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1.
J Med Chem ; 63(10): 5159-5184, 2020 05 28.
Artigo em Inglês | MEDLINE | ID: mdl-32340447

RESUMO

Exchange proteins directly activated by cAMP (EPAC) play a central role in various biological functions, and activation of the EPAC1 protein has shown potential benefits for the treatment of various human diseases. Herein, we report the synthesis and biochemical evaluation of a series of noncyclic nucleotide EPAC1 activators. Several potent EPAC1 binders were identified including 25g, 25q, 25n, 25u, 25e, and 25f, which promote EPAC1 guanine nucleotide exchange factor activity in vitro. These agonists can also activate EPAC1 protein in cells, where they exhibit excellent selectivity toward EPAC over protein kinase A and G protein-coupled receptors. Moreover, 25e, 25f, 25n, and 25u exhibited improved selectivity toward activation of EPAC1 over EPAC2 in cells. Of these, 25u was found to robustly inhibit IL-6-activated signal transducer and activator of transcription 3 (STAT3) and subsequent induction of the pro-inflammatory vascular cell adhesion molecule 1 (VCAM1) cell-adhesion protein. These novel EPAC1 activators may therefore act as useful pharmacological tools for elucidation of EPAC function and promising drug leads for the treatment of relevant human diseases.


Assuntos
AMP Cíclico/metabolismo , Fatores de Troca do Nucleotídeo Guanina/metabolismo , Células Endoteliais da Veia Umbilical Humana/metabolismo , AMP Cíclico/agonistas , Avaliação Pré-Clínica de Medicamentos/métodos , Fatores de Troca do Nucleotídeo Guanina/agonistas , Células HEK293 , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Humanos , Nucleotídeos/síntese química , Nucleotídeos/química , Nucleotídeos/farmacologia , Ligação Proteica/fisiologia
2.
Molecules ; 25(3)2020 Feb 06.
Artigo em Inglês | MEDLINE | ID: mdl-32041321

RESUMO

Phosphoramidate pro-nucleotides (ProTides) have revolutionized the field of anti-viral and anti-cancer nucleoside therapy, overcoming the major limitations of nucleoside therapies and achieving clinical and commercial success. Despite the translation of ProTide technology into the clinic, there remain unresolved in vivo pharmacokinetic and pharmacodynamic questions. Positron Emission Tomography (PET) imaging using [18F]-labelled model ProTides could directly address key mechanistic questions and predict response to ProTide therapy. Here we report the first radiochemical synthesis of [18F]ProTides as novel probes for PET imaging. As a proof of concept, two chemically distinct radiolabelled ProTides have been synthesized as models of 3'- and 2'-fluorinated ProTides following different radiosynthetic approaches. The 3'-[18F]FLT ProTide was obtained via a late stage [18F]fluorination in radiochemical yields (RCY) of 15-30% (n = 5, decay-corrected from end of bombardment (EoB)), with high radiochemical purities (97%) and molar activities of 56 GBq/µmol (total synthesis time of 130 min.). The 2'-[18F]FIAU ProTide was obtained via an early stage [18F]fluorination approach with an RCY of 1-5% (n = 7, decay-corrected from EoB), with high radiochemical purities (98%) and molar activities of 53 GBq/µmol (total synthesis time of 240 min).


Assuntos
Radioisótopos de Flúor/química , Nucleotídeos/síntese química , Compostos Radiofarmacêuticos/síntese química , Halogenação , Tomografia por Emissão de Pósitrons/métodos , Radioquímica/métodos
3.
Org Biomol Chem ; 18(5): 912-919, 2020 02 07.
Artigo em Inglês | MEDLINE | ID: mdl-31919486

RESUMO

Cytosine 2'-deoxyribonucleoside dCTBdp and its triphosphate (dCTBdpTP) bearing tetramethylated thiophene-bodipy fluorophore attached at position 5 were designed and synthesized. The green fluorescent nucleoside dCTBdp showed a perfect dependence of fluorescence lifetime on the viscosity. The modified triphosphate dCTBdpTP was substrate to several DNA polymerases and was used for in vitro enzymatic synthesis of labeled oligonucleotides (ONs) or DNA by primer extension. The labeled single-stranded ONs showed a significant decrease in mean fluorescence lifetime when hybridized to the complementary strand of DNA or RNA and were also sensitive to mismatches. The labeled dsDNA sensed protein binding (p53), which resulted in the increase of its fluorescence lifetime. The triphosphate dCTBdpTP was transported to live cells where its interactions could be detected by FLIM but it did not show incorporation to genomic DNA in cellulo.


