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1.
Biochim Biophys Acta Gen Subj ; 1864(1): 129455, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31669585

RESUMO

BACKGROUND: Borrelia burgdorferi causes Lyme disease, the most common tick-borne illness in the United States. The Center for Disease Control and Prevention estimates that the occurrence of Lyme disease in the U.S. has now reached approximately 300,000 cases annually. Early stage Borrelia burgdorferi infections are generally treatable with oral antibiotics, but late stage disease is more difficult to treat and more likely to lead to post-treatment Lyme disease syndrome. METHODS: Here we examine three unique 5'-methylthioadenosine/S-adenosylhomocysteine (MTA/SAH) nucleosidases (MTNs or MTANs, EC 3.2.2.9) responsible for salvage of adenine and methionine in B. burgdorferi and explore their potential as antibiotic targets to treat Lyme disease. Recombinant Borrelia MTNs were expressed and purified from E. coli. The enzymes were extensively characterized for activity, specificity, and inhibition using a UV spectrophotometric assay. In vitro antibiotic activities of MTN inhibitors were assessed using a bioluminescent BacTiter-Glo™ assay. RESULTS: The three Borrelia MTNs showed unique activities against the native substrates MTA, SAH, and 5'-deoxyadenosine. Analysis of substrate analogs revealed that specific activity rapidly dropped as the length of the 5'-alkylthio substitution increased. Non-hydrolysable nucleoside transition state analogs demonstrated sub-nanomolar enzyme inhibition constants. Lastly, two late stage transition state analogs exerted in vitro IC50 values of 0.3-0.4 µg/mL against cultured B. burgdorferi cells. CONCLUSION: B. burgdorferi is unusual in that it expresses three distinct MTNs (cytoplasmic, membrane bound, and secreted) that are effectively inactivated by nucleoside analogs. GENERAL SIGNIFICANCE: The Borrelia MTNs appear to be promising targets for developing new antibiotics to treat Lyme disease.


Assuntos
Antibacterianos/uso terapêutico , Borrelia burgdorferi/enzimologia , Doença de Lyme/tratamento farmacológico , N-Glicosil Hidrolases/genética , Borrelia burgdorferi/efeitos dos fármacos , Borrelia burgdorferi/patogenicidade , Desoxiadenosinas/metabolismo , Escherichia coli/genética , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Humanos , Doença de Lyme/enzimologia , Doença de Lyme/microbiologia , N-Glicosil Hidrolases/antagonistas & inibidores , S-Adenosil-Homocisteína/metabolismo , Tionucleosídeos/metabolismo
2.
Molecules ; 24(17)2019 Aug 29.
Artigo em Inglês | MEDLINE | ID: mdl-31470553

RESUMO

Thione-containing nucleobases have attracted the attention of the scientific community for their application in oncology, virology, and transplantology. The detailed understanding of the reactivity of the purine derivative 8-thioguanosine (8-TG) with reactive oxygen species (ROS) and free radicals is crucial for its biological relevance. An extensive investigation on the fate of 8-TG under both reductive and oxidative conditions is here reported, and it was tested by employing steady-state photooxidation, laser flash photolysis, as well as γ-radiolysis in aqueous solutions. The characterization of the 8-TG T1 excited state by laser flash photolysis and the photooxidation experiments confirmed that singlet oxygen is a crucial intermediate in the formation of the unexpected reduced product guanosine, without the formation of the usual oxygenated sulfinic or sulfonic acids. Furthermore, a thorough screening of different radiolytic conditions upon γ-radiation afforded the reduced product. These results were rationalized by performing control experiments in the predominant presence of each reactive species formed by radiolysis of water, and the mechanistic pathway scenario was postulated on these bases.


Assuntos
Guanosina/análogos & derivados , Guanosina/química , Oxigênio Singlete/química , Tionucleosídeos/química , Cinética , Lasers , Luz , Oxirredução , Fotólise , Radiólise de Impulso , Soluções , Água/química
3.
Ann Nucl Med ; 33(11): 822-827, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31401773

