significant potential to be safe and effective in humans.
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Lutécio/farmacologia , Radioisótopos/farmacologia , Radiometria/métodos , Compostos Radiofarmacêuticos/farmacologia , Animais , Antígenos de Superfície/química , Ensaios de Seleção de Medicamentos Antitumorais , Glutamato Carboxipeptidase II/química , Humanos , Masculino , Camundongos , Camundongos Nus , Transplante de Neoplasias , Neoplasias/tratamento farmacológico , Radioisótopos/química , Ratos , Ratos Sprague-Dawley , Tomografia Computadorizada com Tomografia Computadorizada de Emissão de Fóton Único , Distribuição Tecidual , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Cannabinoids are emerging as promising antitumor drugs. However, complete tumor eradication solely by cannabinoid therapy remains challenging. In this study, we developed a far-red light activatable cannabinoid prodrug, which allows for tumor-specific and combinatory cannabinoid and photodynamic therapy. This prodrug consists of a phthalocyanine photosensitizer (PS), reactive oxygen species (ROS)-sensitive linker, and cannabinoid. It targets the type-2 cannabinoid receptor (CB2R) overexpressed in various types of cancers. Upon the 690-nm light irradiation, the PS produces cytotoxic ROS, which simultaneously cleaves the ROS-sensitive linker and subsequently releases the cannabinoid drug. We found that this unique multifunctional prodrug design offered dramatically improved therapeutic efficacy, and therefore provided a new strategy for targeted, controlled, and effective antitumor cannabinoid therapy.
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Canabinoides , Fotoquimioterapia/métodos , Pró-Fármacos , Animais , Antineoplásicos/química , Antineoplásicos/farmacologia , Canabinoides/química , Canabinoides/farmacologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Células HEK293 , Humanos , Indóis/química , Indóis/metabolismo , Isoindóis , Camundongos , Compostos de Organossilício/química , Compostos de Organossilício/metabolismo , Fármacos Fotossensibilizantes/química , Fármacos Fotossensibilizantes/farmacologia , Pró-Fármacos/química , Pró-Fármacos/metabolismo , Espécies Reativas de Oxigênio/análise , Espécies Reativas de Oxigênio/metabolismoRESUMO
Triple negative breast cancer (TNBC) is the deadliest form of breast cancer because it is more aggressive, diagnosed at later stage and more likely to develop local and systemic recurrence. Many patients do not experience adequate tumor control after current clinical treatments involving surgical removal, chemotherapy and/or radiotherapy, leading to disease progression and significantly decreased quality of life. Here we report a new combinatory therapy strategy involving cannabinoid-based medicine and photodynamic therapy (PDT) for the treatment of TNBC. This combinatory therapy targets two proteins upregulated in TNBC: the cannabinoid CB2 receptor (CB2R, a G-protein coupled receptor) and translocator protein (TSPO, a mitochondria membrane receptor). We found that the combined CB2R agonist and TSPO-PDT treatment resulted in synergistic inhibition in TNBC cell and tumor growth. This combinatory therapy approach provides new opportunities to treat TNBC with high efficacy. In addition, this study provides new evidence on the therapeutic potential of CB2R agonists for cancer.
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Fotoquimioterapia/métodos , Fármacos Fotossensibilizantes/farmacologia , Receptor CB2 de Canabinoide/agonistas , Receptores de GABA/metabolismo , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Acetamidas/química , Acetamidas/farmacologia , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Terapia Combinada , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Indóis/química , Indóis/farmacologia , Camundongos , Recidiva Local de Neoplasia , Éteres Fenílicos/química , Éteres Fenílicos/farmacologia , Qualidade de Vida , Oxigênio Singlete/metabolismo , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Imaging probes targeting type 2 cannabinoid receptor (CB2R) overexpressed in pancreatic duct adenocarcinoma (PDAC) tissue have the potential to improve early detection and surgical outcome of PDAC. The aim of our study was to evaluate the molecular imaging potential of a CB2R-targeted near-infrared (NIR) fluorescent probe (NIR760-XLP6) for PDAC. CB2R overexpression was observed in both PDAC patient tissues and various pancreatic cancer cell lines. In vitro fluorescence imaging indicated specific binding of NIR760-XLP6 to CB2R in human PDAC PANC-1 cells. In a xenograft mouse tumor model, NIR760-XLP6 showed remarkable 50- (ex vivo) and 3.2-fold (in vivo) tumor to normal contrast enhancement with minimal liver and kidney uptake. In a PDAC lymph node metastasis model, significant signal contrast was observed in bilateral axillary lymph nodes with PDAC metastasis after injection of the probe. In conclusion, NIR760-XLP6 exhibits promising characteristics for imaging PDAC, and CB2R appears to be an attractive target for PDAC imaging.