Assuntos
Compostos de Boro/química , Proteínas de Ligação a DNA/metabolismo , DNA/metabolismo , Hibridização de Ácido Nucleico , Nucleotídeos/química , Sondas de Oligonucleotídeos/metabolismo , Tiofenos/química , Sequência de Bases , Cátions , Linhagem Celular Tumoral , DNA Polimerase Dirigida por DNA/metabolismo , Humanos , Lipídeos/química , Nucleotídeos/síntese química , Ligação Proteica , Solventes/química , Espectrometria de Fluorescência , Temperatura , Viscosidade
4.
J Am Chem Soc ; 141(34): 13286-13289, 2019 08 28.
Artigo em Inglês | MEDLINE | ID: mdl-31298849

RESUMO

Natural and modified nucleoside triphosphates impact nearly every major aspect of healthcare research from DNA sequencing to drug discovery. However, a scalable synthetic route to these molecules has long been hindered by the need for purification by high performance liquid chromatography (HPLC). Here, we describe a fundamentally different approach that uses a novel P(V) pyrene pyrophosphate reagent to generate derivatives that are purified by silica gel chromatography and converted to the desired compounds on scales vastly exceeding those achievable by HPLC. The power of this approach is demonstrated through the synthesis of a broad range of natural and unnatural nucleoside triphosphates (dNTPs and xNTPs) using protocols that are efficient, inexpensive, and operationally straightforward.


Assuntos
Nucleotídeos/síntese química , Técnicas de Química Sintética/métodos , Cromatografia Líquida de Alta Pressão , Difosfatos/síntese química , Difosfatos/química , Indicadores e Reagentes , Nucleotídeos/química , Pirenos/síntese química , Pirenos/química
5.
N Engl J Med ; 380(24): 2307-2316, 2019 06 13.
Artigo em Inglês | MEDLINE | ID: mdl-31059641

RESUMO

BACKGROUND: Huntington's disease is an autosomal-dominant neurodegenerative disease caused by CAG trinucleotide repeat expansion in HTT, resulting in a mutant huntingtin protein. IONIS-HTTRx (hereafter, HTTRx) is an antisense oligonucleotide designed to inhibit HTT messenger RNA and thereby reduce concentrations of mutant huntingtin. METHODS: We conducted a randomized, double-blind, multiple-ascending-dose, phase 1-2a trial involving adults with early Huntington's disease. Patients were randomly assigned in a 3:1 ratio to receive HTTRx or placebo as a bolus intrathecal administration every 4 weeks for four doses. Dose selection was guided by a preclinical model in mice and nonhuman primates that related dose level to reduction in the concentration of huntingtin. The primary end point was safety. The secondary end point was HTTRx pharmacokinetics in cerebrospinal fluid (CSF). Prespecified exploratory end points included the concentration of mutant huntingtin in CSF. RESULTS: Of the 46 patients who were enrolled in the trial, 34 were randomly assigned to receive HTTRx (at ascending dose levels of 10 to 120 mg) and 12 were randomly assigned to receive placebo. Each patient received all four doses and completed the trial. Adverse events, all of grade 1 or 2, were reported in 98% of the patients. No serious adverse events were seen in HTTRx-treated patients. There were no clinically relevant adverse changes in laboratory variables. Predose (trough) concentrations of HTTRx in CSF showed dose dependence up to doses of 60 mg. HTTRx treatment resulted in a dose-dependent reduction in the concentration of mutant huntingtin in CSF (mean percentage change from baseline, 10% in the placebo group and -20%, -25%, -28%, -42%, and -38% in the HTTRx 10-mg, 30-mg, 60-mg, 90-mg, and 120-mg dose groups, respectively). CONCLUSIONS: Intrathecal administration of HTTRx to patients with early Huntington's disease was not accompanied by serious adverse events. We observed dose-dependent reductions in concentrations of mutant huntingtin. (Funded by Ionis Pharmaceuticals and F. Hoffmann-La Roche; ClinicalTrials.gov number, NCT02519036.).