RESUMO

OBJECTIVE: The novel radiotracer, 4'-[methyl-11C]-thiothymidine (11C-4DST), was developed based on the DNA incorporation method as a cell proliferation marker. This study investigated the feasibility of 11C-4DST positron emission tomography/computed tomography (PET/CT) for detection of colorectal cancer, as compared with 2-deoxy-2-18F-fluoro-D-glucose (18F-FDG) PET/CT, and to correlate the two radiotracers with proliferative activity. METHODS: A total of 18 patients with newly diagnosed colorectal cancer underwent both 11C-4DST and 18F-FDG PET/CT. Tumor lesions were identified as areas of focally increased uptake, exceeding that of adjacent normal tissue. For semiquantitative analysis, the maximal standardized uptake value (SUVmax) was calculated. Proliferative activity as quantified by the Ki-67 index was estimated in tumor specimens. RESULTS: In all 18 patients, colorectal cancers were detected by both 11C-4DST and 18F-FDG PET/CT. The median (± SD) SUVmax for 11C-4DST (6.02 ± 2.55) was significantly lower than that for 18F-FDG (13.91 ± 7.62) (P < 0.001). 11C-4DST SUVmax and 18F-FDG SUVmax showed a significant correlation (r = 0.69, P = 0.002). 11C-4DST SUVmax and Ki-67 index were weakly correlated (r = 0.50, P = 0.04). 18F-FDG SUVmax and Ki-67 index were not significantly correlated (r = 0.44, P = 0.06). CONCLUSIONS: Despite a significantly lower uptake of 11C-4DST than that of 18F-FDG, detection of colorectal cancer was also feasible with 11C-4DST PET/CT. 11C-4DST PET/CT might have a role in the noninvasive assessment of proliferation in colorectal cancer.


Assuntos
Neoplasias Colorretais/diagnóstico por imagem , Neoplasias Colorretais/patologia , Fluordesoxiglucose F18 , Tomografia Computadorizada com Tomografia por Emissão de Pósitrons/métodos , Tionucleosídeos , Timidina/análogos & derivados , Adulto , Transporte Biológico , Proliferação de Células , Neoplasias Colorretais/metabolismo , Feminino , Fluordesoxiglucose F18/metabolismo , Humanos , Processamento de Imagem Assistida por Computador , Masculino , Tionucleosídeos/metabolismo , Timidina/metabolismo
4.
N Z Med J ; 132(1491): 46-62, 2019 03 08.
Artigo em Inglês | MEDLINE | ID: mdl-30845128

RESUMO

The incidence of inflammatory bowel disease (IBD) in New Zealand has increased over the last several decades. The management of IBD has been transformed since the introduction of monoclonal antibody drugs. Other medications used in the treatment of IBD include amino-salicylates, steroids, thiopurines and methotrexate. Therapeutic drug monitoring (TDM) involves the measurement of serum drug levels or active metabolites and anti-drug antibodies. TDM is essential for a personalised approach to the management of patients with IBD and is used to optimise drug efficacy and reduce the risk of toxicity. In IBD, TDM can be used for checking adherence, evaluating drug toxicity, identifying hypermethylators, assessing loss of response and in decisions regarding treatment escalation or de-escalation. Management decisions in patients on a thiopurine are facilitated by checking TPMT enzyme activity and thiopurine metabolite levels. Measurement of drug trough levels and anti-drug antibodies can result in individualised treatment decisions in patients on biologics. In addition to using TDM in patients who fail therapy, proactive TDM can potentially facilitate early treatment decisions, albeit more work is needed in this area. The clinical benefits of reactive TDM are well documented and this has been shown to be cost effective. Studies have shown that combination therapy in patients on a biologic leads to better clinical outcomes. Effective use of drugs in the treatment of IBD is even more imperative in the New Zealand setting due to relatively fewer options of funded treatment, and the limitations on the use of available drugs. This document represents the current guidelines of the New Zealand Society of Gastroenterology on TDM in IBD.


Assuntos
Monitoramento de Medicamentos/normas , Fármacos Gastrointestinais/uso terapêutico , Doenças Inflamatórias Intestinais/tratamento farmacológico , Tionucleosídeos/sangue , Gastroenterologia/normas , Fármacos Gastrointestinais/metabolismo , Humanos , Doenças Inflamatórias Intestinais/metabolismo , Nova Zelândia , Tionucleosídeos/uso terapêutico
5.
AAPS PharmSciTech ; 20(2): 74, 2019 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-30631981

RESUMO

The present study aimed to orally deliver methylthioadenosine (MTA) to the brain employing solid lipid nanoparticles (SLNs) for the management of neurological conditions like multiple sclerosis. The stearic acid-based SLNs were below 100 nm with almost neutral zeta potential and offered higher drug entrapment and drug loading. Cuprizone-induced demyelination model in mice was employed to mimic the multiple sclerosis-like conditions. It was observed that the MTA-loaded SLNs were able to maintain the normal metabolism, locomotor activity, motor coordination, balancing, and grip strength of the rodents in substantially superior ways vis-à-vis plain MTA. Histopathological studies of the corpus callosum and its subsequent staining with myelin staining dye luxol fast blue proved the potential of MTA-loaded SLNs in the remyelination of neurons. The pharmacokinetic studies provided the evidences for improved bioavailability and enhanced bioresidence supporting the pharmacodynamic findings. The studies proved that SLN-encapsulated MTA can be substantially delivered to the brain and can effectively remyelinate the neurons. It can reverse the multiple sclerosis-like symptoms in a safer and effective manner, that too by oral route.