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Despite established clinical utilisation, there is an increasing need for safer, more inert gadolinium-based contrast agents, and for chelators that react rapidly with radiometals. Here we report the syntheses of a series of chiral DOTA chelators and their corresponding metal complexes and reveal properties that transcend the parent DOTA compound. We incorporated symmetrical chiral substituents around the tetraaza ring, imparting enhanced rigidity to the DOTA cavity, enabling control over the range of stereoisomers of the lanthanide complexes. The Gd chiral DOTA complexes are shown to be orders of magnitude more inert to Gd release than [GdDOTA]-. These compounds also exhibit very-fast water exchange rates in an optimal range for high field imaging. Radiolabeling studies with (Cu-64/Lu-177) also demonstrate faster labelling properties. These chiral DOTA chelators are alternative general platforms for the development of stable, high relaxivity contrast agents, and for radiometal complexes used for imaging and/or therapy.
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Quelantes/química , Compostos Heterocíclicos com 1 Anel/química , Animais , Imageamento por Ressonância Magnética , Masculino , Camundongos , Camundongos Endogâmicos C57BLRESUMO
Prostate-specific membrane antigen (PSMA) continues to be an active biomarker for small-molecule PSMA-targeted imaging and therapeutic agents for prostate cancer and various non-prostatic tumors that are characterized by PSMA expression on their neovasculature. One of the challenges for small-molecule PSMA inhibitors with respect to delivering therapeutic payloads is their rapid renal clearance. In order to overcome this pharmacokinetic challenge, we outfitted a 177Lu-labeled phosphoramidate-based PSMA inhibitor (CTT1298) with an albumin-binding motif (CTT1403) and compared its in vivo performance with that of an analogous compound lacking the albumin-binding motif (CTT1401). The radiolabeling of CTT1401 and CTT1403 was achieved using click chemistry to connect 177Lu-DOTA-N3 to the dibenzocyclooctyne (DBCO)-bearing CTT1298 inhibitor cores. A direct comparison in vitro and in vivo performance was made for CTT1401 and CTT1403; the specificity and efficacy by means of cellular uptake and internalization, biodistribution, and therapeutic efficacy were determined for both compounds. While both compounds displayed excellent uptake and rapid internalization in PSMA+ PC3-PIP cells, the albumin binding moiety in CTT1403 conferred clear advantages to the PSMA-inhibitor scaffold including increased circulating half-life and prostate tumor uptake that continued to increase up to 168 h post-injection. This increased tumor uptake translated into superior therapeutic efficacy of CTT1403 in PSMA+ PC3-PIP human xenograft tumors.
