RESUMO
A nonenzymatic Pictet-Spengler reaction has been postulated to give rise to a subset of naturally occurring uridyl peptide antibiotics (UPAs). Here, using a combination of strain engineering and synthetic chemistry, we demonstrate that Pictet-Spengler chemistry may be employed to generate even greater diversity in the UPAs. We use an engineered strain to afford access to meta-tyrosine containing pacidamycin 4. Pictet-Spengler diversification of this compound using a small series of aryl-aldehydes was achieved with some derivatives affording remarkable diastereomeric control.
Assuntos
Antibacterianos/síntese química , Oligopeptídeos/síntese química , Peptídeos/síntese química , Streptomyces/metabolismo , Uridina/análogos & derivados , Uridina/síntese químicaRESUMO
Fluorinated nucleoside analogues have attracted much attention as anticancer and antiviral agents and as probes for enzymatic function. However, the lack of direct synthetic methods, especially for 2',3'-dideoxy-2',3'-difluoro nucleosides, hamper their practical utility. In order to design more efficient synthetic methods, a better understanding of the conformation and mechanism of formation of these molecules is important. Herein, we report the synthesis and conformational analysis of a 2',3'-dideoxy-2',3'-difluoro and a 2'-deoxy-2'-fluoro uridine derivative and provide an insight into the reaction mechanism. We suggest that the transformation most likely diverges from the SN1 or SN2 pathway, but instead operates via a neighbouring-group participation mechanism.
Assuntos
Técnicas de Química Sintética , Flúor/química , Conformação Molecular , Uridina/química , Fenômenos Mecânicos , Modelos Moleculares , Análise Espectral , Relação Estrutura-Atividade , Uridina/análogos & derivados , Uridina/síntese químicaRESUMO
Nucleoside derivatives, in particular those featuring uridine, are familiar components of the nucleoside family of bioactive natural products. The structural complexity and biological activities of these compounds have inspired research from organic chemistry and chemical biology communities seeking to develop novel approaches to assemble the challenging molecular targets, to gain inspiration for enzyme inhibitor development and to fuel antibiotic discovery efforts. This review will present recent case studies describing the total synthesis and biosynthesis of uridine natural products, and de novo synthetic efforts exploiting features of the natural products to produce simplified scaffolds. This research has culminated in the development of complementary strategies that can lead to effective uridine-based inhibitors and antibiotics. The strengths and challenges of the juxtaposing methods will be illustrated by examining select uridine natural products. Moreover, structure-activity relationships (SAR) for each natural product-inspired scaffold will be discussed, highlighting the impact on inhibitor development, with the aim of future uridine-based small molecule expansion.
Assuntos
Produtos Biológicos/síntese química , Inibidores Enzimáticos/síntese química , Uridina/síntese química , Antibacterianos/farmacologia , Produtos Biológicos/metabolismo , Produtos Biológicos/farmacologia , Descoberta de Drogas , Inibidores Enzimáticos/metabolismo , Inibidores Enzimáticos/farmacologia , Humanos , Estrutura Molecular , Fosfatos/química , Poliprenois/química , Relação Estrutura-Atividade , Uridina/metabolismo , Uridina/farmacologiaRESUMO
A concise synthetic strategy to 5-dihydroxyboryldexoyuridine (5boU) phosphoramidite has been developed. 5boU was introduced into short oligonucleotides in a site-specific manner, demonstrating compatibility of the boronic acid moiety with standard solid-phase DNA synthesis chemistry. Electrophilic 5boU DNAs inhibited thymine DNA glycosylase, a cancer-relevant DNA-modifying enzyme. We envisage diverse applications of 5boU in organic synthesis, medicinal chemistry, and chemical biology.