Assuntos
Proteína Huntingtina/antagonistas & inibidores , Doença de Huntington/tratamento farmacológico , Nucleotídeos/farmacologia , Oligonucleotídeos/uso terapêutico , Adulto , Relação Dose-Resposta a Droga , Feminino , Humanos , Proteína Huntingtina/líquido cefalorraquidiano , Proteína Huntingtina/genética , Injeções Espinhais , Masculino , Pessoa de Meia-Idade , Mutação , Nucleotídeos/síntese química , Oligonucleotídeos/líquido cefalorraquidiano
6.
Med Sci (Paris) ; 35(5): 483-485, 2019 May.
Artigo em Francês | MEDLINE | ID: mdl-31115333

RESUMO

The synthesis of four new nucleotide analogues that can form hydrogen bonds within the DNA double helix and can be incorporated without distortion of the structure extends the possibilities of synthetic biology. Although functional use of these analogues remains in the future, they already have interesting applications and represent an important step forward.


Assuntos
DNA/química , Nucleotídeos/química , Adenina/análogos & derivados , Adenina/química , Citosina/análogos & derivados , Citosina/química , Guanina/análogos & derivados , Guanina/química , Ligação de Hidrogênio , Estrutura Molecular , Nucleotídeos/síntese química , Oligonucleotídeos/química , Biologia Sintética , Timina/análogos & derivados , Timina/química
7.
PLoS Biol ; 17(4): e3000204, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30951520

RESUMO

Telomerase, a unique reverse transcriptase that specifically extends the ends of linear chromosomes, is up-regulated in the vast majority of cancer cells. Here, we show that an indole nucleotide analog, 5-methylcarboxyl-indolyl-2'-deoxyriboside 5'-triphosphate (5-MeCITP), functions as an inhibitor of telomerase activity. The crystal structure of 5-MeCITP bound to the Tribolium castaneum telomerase reverse transcriptase reveals an atypical interaction, in which the nucleobase is flipped in the active site. In this orientation, the methoxy group of 5-MeCITP extends out of the canonical active site to interact with a telomerase-specific hydrophobic pocket formed by motifs 1 and 2 in the fingers domain and T-motif in the RNA-binding domain of the telomerase reverse transcriptase. In vitro data show that 5-MeCITP inhibits telomerase with a similar potency as the clinically administered nucleoside analog reverse transcriptase inhibitor azidothymidine (AZT). In addition, cell-based studies show that treatment with the cell-permeable nucleoside counterpart of 5-MeCITP leads to telomere shortening in telomerase-positive cancer cells, while resulting in significantly lower cytotoxic effects in telomerase-negative cell lines when compared with AZT treatment.


Assuntos
Nucleosídeos/metabolismo , Telomerase/antagonistas & inibidores , Telomerase/fisiologia , Animais , Domínio Catalítico/efeitos dos fármacos , Células HCT116 , Células HEK293 , Células HeLa , Humanos , Modelos Moleculares , Nucleosídeos/síntese química , Nucleosídeos/fisiologia , Nucleotídeos/síntese química , Nucleotídeos/metabolismo , RNA/metabolismo , Inibidores da Transcriptase Reversa/farmacologia , Telômero , Tribolium/genética , Tribolium/metabolismo , Zidovudina/metabolismo , Zidovudina/farmacologia
8.
Nucleic Acids Res ; 47(5): 2160-2168, 2019 03 18.
Artigo em Inglês | MEDLINE | ID: mdl-30698800