Assuntos
Encéfalo/efeitos dos fármacos , Desoxiadenosinas/administração & dosagem , Sistemas de Liberação de Medicamentos , Atividade Motora/efeitos dos fármacos , Esclerose Múltipla/tratamento farmacológico , Nanopartículas/administração & dosagem , Ácidos Esteáricos/administração & dosagem , Tionucleosídeos/administração & dosagem , Administração Oral , Animais , Disponibilidade Biológica , Encéfalo/patologia , Desoxiadenosinas/farmacocinética , Camundongos , Ratos , Ratos Wistar , Tionucleosídeos/farmacocinética
6.
J Am Chem Soc ; 140(44): 14567-14570, 2018 11 07.
Artigo em Inglês | MEDLINE | ID: mdl-30353734

RESUMO

RNA-sequencing (RNA-seq) measures RNA abundance in a biological sample but does not provide temporal information about the sequenced RNAs. Metabolic labeling can be used to distinguish newly made RNAs from pre-existing RNAs. Mutations induced from chemical recoding of the hydrogen bonding pattern of the metabolic label can reveal which RNAs are new in the context of a sequencing experiment. These nucleotide recoding strategies have been developed for a single uridine analogue, 4-thiouridine (s4U), limiting the scope of these experiments. Here we report the first use of nucleoside recoding with a guanosine analogue, 6-thioguanosine (s6G). Using TimeLapse sequencing (TimeLapse-seq), s6G can be recoded under RNA-friendly oxidative nucleophilic-aromatic substitution conditions to produce adenine analogues (substituted 2-aminoadenosines). We demonstrate the first use of s6G recoding experiments to reveal transcriptome-wide RNA population dynamics.


Assuntos
Guanosina/análogos & derivados , Nucleosídeos/metabolismo , RNA/metabolismo , Tionucleosídeos/metabolismo , Guanosina/química , Guanosina/metabolismo , Ligação de Hidrogênio , Nucleosídeos/química , RNA/química , Tionucleosídeos/química
7.
Neoplasia ; 20(8): 826-837, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-30015158

RESUMO

Standard and targeted cancer therapies for late-stage cancer patients almost universally fail due to tumor heterogeneity/plasticity and intrinsic or acquired drug resistance. We used the telomerase substrate nucleoside precursor, 6-thio-2'-deoxyguanosine (6-thio-dG), to target telomerase-expressing non-small cell lung cancer cells resistant to EGFR-inhibitors and commonly used chemotherapy combinations. Colony formation assays, human xenografts as well as syngeneic and genetically engineered immune competent mouse models of lung cancer were used to test the effect of 6-thio-dG on targeted therapy- and chemotherapy-resistant lung cancer human cells and mouse models. We observed that erlotinib-, paclitaxel/carboplatin-, and gemcitabine/cisplatin-resistant cells were highly sensitive to 6-thio-dG in cell culture and in mouse models. 6-thio-dG, with a known mechanism of action, is a potential novel therapeutic approach to prolong disease control of therapy-resistant lung cancer patients with minimal toxicities.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/metabolismo , Telomerase/metabolismo , Animais , Linhagem Celular Tumoral , Desoxiguanosina/análogos & derivados , Desoxiguanosina/farmacologia , Feminino , Humanos , Camundongos , Camundongos Nus , Tionucleosídeos/farmacologia , Ensaios Antitumorais Modelo de Xenoenxerto/métodos
8.
Ann Nucl Med ; 32(9): 634-641, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30039191

RESUMO

OBJECTIVE: We examined expressions of human equilibrative nucleoside transporter-1 (hENT1) and thymidine kinase-1 (TK1), the key enzyme in 4'-[methyl-11C]-thiothymidine (4DST) phosphorylation, to elucidate the mechanism of 4DST uptake in patients with newly diagnosed gliomas. METHODS: A total of 19 patients with newly diagnosed gliomas were examined with 4DST PET. Tumor lesions were identified as areas of focally increased uptake, exceeding that of normal brain background. For semi-quantitative analysis, tumor-to-contralateral normal brain tissue (T/N) ratio was determined by dividing the maximal standardized uptake value (SUV) for tumor by that of the mean SUV for reference tissue. The expressions of hENT1, TK1 and Ki-67 in tumor specimens were examined by immunohistochemistry and compared with 4DST T/N ratio. RESULTS: All but two gliomas showed focally increased 4DST uptake. All gliomas showed hENT1 staining, except one grade II glioma, which was also not visualized on 4DST PET. A significant correlation was observed between T/N ratio and hENT1 score (ρ = 0.90, p < 0.001). All gliomas showed TK1 staining, except two gliomas which were also not visualized on 4DST PET. There was a significant correlation between T/N ratio and TK1 score (ρ = 0.92, p < 0.001). There was a significant correlation between T/N ratio and Ki-67 index (ρ = 0.50, p < 0.03). CONCLUSION: Results of this preliminary study indicate that expressions of hENT1 and TK1 appear to be important determinants of 4DST uptake in newly diagnosed gliomas.