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Amidas/farmacologia , Antineoplásicos/farmacologia , Glutamato Carboxipeptidase II/antagonistas & inibidores , Lutécio/farmacologia , Ácidos Fosfóricos/farmacologia , Neoplasias da Próstata/tratamento farmacológico , Radioisótopos/farmacologia , Albuminas/metabolismo , Amidas/administração & dosagem , Amidas/farmacocinética , Animais , Antígenos de Superfície , Antineoplásicos/administração & dosagem , Antineoplásicos/farmacocinética , Linhagem Celular Tumoral , Modelos Animais de Doenças , Xenoenxertos , Humanos , Lutécio/administração & dosagem , Lutécio/farmacocinética , Masculino , Camundongos , Camundongos Nus , Ácidos Fosfóricos/administração & dosagem , Ácidos Fosfóricos/farmacocinética , Radioisótopos/administração & dosagem , Radioisótopos/farmacocinética , Resultado do TratamentoRESUMO
Recent efforts to develop tumor-targeted photodynamic therapy (PDT) photosensitizers (PSs) have greatly advanced the potential of PDT in cancer therapy, although complete eradication of tumor cells by PDT alone remains challenging. As a way to improve PDT efficacy, we report a new combinatory PDT therapy technique that specifically targets multilayers of cells. Simply mixing different PDT PSs, even those that target distinct receptors (this may still lead to similar cell-killing pathways), may not achieve ideal therapeutic outcomes. Instead, significantly improved outcomes likely require synergistic therapies that target various cellular pathways. In this study, we target two proteins upregulated in cancers: the cannabinoid CB2 receptor (CB2R, a G-protein coupled receptor) and translocator protein (TSPO, a mitochondria membrane receptor). We found that the CB2R-targeted PS, IR700DX-mbc94, triggered necrotic cell death upon light irradiation, whereas PDT with the TSPO-targeted IR700DX-6T agent led to apoptotic cell death. Both PSs significantly inhibited tumor growth in vivo in a target-specific manner. As expected, the combined CB2R- and TSPO-PDT resulted in enhanced cell killing efficacy and tumor inhibition with lower drug dose. The median survival time of animals with multilayer PDT treatment was extended by as much as 2.8-fold over single PDT treatment. Overall, multilayer PDT provides new opportunities to treat cancers with high efficacy and low side effects. STATEMENT OF SIGNIFICANCE: Photodynamic therapy (PDT) is increasingly used as a minimally invasive, controllable and effective therapeutic procedure for cancer treatment. However, complete eradication of tumor cells by PDT alone remains challenging. In this study, we investigate the potential of multilayer PDT in cancer treatment with high efficacy and low side effects. Through PDT targeting two cancer biomarkers located at distinct subcellular localizations, remarkable synergistic effects in cancer cell killing and tumor inhibition were observed in both in vitro and in vivo experiments. This strategy may be widely applied to treat various cancer types by using strategically designed PDT photosensitizers that target corresponding upregulated receptors at tactical subcellular localization.
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Antineoplásicos/farmacologia , Neoplasias da Mama/tratamento farmacológico , Sistemas de Liberação de Medicamentos/métodos , Fotoquimioterapia/métodos , Animais , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Feminino , Humanos , Camundongos , Camundongos Nus , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Targeted molecular imaging probes are essential tools for visualization of specific molecular processes in cells and living systems. Among these, targeted fluorescent probes are widely used due to the high sensitivity and resolution of fluorescence imaging. The conventional strategy for developing targeted fluorescent probes is to couple targeting ligands with fluorescent dyes by covalent bond via bioconjugation. Here, we describe several commonly used bioconjugation methods, from traditional amide and thiol coupling, to metal-catalyzed coupling reaction and catalyst free cycloaddition.
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Reação de Cicloadição/métodos , Corantes Fluorescentes/química , Química Click , Ligantes , Imagem MolecularRESUMO
The impact of remote substituents on the affinity of cucurbit[n]urils (CB[n]) towards a homologous series of guests, which differ from one another only by a single substituent, and adopt the same geometry within the cavity of the macrocycle, is presented for the first time, and is used to decipher the competition between water and the carbonylated portal of CB[7] for the stabilization of positively charged guests. Binding affinities of CB[7] towards substituted N-benzyl-trimethylsilylmethylammonium cations relative to the unsubstituted member (X = H) range from 0.9 (X = CH3) to 3.1 (X = SO2CF3), and correlate very precisely with a linear combination of Swain-Lupton field/inductive (F; 67%) and resonance (R; 33%) parameters tabulated for each substituent. We show that this subtle sensitivity results exclusively from the balance between two competing mechanisms, on which the substituents exert an approximately 11 times greater impact: (1) the solvation of the ammonium unit and its immediate surroundings by water in the free guests, and (2) the coulombic attraction between the ammonium unit and the rim of CB[7] in the complexes.