Assuntos
Sondas Moleculares/farmacologia , Oligonucleotídeos/farmacologia , Compostos Organofosforados/farmacologia , Timina DNA Glicosilase/antagonistas & inibidores , Uridina/farmacologia , Química Farmacêutica , Sondas Moleculares/síntese química , Sondas Moleculares/química , Estrutura Molecular , Oligonucleotídeos/química , Compostos Organofosforados/síntese química , Compostos Organofosforados/química , Técnicas de Síntese em Fase Sólida , Timina DNA Glicosilase/metabolismo , Uridina/síntese química , Uridina/químicaRESUMO
We report the synthesis and biological evaluation of a series of 4'-fluoro-2'- C-substituted uridines. Triphosphates of the uridine analogues exhibited a potent inhibition of hepatitis C virus (HCV) NS5B polymerase with IC50 values as low as 27 nM. In an HCV subgenomic replicon assay, the phosphoramidate prodrugs of these uridine analogues demonstrated a very potent activity with EC50 values as low as 20 nM. A lead compound AL-335 (53) demonstrated high levels of the nucleoside triphosphate in vitro in primary human hepatocytes and Huh-7 cells as well as in dog liver following a single oral dose. Compound 53 was selected for the clinical development where it showed promising results in phase 1 and 2 trials.
Assuntos
Alanina/análogos & derivados , Antivirais/farmacologia , Hepacivirus/efeitos dos fármacos , Pró-Fármacos/farmacologia , Nucleotídeos de Uracila/farmacologia , Uridina/análogos & derivados , Alanina/síntese química , Alanina/farmacologia , Animais , Antivirais/síntese química , Linhagem Celular Tumoral , Cães , Hepacivirus/enzimologia , Hepatite C/tratamento farmacológico , Humanos , Inibidores da Síntese de Ácido Nucleico/síntese química , Inibidores da Síntese de Ácido Nucleico/farmacologia , Fosforamidas , Pró-Fármacos/síntese química , Replicon/efeitos dos fármacos , Nucleotídeos de Uracila/síntese química , Nucleotídeos de Uracila/metabolismo , Uridina/síntese química , Uridina/farmacologia , Proteínas não Estruturais Virais/antagonistas & inibidoresRESUMO
We have explored a method to convert a muraymycin biosynthetic intermediate 3 to an anticancer drug lead 2 for in vivo and thorough preclinical studies. Cu(OAc)2 forms a stable complex with the amide 4 and prevents electrophilic reactions at the 2-((3-aminopropyl)amino)acetamide moiety. Under the present conditions, the desired 5â³-primary amine was selectively protected with (Boc)2O to yield 6. The intermediate 6 was converted to 2 in two steps with 90% yield.
Assuntos
Antineoplásicos/síntese química , Benzamidas/química , Inibidores Enzimáticos/farmacologia , N-Acetilglucosaminiltransferases/antagonistas & inibidores , Nucleosídeos/química , Compostos de Fenilureia/síntese química , Piperidinas/síntese química , Uridina/análogos & derivados , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Inibidores Enzimáticos/química , Inibidores Enzimáticos/metabolismo , Humanos , Conformação Molecular , N-Acetilglucosaminiltransferases/metabolismo , Nucleosídeos/metabolismo , Nucleotídeos/química , Peptídeos/química , Compostos de Fenilureia/farmacologia , Piperidinas/farmacologia , Relação Estrutura-Atividade , Ureia/química , Uridina/síntese química , Uridina/farmacologiaRESUMO
A new family of thirteen phosphoramidate prodrugs (ProTides) of different 6-substituted-5-fluorouridine nucleoside analogues were synthesized and evaluated as potential anticancer agents. In addition, antiviral activity against Chikungunya (CHIKV) virus was evaluated using a cytopathic effect inhibition assay. Although a carboxypeptidase Y assay supported a putative mechanism of activation of ProTides built on 5-fluorouridine with such C6-modifications, the Hint docking studies revealed a compromised substrate-activity for the Hint phosphoramidase-type enzyme that is likely responsible for phosphoramidate bioactivation through P-N bond cleavage and free nucleoside 5'-monophosphate delivery. Our observations may support and explain to some extent the poor in vitro biological activity generally demonstrated by the series of 6-substituted-5-fluorouridine phosphoramidates (ProTides) and will be of guidance for the design of novel phosphoramidate prodrugs.