Assuntos
Transportador Equilibrativo 1 de Nucleosídeo/metabolismo , Regulação Neoplásica da Expressão Gênica , Glioma/metabolismo , Tionucleosídeos/metabolismo , Timidina Quinase/metabolismo , Timidina/análogos & derivados , Idoso , Transporte Biológico , Feminino , Glioma/diagnóstico , Humanos , Masculino , Pessoa de Meia-Idade , Tomografia por Emissão de Pósitrons , Timidina/metabolismo , Adulto Jovem
9.
J Gastroenterol ; 53(9): 989-998, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-29980848

RESUMO

Crohn's disease (CD) is a chronic, progressive, and destructive disease of the gastrointestinal tract. Although its incidence appears to be stable or decreasing in most countries in the North America and Europe, the incidence is rising rapidly in Asian countries. Immunomodulators and biologics are increasingly used to avoid long-term bowel damage and subsequent disability. Therapeutic drug monitoring facilitates optimizing thiopurines and anti-TNFs use. New biologic agents targeting various pathological pathways of CD are blooming in recent years, and the high cost of biologics and expiration of patents for several biologic agents have driven the utility of biosimilars for CD treatment. Here, the literature regarding the efficacy, safety, and withdrawal of the drugs, as well as the evolution of therapeutic targets will be reviewed.


Assuntos
Doença de Crohn/tratamento farmacológico , Doença de Crohn/epidemiologia , Imunomodulação , Purinas/uso terapêutico , Tionucleosídeos/uso terapêutico , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Corticosteroides/efeitos adversos , Corticosteroides/uso terapêutico , Ásia/epidemiologia , Azatioprina/efeitos adversos , Azatioprina/uso terapêutico , Monitoramento de Medicamentos , Humanos , Imunossupressores/efeitos adversos , Imunossupressores/uso terapêutico , Incidência , Infliximab/efeitos adversos , Infliximab/uso terapêutico , Metotrexato/efeitos adversos , Metotrexato/uso terapêutico , Purinas/efeitos adversos , Indução de Remissão , Talidomida/efeitos adversos , Talidomida/uso terapêutico , Tionucleosídeos/efeitos adversos , Resultado do Tratamento
10.
Phys Chem Chem Phys ; 20(24): 16428-16436, 2018 Jun 20.
Artigo em Inglês | MEDLINE | ID: mdl-29873362

RESUMO

The decay of the triplet state of photosensitizers is essential to their performance in singlet-oxygen generation. Experiments have shown that in thionucleosides, this decay is enhanced compared to that in the corresponding thionucleobases. In this work, we applied quantum-chemical methods and chemical-kinetic modeling to investigate the effects of the sugar substituent on the triplet decay of thionucleosides. The computed rates for the energetically favored conformers of thiothymidine, thiouridine, and thioguanosine (and the respective thionucleobases) show a remarkable quantitative agreement with the experimental results. We additionally show that the triplet decay enhancement is caused by the repulsion interaction between the sugar group and the sulfur atom, which reduces the activation energy for intersystem crossing by destabilizing the T1 minimum. In some instances, an intramolecular hydrogen bond stabilizes the energy of the T1/S0 crossing point, also reducing the activation energy. This molecular understanding of the mechanism of enhanced triplet decay provides a guideline to control the triplet decay rate, which was tested in new thiothymidine derivatives.


Assuntos
Fármacos Fotossensibilizantes/química , Tionucleosídeos/química , Desoxirribose/química , Glicosilação , Cinética , Modelos Químicos , Conformação Molecular , Teoria Quântica , Tioguanina/química , Timidina/análogos & derivados , Timidina/química
11.
Bioorg Med Chem ; 26(13): 3785-3790, 2018 07 30.
Artigo em Inglês | MEDLINE | ID: mdl-29914771

RESUMO

This study aimed to synthesize triplex-forming oligonucleotides (TFOs) containing 2'-deoxy-6-thioxanthosine (s6X) and 2'-deoxy-6-thioguanosine (s6Gs) residues and examined their triplex-forming ability. Consecutive arrangement of s6X and s6Gs residues increased the triplex-forming ability of the oligonucleotides more than 50 times, compared with the unmodified TFOs. Moreover, the stability of triplex containing a mismatched pair was much lower than that of the full-matched triplex, though s6X could form a s6X-GC mismatched pair via tautomerization of s6X. The present results reveal excellent properties of modified TFOs containing s6Xs and s6Gs residues, which may be harnessed in gene therapy and DNA nanotechnology.