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Photodynamic therapy (PDT) has been proven to be a minimally invasive and effective therapeutic strategy for cancer treatment. It can be used alone or as a complement to conventional cancer treatments, such as surgical debulking and chemotherapy. The mitochondrion is an attractive target for developing novel PDT agents, as it produces energy for cells and regulates apoptosis. Current strategy of mitochondria targeting is mainly focused on utilizing cationic photosensitizers that bind to the negatively charged mitochondria membrane. However, such an approach is lack of selectivity of tumor cells. To minimize the damage on healthy tissues and improve therapeutic efficacy, an alternative targeting strategy with high tumor specificity is in critical need. Herein, we report a tumor mitochondria-specific PDT agent, IR700DX-6T, which targets the 18kDa mitochondrial translocator protein (TSPO). IR700DX-6T induced apoptotic cell death in TSPO-positive breast cancer cells (MDA-MB-231) but not TSPO-negative breast cancer cells (MCF-7). In vivo PDT study suggested that IR700DX-6T-mediated PDT significantly inhibited the growth of MDA-MB-231 tumors in a target-specific manner. These combined data suggest that this new TSPO-targeted photosensitizer has great potential in cancer treatment. STATEMENT OF SIGNIFICANCE: Photodynamic therapy (PDT) is an effective and minimally invasive therapeutic technique for treating cancers. Mitochondrion is an attractive target for developing novel PDT agents, as it produces energy to cells and regulates apoptosis. Current mitochondria targeted photosensitizers (PSs) are based on cationic molecules, which interact with the negatively charged mitochondria membrane. However, such PSs are not specific for cancerous cells, which may result in unwanted side effects. In this study, we developed a tumor mitochondria-targeted PS, IR700DX-6T, which binds to translocator protein (TSPO). This agent effectively induced apoptosis in TSPO-positive cancer cells and significantly inhibited tumor growth in TSPO-positive tumor-bearing mice. These combined data suggest that IR700DX-6T could become a powerful tool in the treatment of multiple cancers that upregulate TSPO.
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Mitocôndrias/efeitos dos fármacos , Neoplasias/patologia , Fotoquimioterapia , Fármacos Fotossensibilizantes/farmacologia , Animais , Apoptose , Linhagem Celular Tumoral , Humanos , Camundongos , Microscopia de FluorescênciaRESUMO
A new heterobifunctional reactive oxygen species (ROS) responsive thioketal linker and its synthesis are described. This linker allows for developing new ROS-responsive agents with two distinct functionalities using universal bioconjugation methods. The reaction kinetics of the thioketal cleavage in the presence of ROS is also described.
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Chronic inflammation is considered as a critical cause of a host of disorders, such as cancer, rheumatoid arthritis, atherosclerosis, and neurodegenerative diseases, although the exact mechanism is yet to be explored. Imaging tools that can specifically target inflammation are therefore important to help reveal the role of inflammation in disease progression, and allows for developing new therapeutic strategies to ultimately improve patient care. The purpose of this study was to develop a new in vivo inflammation imaging approach by targeting the cannabinoid receptor type 2 (CB2R), an emerging inflammation biomarker, using a unique near infrared (NIR) fluorescent probe. Herein, we report the first in vivo CB2R-targeted NIR inflammation imaging study using a synthetic fluorescent probe developed in our laboratory, NIR760-mbc94. In vitro binding assay and fluorescence microscopy study indicate NIR760-mbc94 specifically binds towards CB2R in mouse RAW264.7 macrophage cells. Furthermore, in vivo imaging was performed using a Complete Freund's Adjuvant (CFA)-induced inflammation mouse model. NIR760-mbc94 successfully identified inflamed tissues and the probe uptake was blocked by a CB2R ligand, SR144528. Additionally, immunofluorescence staining in cryosectioned tissues validated the NIR760-mbc94 uptake in inflamed tissues. In conclusion, this study reports the first in vivo CB2R-targeted inflammation imaging using an NIR fluorescent probe. Specific targeting of NIR760-mbc94 has been demonstrated in macrophage cells, as well as a CFA-induced inflammation mouse model. The combined evidence indicates that NIR760-mbc94 is a promising inflammation imaging probe. Moreover, in vivo CB2R-targeted fluorescence imaging may have potential in the study of inflammation-related diseases.