RESUMO

Six 1',5'-anhydrohexitol uridine triphosphates were synthesized with aromatic substitutions appended via a carboxamide linker to the 5-position of their bases. An improved method for obtaining such 5-substituted hexitol nucleosides and nucleotides is described. The incorporation profile of the nucleotide analogues into a DNA duplex overhang using recently evolved XNA polymerases is compared. Long, mixed HNA sequences featuring the base modifications are generated. The apparent binding affinity of four of the nucleotides to the enzyme, the rate of the chemical step and of product release, plus the specificity constant for the incorporation of these modified nucleotides into a DNA duplex overhang using the HNA polymerase T6G12_I521L are determined via pre-steady-state kinetics. HNA polymers displaying aromatic functional groups could have significant impact on the isolation of stable and high-affinity binders and catalysts, or on the design of nanomaterials.


Assuntos
DNA Polimerase Dirigida por DNA/metabolismo , Nucleotídeos/síntese química , Nucleotídeos/metabolismo , Álcoois Açúcares/química , Álcoois Açúcares/metabolismo , Cinética , Nucleotídeos/química , Engenharia de Proteínas , Especificidade por Substrato
9.
J Org Chem ; 84(8): 4723-4734, 2019 04 19.
Artigo em Inglês | MEDLINE | ID: mdl-30412402

RESUMO

ABBV-168 is a dihalogenated nucleotide under investigation for the treatment of hepatitis C virus. Three synthetic routes aimed at achieving the stereoselective installation of the C2' gem-Br,F substitution and subsequent Vorbruggen glycosylation were explored to prepare the penultimate nucleoside intermediate. Development culminated in a route to ABBV-168 featuring a de novo chromatography-free furanose synthesis, protecting group-directed Vorbruggen glycosylation, and highly selective phosphoramidation to furnish the API.


Assuntos
Antivirais/farmacologia , Hepacivirus/efeitos dos fármacos , Hepatite C/tratamento farmacológico , Nucleotídeos/farmacologia , Antivirais/síntese química , Antivirais/química , Humanos , Testes de Sensibilidade Microbiana , Conformação Molecular , Nucleotídeos/síntese química , Nucleotídeos/química
10.
Bioorg Med Chem ; 27(12): 2332-2339, 2019 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-30578076

RESUMO

Herpes simplex virus (HSV) infection has been recognized as the most common mucosal disease in humans, manifesting as a life-threatening infection especially for patients with compromised immunity. When combined with the emergence of resistance due to the long-term use of classical antiviral agents, these threats make novel therapeutics for HSV a clinically necessity. We therefore designed and synthesized a series of Janus-type nucleosides by combining the natural genetic alphabets into a singular nucleoside structural unit. We also synthesized a series of new compounds and systematically evaluated their antiviral activity and structure-antiviral activity relationship. The results indicated that both nucleosides and their related intermediates exhibited high anti-HSV-1 activity. Compounds HY17 and HY19, in particular, possessed excellent anti-HSV-1 activity with IC50 values of 0.05 and 0.04 µg/mL, respectively. They also showed broad-spectrum antiviral activity against a multitude of diverse viruses, such as HSV-2, influenza virus A (H3N2), CVB3, HBV, HCV, and HPV. These results suggest that once their mechanisms are fully elucidated, these compounds will prove to be promising candidates as antiviral agents.


Assuntos
Antivirais/farmacologia , Nucleotídeos/farmacologia , Oximas/farmacologia , Animais , Antivirais/síntese química , Antivirais/química , Chlorocebus aethiops , Herpesvirus Humano 1/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Estrutura Molecular , Nucleotídeos/síntese química , Nucleotídeos/química , Oximas/síntese química , Oximas/química , Relação Estrutura-Atividade , Células Vero
11.
Nat Commun ; 9(1): 5176, 2018 12 12.
Artigo em Inglês | MEDLINE | ID: mdl-30538225

RESUMO

Synthesis of activated nucleotides has been accomplished under 'prebiotically plausible' conditions, but bears little resemblance to the chemistry of life as we know it. Here we argue that life is an indispensable guide to its own origins.