Assuntos
DNA/síntese química , Oligonucleotídeos/química , Ribonucleosídeos/química , Pareamento de Bases , Sequência de Bases , DNA/química , Desoxiguanosina/análogos & derivados , Desoxiguanosina/química , Oligonucleotídeos/síntese química , Tionucleosídeos/química
12.
Cancer Res ; 78(15): 4386-4395, 2018 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-29844120

RESUMO

Homozygous deletion of the methylthioadenosine phosphorylase (MTAP) gene is a frequent event in a wide variety of human cancers and is a possible molecular target for therapy. One potential therapeutic strategy to target MTAP-deleted tumors involves combining toxic purine analogues such as 6'-thioguanine (6TG) or 2'-fluoroadenine (2FA) with the MTAP substrate 5'-deoxy-5'-methylthioadenosine (MTA). The rationale is that excess MTA will protect normal MTAP+ cells from purine analogue toxicity because MTAP catalyzes the conversion of MTA to adenine, which then inhibits the conversion of purine base analogues into nucleotides. However, in MTAP- tumor cells, no protection takes place because adenine is not formed. Here, we examine the effects of 6TG and 2FA in combination with MTA in vitro and in vivoIn vitro, MTA protected against both 6TG and 2FA toxicity in an MTAP-dependent manner, shifting the IC50 concentration by one to three orders of magnitude. However, in mice, MTA protected against toxicity from 2FA but failed to protect against 6TG. Addition of 100 mg/kg MTA to 20 mg/kg 2FA entirely reversed the toxicity of 2FA in a variety of tissues and the treatment was well tolerated by mice. The 2FA+MTA combination inhibited tumor growth of four different MTAP- human tumor cell lines in mouse xenograft models. Our results suggest that 2FA+MTA may be a promising combination for treating MTAP-deleted tumors.Significance: Loss of MTAP occurs in about 15% of all human cancers; the MTAP protection strategy presented in this study could be very effective in treating these cancers. Cancer Res; 78(15); 4386-95. ©2018 AACR.


Assuntos
Adenina/análogos & derivados , Desoxiadenosinas/farmacologia , Proteínas Associadas aos Microtúbulos/antagonistas & inibidores , Tionucleosídeos/farmacologia , Adenina/metabolismo , Adenina/farmacologia , Animais , Linhagem Celular , Linhagem Celular Tumoral , Homozigoto , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos SCID , Células NIH 3T3 , Purina-Núcleosídeo Fosforilase/metabolismo , Deleção de Sequência/efeitos dos fármacos , Tioguanina/farmacologia
13.
mBio ; 9(2)2018 04 10.
Artigo em Inglês | MEDLINE | ID: mdl-29636438

RESUMO

5'-Methyl-thioadenosine (MTA) is a dead-end, sulfur-containing metabolite and cellular inhibitor that arises from S-adenosyl-l-methionine-dependent reactions. Recent studies have indicated that there are diverse bacterial methionine salvage pathways (MSPs) for MTA detoxification and sulfur salvage. Here, via a combination of gene deletions and directed metabolite detection studies, we report that under aerobic conditions the facultatively anaerobic bacterium Rhodopseudomonas palustris employs both an MTA-isoprenoid shunt identical to that previously described in Rhodospirillum rubrum and a second novel MSP, both of which generate a methanethiol intermediate. The additional R. palustris aerobic MSP, a dihydroxyacetone phosphate (DHAP)-methanethiol shunt, initially converts MTA to 2-(methylthio)ethanol and DHAP. This is identical to the initial steps of the recently reported anaerobic ethylene-forming MSP, the DHAP-ethylene shunt. The aerobic DHAP-methanethiol shunt then further metabolizes 2-(methylthio)ethanol to methanethiol, which can be directly utilized by O-acetyl-l-homoserine sulfhydrylase to regenerate methionine. This is in contrast to the anaerobic DHAP-ethylene shunt, which metabolizes 2-(methylthio)ethanol to ethylene and an unknown organo-sulfur intermediate, revealing functional diversity in MSPs utilizing a 2-(methylthio)ethanol intermediate. When MTA was fed to aerobically growing cells, the rate of volatile methanethiol release was constant irrespective of the presence of sulfate, suggesting a general housekeeping function for these MSPs up through the methanethiol production step. Methanethiol and dimethyl sulfide (DMS), two of the most important compounds of the global sulfur cycle, appear to arise not only from marine ecosystems but from terrestrial ones as well. These results reveal a possible route by which methanethiol might be biologically produced in soil and freshwater environments.IMPORTANCE Biologically available sulfur is often limiting in the environment. Therefore, many organisms have developed methionine salvage pathways (MSPs) to recycle sulfur-containing by-products back into the amino acid methionine. The metabolically versatile bacterium Rhodopseudomonas palustris is unusual in that it possesses two RuBisCOs and two RuBisCO-like proteins. While RuBisCO primarily serves as the carbon fixation enzyme of the Calvin cycle, RuBisCOs and certain RuBisCO-like proteins have also been shown to function in methionine salvage. This work establishes that only one of the R. palustris RuBisCO-like proteins functions as part of an MSP. Moreover, in the presence of oxygen, to salvage sulfur, R. palustris employs two pathways, both of which result in production of volatile methanethiol, a key compound of the global sulfur cycle. When total available sulfur was plentiful, methanethiol was readily released into the environment. However, when sulfur became limiting, methanethiol release decreased, presumably due to methanethiol utilization to regenerate needed methionine.