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The type 2 cannabinoid receptors (CB2R) have gained much attention recently due to their important regulatory role in a host of pathophysiological processes. However, the exact biological function of CB2R and how this function might change depending on disease progression remains unclear and could be better studied with highly sensitive and selective imaging tools for identifying the receptors. Here we report the first near infrared fluorescence imaging probe (NIR760-XLP6) that binds preferentially to CB2R over the type 1 cannabinoid receptors (CB1R). The selectivity of the probe was demonstrated by fluorescence microscopy using DBT-CB2 and DBT-CB1 cells. Furthermore, in mouse tumor models, NIR760-XLP6 showed significantly higher uptake in DBT-CB2 than that in DBT-CB1 tumors. These findings indicate that NIR760-XLP6 is a promising imaging tool for the study of CB2R regulation.
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Corantes Fluorescentes/química , Neoplasias/patologia , Imagem Óptica , Receptores de Canabinoides/análise , Animais , Feminino , Corantes Fluorescentes/metabolismo , Camundongos , Neoplasias/metabolismo , Receptores de Canabinoides/metabolismo , Imagem Corporal TotalRESUMO
Cannabinoid CB2 receptors (CB2R) hold promise as therapeutic targets for treating diverse diseases, such as cancers, neurodegenerative diseases, pain, inflammation, osteoporosis, psychiatric disorders, addiction, and immune disorders. However, the fundamental role of CB2R in the regulation of diseases remains unclear, largely due to a lack of reliable imaging tools for the receptors. The goal of this study was to develop a CB2R-targeted molecular imaging probe and evaluate the specificity of the probe using human tumor cells that naturally overexpress CB2R. To synthesize the CB2R-targeted probe (NIR760-Q), a conjugable CB2R ligand based on the quinolone structure was first prepared, followed by bioconjugation with a near-infrared (NIR) fluorescent dye, NIR760. In vitro fluorescence imaging and competitive binding studies showed higher uptake of NIR760-Q than free NIR760 dye in Jurkat human acute T-lymphoblastic leukemia cells. In addition, the high uptake of NIR760-Q was significantly inhibited by the blocking agent, 4-quinolone-3-carboxamide, indicating specific binding of NIR760-Q to the target receptors. These results indicate that the NIR760-Q has potential in diagnostic imaging of CB2R positive cancers and elucidating the role of CB2R in the regulation of disease progression.
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Biomarcadores Tumorais/análise , Corantes Fluorescentes/metabolismo , Imagem Molecular/métodos , Sondas Moleculares/metabolismo , Quinolonas/química , Receptor CB2 de Canabinoide/análise , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Corantes Fluorescentes/análise , Corantes Fluorescentes/química , Humanos , Células Jurkat , Sondas Moleculares/análise , Sondas Moleculares/química , Receptor CB2 de Canabinoide/genética , Receptor CB2 de Canabinoide/metabolismoRESUMO
The dethreading rate of a polyaminated axle flanked by two benzo-15-crown-5 stoppers from the cavity of Cucurbit[7]uril (CB[7]) was enhanced by up to 500 times in the presence of aqueous metallic and organic cations. Cations likely stabilize the highest energy transition state of the dethreading process by interacting with both crown ether and CB[7] units.
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The kinetics of cucurbit[6]uril slippage along a polyaminated axle are highly dependent on even minor sterical alterations of the guest. According to in silico experiments, a plausible threading mechanism includes the deprotonation of the ammoniums prior to slippage, their tunneling through the cavitand as neutral amines, and their reprotonation upon exiting cucurbit[6]uril.
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Cucurbit[6]-, cucurbit[7]-, and cucurbit[6]uril cavitands can be aligned along a spermine derivative axle in a well-defined, kinetically favored sequence at room temperature, and can undergo a reorganization toward a more stable [4]pseudorotaxane bearing three cucurbit[6]uril units upon thermally induced scrambling.