Assuntos
Evolução Química , Nucleotídeos/química , Origem da Vida , RNA/química , Aminoácidos/síntese química , Aminoácidos/química , Dióxido de Carbono/química , Hidrogênio/química , Modelos Químicos , Estrutura Molecular , Nucleotídeos/síntese química , RNA/síntese química
12.
J Am Chem Soc ; 140(47): 16115-16123, 2018 11 28.
Artigo em Inglês | MEDLINE | ID: mdl-30418780

RESUMO

We have developed a family of unnatural base pairs (UBPs), exemplified by the pair formed between dNaM and dTPT3, for which pairing is mediated not by complementary hydrogen bonding but by hydrophobic and packing forces. These UBPs enabled the creation of the first semisynthetic organisms (SSOs) that store increased genetic information and use it to produce proteins containing noncanonical amino acids. However, retention of the UBPs was poor in some sequence contexts. Here, to optimize the SSO, we synthesize two novel benzothiophene-based dNaM analogs, dPTMO and dMTMO, and characterize the corresponding UBPs, dPTMO-dTPT3 and dMTMO-dTPT3. We demonstrate that these UBPs perform similarly to, or slightly worse than, dNaM-dTPT3 in vitro. However, in the in vivo environment of an SSO, retention of dMTMO-dTPT3, and especially dPTMO-dTPT3, is significantly higher than that of dNaM-dTPT3. This more optimal in vivo retention results from better replication, as opposed to more efficient import of the requisite unnatural nucleoside triphosphates. Modeling studies suggest that the more optimal replication results from specific internucleobase interactions mediated by the thiophene sulfur atoms. Finally, we show that dMTMO and dPTMO efficiently template the transcription of RNA containing TPT3 and that their improved retention in DNA results in more efficient production of proteins with noncanonical amino acids. This is the first instance of using performance within the SSO as part of the UBP evaluation and optimization process. From a general perspective, the results demonstrate the importance of evaluating synthetic biology "parts" in their in vivo context and further demonstrate the ability of hydrophobic and packing interactions to replace the complementary hydrogen bonding that underlies the replication of natural base pairs. From a more practical perspective, the identification of dMTMO-dTPT3 and especially dPTMO-dTPT3 represents significant progress toward the development of SSOs with an unrestricted ability to store and retrieve increased information.


Assuntos
DNA/genética , Nucleotídeos/genética , Pareamento de Bases , Sequência de Bases , DNA/química , Replicação do DNA , Escherichia coli/genética , Código Genético , Proteínas de Fluorescência Verde/genética , Interações Hidrofóbicas e Hidrofílicas , Cinética , Methanosarcina barkeri/genética , Nucleotídeos/síntese química , Nucleotídeos/química , Biossíntese de Proteínas , RNA de Transferência/genética , Biologia Sintética/métodos
13.
Curr Protoc Nucleic Acid Chem ; 75(1): e62, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30307714

RESUMO

This article describes a straight-forward chemical method for the synthesis of nucleoside-5'-O-tetraphosphates, such as cytosine-, guanosine-, adenosine-, and uridine-5'-O-tetraphosphates, starting from the corresponding nucleoside monophosphates and trimetaphosphate, a readily available and inexpensive starting material. The procedure involves reacting the tri(tetrabutylammonium) salt of trimetaphosphate with mesitylenesulfonyl chloride and N-methylimidazole. The resulting activated cyclic trimetaphosphate is reacted with the tetrabutylammonium salts of nucleoside monophosphates. After quenching the reaction with buffer and high-performance liquid chromatography purification, the desired nucleoside-5'-O-tetraphosphates were obtained in yields of 84% to 86%. © 2018 by John Wiley & Sons, Inc.