Assuntos
Desoxiadenosinas/metabolismo , Redes e Vias Metabólicas , Metionina/metabolismo , Rodopseudomonas/metabolismo , Compostos de Sulfidrila/metabolismo , Tionucleosídeos/metabolismo , Aerobiose , Fosfato de Di-Hidroxiacetona/metabolismo , Deleção de Genes , Rodopseudomonas/genética , Sulfetos/metabolismo
14.
Mol Cancer Ther ; 17(7): 1504-1514, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29654065

RESUMO

Brain tumors remain the leading cause of cancer-related deaths in children and often are associated with long-term sequelae among survivors of current therapies. Hence, there is an urgent need to identify actionable targets and to develop more effective therapies. Telomerase and telomeres play important roles in cancer, representing attractive therapeutic targets to treat children with poor-prognosis brain tumors such as diffuse intrinsic pontine glioma (DIPG), high-grade glioma (HGG), and high-risk medulloblastoma. We have previously shown that DIPG, HGG, and medulloblastoma frequently express telomerase activity. Here, we show that the telomerase-dependent incorporation of 6-thio-2'deoxyguanosine (6-thio-dG), a telomerase substrate precursor analogue, into telomeres leads to telomere dysfunction-induced foci (TIF) along with extensive genomic DNA damage, cell growth inhibition, and cell death of primary stem-like cells derived from patients with DIPG, HGG, and medulloblastoma. Importantly, the effect of 6-thio-dG is persistent even after drug withdrawal. Treatment with 6-thio-dG elicits a sequential activation of ATR and ATM pathways and induces G2-M arrest. In vivo treatment of mice bearing medulloblastoma xenografts with 6-thio-dG delays tumor growth and increases in-tumor TIFs and apoptosis. Furthermore, 6-thio-dG crosses the blood-brain barrier and specifically targets tumor cells in an orthotopic mouse model of DIPG. Together, our findings suggest that 6-thio-dG is a promising novel approach to treat therapy-resistant telomerase-positive pediatric brain tumors. Mol Cancer Ther; 17(7); 1504-14. ©2018 AACR.


Assuntos
Neoplasias Encefálicas/terapia , Neoplasias do Tronco Encefálico/terapia , Glioma/terapia , Telomerase/genética , Animais , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , Neoplasias do Tronco Encefálico/genética , Neoplasias do Tronco Encefálico/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Dano ao DNA/efeitos dos fármacos , Desoxiguanosina/análogos & derivados , Desoxiguanosina/farmacologia , Resistencia a Medicamentos Antineoplásicos/genética , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Glioma/genética , Glioma/patologia , Humanos , Meduloblastoma/genética , Meduloblastoma/patologia , Meduloblastoma/terapia , Camundongos , Células-Tronco Neoplásicas/efeitos dos fármacos , Prognóstico , Telomerase/uso terapêutico , Telômero/efeitos dos fármacos , Telômero/genética , Tionucleosídeos/farmacologia , Ensaios Antitumorais Modelo de Xenoenxerto
15.
Clin Cancer Res ; 24(19): 4771-4784, 2018 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-29563139

RESUMO

Purpose: Telomerase promoter mutations are highly prevalent in human tumors including melanoma. A subset of patients with metastatic melanoma often fail multiple therapies, and there is an unmet and urgent need to prolong disease control for those patients.Experimental Design: Numerous preclinical therapy-resistant models of human and mouse melanoma were used to test the efficacy of a telomerase-directed nucleoside, 6-thio-2'-deoxyguanosine (6-thio-dG). Integrated transcriptomics and proteomics approaches were used to identify genes and proteins that were significantly downregulated by 6-thio-dG.Results: We demonstrated the superior efficacy of 6-thio-dG both in vitro and in vivo that results in telomere dysfunction, leading to apoptosis and cell death in various preclinical models of therapy-resistant melanoma cells. 6-thio-dG concomitantly induces telomere dysfunction and inhibits the expression level of AXL.Conclusions: In summary, this study shows that indirectly targeting aberrant telomerase in melanoma cells with 6-thio-dG is a viable therapeutic approach in prolonging disease control and overcoming therapy resistance. Clin Cancer Res; 24(19); 4771-84. ©2018 AACR See related commentary by Teh and Aplin, p. 4629.