Assuntos
Nucleotídeos/síntese química , Polifosfatos/química , Espectroscopia de Ressonância Magnética Nuclear de Carbono-13 , Cromatografia Líquida de Alta Pressão , Espectrometria de Massas , Nucleotídeos/química , Nucleotídeos/isolamento & purificação , Espectroscopia de Prótons por Ressonância Magnética
14.
Sci Rep ; 8(1): 12598, 2018 08 22.
Artigo em Inglês | MEDLINE | ID: mdl-30135473

RESUMO

Neutral DNA analogs as probes for the detection of target oligomers on the biosensors based on the field-effect transistor (FET) configuration feature advantages in the enhancement of sensitivity and signal-to-noise ratio. Herein, we used phosphate-methylated nucleotides to synthesize two partially neutralized chimeric DNA products and a fully neutralized DNA sequence and adopted a regular DNA oligomer as probes on the polycrystalline silicon nanowire (NW) FET devices. The sequences of two neutralized chimeric DNAs close to the 5' end were alternately modified with the phosphate-methylated nucleotides, and all probes were immobilized via their 5' end on the NW surface. The non-specific-to-specific binding ratio indicated that the two 5'-end partially neutralized chimeric DNAs featured better performance than the regular and fully neutralized DNA oligomers. The partially neutralized probe design reduces the ionic strength needed for hybridization and increases the Debye length of detection, thus promoting the detection sensitivity of FET and achieving the limit of detection of 0.1 fM. By using an appropriate probe design, applying DNA oligomers with embedded phosphate-methylated nucleotides in the FET biosensors is a promising way for gene detection with high sensitivity and specificity.


Assuntos
Aptâmeros de Nucleotídeos/síntese química , Sondas de DNA/síntese química , Nanofios/química , Aptâmeros de Nucleotídeos/genética , Aptâmeros de Nucleotídeos/metabolismo , Técnicas Biossensoriais/instrumentação , DNA/genética , Desenho de Equipamento/métodos , Hibridização de Ácido Nucleico , Nucleotídeos/síntese química , Análise de Sequência com Séries de Oligonucleotídeos/métodos , Sensibilidade e Especificidade , Silício/química , Transistores Eletrônicos
15.
Chemistry ; 24(57): 15267-15274, 2018 Oct 12.
Artigo em Inglês | MEDLINE | ID: mdl-29931815

RESUMO

The self-priming synthesis of multiply modified DNA by the extension of repeating unit duplex "oligoseeds" provides a source of versatile DNA. Sterically-demanding nucleotides 5-Br-dUTP, 7-deaza-7-I-dATP, 6-S-dGTP, 5-I-dCTP as well as 5-(octadiynyl)-dCTP were incorporated into two extending oligoseeds; [GATC]5 /[GATC]5 and [A4 G]4 /[CT4 ]4 . The products contained modifications on one or both strands of DNA, demonstrating their recognition by the polymerase as both template (reading) and substrate (writing). Nucleobase modifications that lie in the major groove were reliably read and written by the polymerase during the extension reaction, even when bulky or in contiguous sequences. Repeat sequence DNA over 500 bp long, bearing four different modified units was produced by this method. The number, position and type of modification, as well as the overall length of the DNA can be controlled to yield designer DNA that offers sequence-determined sites for further chemical adaptations, targeted small molecule binding studies, or sensing and sequencing applications.


Assuntos
DNA/síntese química , Nucleotídeos/síntese química , Sequência de Bases , DNA/química , DNA/genética , Conformação de Ácido Nucleico , Nucleotídeos/química , Nucleotídeos/genética , Reação em Cadeia da Polimerase
16.
Curr Protoc Nucleic Acid Chem ; 72(1): 4.79.1-4.79.21, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29927121

RESUMO

2'-O,4'-C-Ethylene-bridged nucleic acid (ENA) is a sugar-modified oligonucleotide with an ethylene bridge between the 2'-oxygen and 4'-carbon of ribose. ENA not only has as high binding affinity to complementary RNA as conventional bridged/locked nucleic acid, but also has much higher nuclease resistance in plasma, which makes it a promising candidate for antisense therapeutics. This unit presents detailed protocols for the synthesis and characterization of ENA nucleosides and oligonucleotides. © 2018 by John Wiley & Sons, Inc.


Assuntos
Nucleotídeos/síntese química , Ribose/análogos & derivados , Amidas/química , Etilenos/química , Nucleotídeos/química , Ácidos Fosfóricos/química , RNA/química , Ribonucleases/química , Ribose/síntese química , Ribose/química
18.
Chem Pharm Bull (Tokyo) ; 66(1): 84-95, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29311516

RESUMO

A solid-phase synthesis of Park nucleotide as well as lipids I and II analogues, which is applicable to the synthesis of a range of analogues, is described in this work. This technique allows highly functionalized macromolecules to be modularly labeled. Multiple steps are used in a short time (4 d) with a single purification step to synthesize the molecules by solid-phase synthesis.


Assuntos
Monossacarídeos/síntese química , Nucleotídeos/síntese química , Oligopeptídeos/síntese química , Técnicas de Síntese em Fase Sólida , Uridina Difosfato Ácido N-Acetilmurâmico/análogos & derivados , Conformação Molecular , Monossacarídeos/química , Nucleotídeos/química , Oligopeptídeos/química , Uridina Difosfato Ácido N-Acetilmurâmico/síntese química , Uridina Difosfato Ácido N-Acetilmurâmico/química
19.
Bioorg Med Chem Lett ; 28(3): 260-264, 2018 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-29305188

RESUMO

Human serum albumin is playing an increasing role as a drug carrier in clinical settings. Biotin molecules are often used as suitable tags in targeted anti-tumor drug delivery systems. We report on the synthesis and properties of a new multimodal theranostic conjugate based on an anti-cancer fluorinated nucleotide conjugated with a biotinylated dual-labeled albumin. Interestingly, in vitro and in vivo study revealed stronger anti-tumor activity of the non-tagged theranostic conjugate than that of the biotin-tagged conjugate, which can be explained by decreased binding of the biotin-tagged conjugate to cellular receptors. Our study sheds light on the importance of site-specific albumin modification for the design of albumin-based drugs with desirable pharmaceutical properties.


Assuntos
Antineoplásicos/farmacologia , Biotina/química , Nucleotídeos/farmacologia , Albumina Sérica Humana/química , Nanomedicina Teranóstica , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Camundongos , Camundongos SCID , Estrutura Molecular , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/patologia , Nucleotídeos/síntese química , Nucleotídeos/química , Relação Estrutura-Atividade
20.
Eur J Med Chem ; 144: 682-691, 2018 Jan 20.
Artigo em Inglês | MEDLINE | ID: mdl-29289891

RESUMO

We have designed and synthesized new 5-fluoro-2'-deoxyuridine 5'-phosphate pronucleotides which can function as potential agents against the glioblastoma multiforme tumor. Their anti-malignant potency has been tested against T98G, U-118 MG, U-87 MG gliomas, HeLa, and Caco-2 cancer cell lines, using MRC-5 healthy cells as a reference. Five of the sixteen compounds (4c, 4f-i) exhibited significant anticancer potency and high selectivity indices (SI 12-66). It is likely that these zwitterionic pronucleotides may function in a similar manner to zwitterionic phospholipids, by inducing cell membrane charge disorder, making the cell permeable to bioactive agents. The most promising therapeutic pronucleotides 4c, 4f-h, have high intestinal-blood uptake potency (Caco-2 cell line), and may be considered as potential, orally administrated, anticancer drugs.


Assuntos
Antineoplásicos/farmacologia , Citidina Monofosfato/análogos & derivados , Glioblastoma/tratamento farmacológico , Nucleotídeos/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Citidina Monofosfato/química , Citidina Monofosfato/farmacologia , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Glioblastoma/patologia , Humanos , Estrutura Molecular , Nucleotídeos/síntese química , Nucleotídeos/química , Relação Estrutura-Atividade , Células Tumorais Cultivadas
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