Assuntos
Desoxiguanosina/análogos & derivados , Melanoma/tratamento farmacológico , Regiões Promotoras Genéticas/genética , Telomerase/genética , Tionucleosídeos/farmacologia , Animais , Linhagem Celular Tumoral , Desoxiguanosina/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Humanos , Melanoma/genética , Melanoma/patologia , Camundongos , Mutação , Telômero/efeitos dos fármacos , Telômero/genética
16.
Clin Nucl Med ; 43(6): 458-459, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29538030

RESUMO

A 75-year-old woman with a history of sarcoidosis presenting with low cardiac output and complete right bundle-branch block underwent 4'-[methyl-C]-thiothymidine (4DST) PET/CT after cardiac MRI and FDG PET/CT for the evaluation of suspected cardiac sarcoidosis (CS) before treatment. Cardiac MRI revealed late gadolinium enhancement on the anterior-to-lateral and posterior wall, indicating CS. FDG uptake was shown on the anterior-to-lateral wall, but not on the posterior wall. In contrast, 4DST uptake was demonstrated on both anterior-to-lateral and posterior walls. Use of 4DST appears promising for detecting CS without dietary restriction, due to the lack of physiological uptake in myocardium.


Assuntos
Cardiomiopatias/diagnóstico por imagem , Imagem por Ressonância Magnética , Tomografia Computadorizada com Tomografia por Emissão de Pósitrons , Sarcoidose/diagnóstico por imagem , Idoso , Feminino , Fluordesoxiglucose F18 , Humanos , Compostos Radiofarmacêuticos , Tionucleosídeos , Timidina/análogos & derivados
17.
Photochem Photobiol ; 94(4): 677-684, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29420844

RESUMO

6-Thioguanine (1a) is considered to be photochemotherapeutic due to its specific characteristics of photosensitivity to UVA light and singlet molecular oxygen generation. To extend its phototherapeutic ability, two related thioguanines, 8-thioguanine (2a) and 6,8-dithioguanine (3a), have been designed and explored. Since the solubility of these thioguanines in dehydrated organic solvents is too poor to study, their triacetyl-protected ribonucleosides, that is, 2',3',5'-tri-O-acetyl-6-thioguanosine (1c), 2',3',5'-tri-O-acetyl-8-thioguanosine (2c) and 2',3',5'-tri-O-acetyl-6,8-dithioguanosine (3c) were prepared and investigated. The absorption maxima of 1c, 2c and 3c in acetonitrile were found at longer wavelengths than that of unthiolated guanosine (4c). Especially, 3c has the longest wavelength for absorption maximum and the highest value in terms of molar absorption coefficient among all thionucleobases and thionucleosides reported. These absorption properties were also well reproduced by quantum chemical calculations. Quantum yields of singlet oxygen generation of 2c and 3c were determined by near-infrared emission measurements to be as large as that of 1c. These results suggest that the newly synthesized thioguanosines, in particular 3c, can be further developed as a potential photosensitive agent for light-induced therapies.


Assuntos
Guanosina/análogos & derivados , Teoria Quântica , Oxigênio Singlete/química , Tionucleosídeos/química , Espectroscopia de Ressonância Magnética Nuclear de Carbono-13 , Guanosina/síntese química , Guanosina/química , Processos Fotoquímicos , Fotoquimioterapia , Fármacos Fotossensibilizantes/síntese química , Espectrofotometria Ultravioleta , Espectroscopia de Luz Próxima ao Infravermelho , Tionucleosídeos/síntese química
18.
Chem Pharm Bull (Tokyo) ; 66(2): 139-146, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29386464

RESUMO

Many attempts have been made to synthesize structurally novel nucleoside derivatives in order to identify effective compounds for the treatment of tumors and virus-caused disease. At our laboratories, as part of our efforts to synthesize 4'-thionucleosides, we have identified and characterized biologically active nucleosides. During the course of our synthetic study, we developed the Pummerer-type thioglycosylation reaction. As a result, we synthesized a potent antineoplastic nucleoside, 1-(2-deoxy-2-fluoro-ß-D-4-thio-arabino-furanosyl)cytosine (4'-thioFAC), and several novel 4'-thionucleosides that possess antiherpes virus activities.


Assuntos
Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Antivirais/síntese química , Antivirais/farmacologia , Tionucleosídeos/síntese química , Tionucleosídeos/farmacologia , Desenho de Fármacos , Humanos , Estrutura Molecular , Relação Estrutura-Atividade
19.
Balkan Med J ; 35(3): 272-274, 2018 05 29.
Artigo em Inglês | MEDLINE | ID: mdl-29219112

RESUMO

Background: Ovotesticular disorder is characterized by the presence of testicular and ovarian tissues in the same individual. Single gene mutations in SRY, SOX9, DMRT1 and DAX1 can lead to ovotesticular disorder of sexual development. Case Report: Herein, we report a 3-month-old phenotypically female baby in whom differentiated tissues of both Müllerian and Wolffian ducts were detected on pathological analysis of laparoscopic biopsy material. Chromosomal analysis observed 46,XY, der(9)t(3;9)(p25;p24) with deletion of 9p24.3p23 including the DMRT gene cluster and duplication of 3p26.3p24.3 on array comparative genomic hybridisation. Conclusion: In support of previous literature, we found that haploinsufficiency of the DMRT gene cluster leads to ovotesticular disorder of sexual development. In addition, we emphasize that array comparative genomic hybridisation is an important technique in the molecular diagnosis of ovotesticular disorder of sexual.


Assuntos
Trifosfato de Adenosina/análogos & derivados , Haploinsuficiência/genética , Transtornos Ovotesticulares do Desenvolvimento Sexual/genética , Tionucleosídeos/genética , Trifosfato de Adenosina/genética , Feminino , Disgenesia Gonadal 46 XY/diagnóstico , Disgenesia Gonadal 46 XY/genética , Humanos , Hibridização in Situ Fluorescente , Lactente , Masculino , Família Multigênica , Transtornos Ovotesticulares do Desenvolvimento Sexual/diagnóstico , Fatores de Transcrição SOX9 , Testículo
20.
BMC Struct Biol ; 17(1): 9, 2017 Dec 19.
Artigo em Inglês | MEDLINE | ID: mdl-29258562

RESUMO

BACKGROUND: The 5'-methylthioadenosine phosphorylase (MTAP), an enzyme involved in purine and polyamine metabolism and in the methionine salvage pathway, is considered as a potential drug target against cancer and trypanosomiasis. In fact, Trypanosoma and Leishmania parasites lack de novo purine pathways and rely on purine salvage pathways to meet their requirements. Herein, we propose the first comprehensive bioinformatic and structural characterization of the putative Leishmania infantum MTAP (LiMTAP), using a comparative computational approach. RESULTS: Sequence analysis showed that LiMTAP shared higher identity rates with the Trypanosoma brucei (TbMTAP) and the human (huMTAP) homologs as compared to the human purine nucleoside phosphorylase (huPNP). Motifs search using MEME identified more common patterns and higher relatedness of the parasite proteins to the huMTAP than to the huPNP. The 3D structures of LiMTAP and TbMTAP were predicted by homology modeling and compared to the crystal structure of the huMTAP. These models presented conserved secondary structures compared to the huMTAP, with a similar topology corresponding to the Rossmann fold. This confirmed that both LiMTAP and TbMTAP are members of the NP-I family. In comparison to the huMTAP, the 3D model of LiMTAP showed an additional α-helix, at the C terminal extremity. One peptide located in this specific region was used to generate a specific antibody to LiMTAP. In comparison with the active site (AS) of huMTAP, the parasite ASs presented significant differences in the shape and the electrostatic potentials (EPs). Molecular docking of 5'-methylthioadenosine (MTA) and 5'-hydroxyethylthio-adenosine (HETA) on the ASs on the three proteins predicted differential binding modes and interactions when comparing the parasite proteins to the human orthologue. CONCLUSIONS: This study highlighted significant structural peculiarities, corresponding to functionally relevant sequence divergence in LiMTAP, making of it a potential drug target against Leishmania.


Assuntos
Leishmania infantum/enzimologia , Simulação de Acoplamento Molecular/métodos , Purina-Núcleosídeo Fosforilase/química , Purina-Núcleosídeo Fosforilase/metabolismo , Análise de Sequência de DNA/métodos , Trypanosoma brucei brucei/ultraestrutura , Adenosina/análogos & derivados , Adenosina/metabolismo , Motivos de Aminoácidos , Sequência de Aminoácidos , Anticorpos/metabolismo , Sítios de Ligação de Anticorpos , Domínio Catalítico , Desoxiadenosinas/metabolismo , Humanos , Fragmentos de Peptídeos/química , Fragmentos de Peptídeos/metabolismo , Ligação Proteica , Conformação Proteica , Homologia de Sequência , Eletricidade Estática , Especificidade por Substrato , Tionucleosídeos/metabolismo
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