Assuntos
Fosforamidas/síntese química , Pró-Fármacos/síntese química , Uridina/análogos & derivados , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/toxicidade , Antivirais/síntese química , Antivirais/química , Antivirais/farmacologia , Sítios de Ligação , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Vírus Chikungunya/fisiologia , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Simulação de Acoplamento Molecular , Proteínas do Tecido Nervoso/química , Proteínas do Tecido Nervoso/metabolismo , Fosforamidas/química , Fosforamidas/farmacologia , Pró-Fármacos/química , Pró-Fármacos/farmacologia , Estrutura Terciária de Proteína , Relação Estrutura-Atividade , Uridina/síntese química , Uridina/química , Uridina/farmacologia , Internalização do Vírus/efeitos dos fármacosRESUMO
Internucleoside amide linkages are excellent mimics of phosphodiesters in RNA and may be used to optimize the properties of short interfering RNAs. Herein we report a remarkably straightforward, efficient and step economic synthesis of C3'-homologated uridine and adenosine amino acids starting from nucleosides in six steps (31% overall yield) and eight steps (16% overall yield), respectively. The key enabling step is a one-pot multifunctional group transformation including a stereoselective hydrogenation, termed "Global Hydrogenation".
Assuntos
Adenosina/análogos & derivados , Adenosina/síntese química , Aminoácidos/síntese química , Uridina/análogos & derivados , Uridina/síntese química , Catálise , Hidrogenação , Estrutura Molecular , Paládio/químicaRESUMO
It has been postulated that sugar radicals and related species are involved in oxidative events involving RNA. To determine the contribution, if any, of these species to the deleterious effects of the endogenous exposome, it is important to unambiguously identify their degradation products. C5'-Pivaloyl uridine was successfully synthesized and subsequently photolytically converted to a C5'-uridinyl radical. Generation of the radical under anaerobic conditions in the presence of glutathione led to the formation of the expected reduction product, uridine. However, regardless of the presence or absence of reductant, the base elimination product, uracil, was also observed. Mass balances and product distributions were dependent upon the pH of the photolysis mixture. At low pH, trapping with glutathione successfully competed with base loss. These results indicate that this precursor should function efficiently in an investigation of the fate of the C5'-uridinyl radical in RNA oligomers.
Assuntos
Radicais Livres/química , Uridina/química , Cristalografia por Raios X , Glutationa/química , Concentração de Íons de Hidrogênio , Luz , Conformação Molecular , Fotólise/efeitos da radiação , RNA/química , Uridina/síntese químicaRESUMO
The impact of a number of synthetic nucleoside derivatives on the growth and survival of cultured human ovarian tumor cells (line SKOV-3) and normal human lung fibroblasts was investigated. It was shown that the dialdehyde derivatives of uridine, 1-ß-D-eritrofuranozyl uracil and 3'-O-ß-D-ribofuranosyl-2'-deoxythymidine, in contrast to their unoxidized counterparts, exert marked toxic effect on SKOV-3 cells. Cultured human fibroblasts were less susceptible to the damaging effect of the dialdehyde nucleosides. The dialdehyde derivative of 1-ß-D-eritrofuranozyl uracil demonstrated greatest differences in the cytotoxic effect on these cultures: inhibition of tumor SKOV-3 cells growth on 50% or more was achieved at the concentrations of this compound ten times lower than in the case of normal fibroblasts.
Assuntos
Aldeídos/farmacologia , Antineoplásicos/farmacologia , Citotoxinas/farmacologia , Furanos/farmacologia , Uridina/farmacologia , Aldeídos/síntese química , Antineoplásicos/síntese química , Linhagem Celular , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Citotoxinas/síntese química , Feminino , Fibroblastos/citologia , Fibroblastos/efeitos dos fármacos , Furanos/síntese química , Humanos , Concentração Inibidora 50 , Especificidade de Órgãos , Ovário/efeitos dos fármacos , Ovário/patologia , Uridina/análogos & derivados , Uridina/síntese químicaRESUMO
A series of lipophilic nucleosides comprising natural and non-natural bases that are π-conjugated to a short oligophenylene-ethynylene fragment has been synthesized. These bases comprise guanosine, isoguanosine, and 2-aminoadenosine as purine heterocycles, and cytidine, isocytosine and uridine as complementary pyrimidine bases. The hydrogen-bonding dimerization and association processes between complementary bases were also studied by (1)H NMR and absorption spectroscopy in order to obtain the relevant association constants.
Assuntos
Nucleosídeos/química , Polímeros/química , Adenosina/análogos & derivados , Adenosina/síntese química , Adenosina/química , Citosina/análogos & derivados , Citosina/síntese química , Citosina/química , Dimerização , Guanosina/síntese química , Guanosina/química , Ligação de Hidrogênio , Nucleosídeos/síntese química , Polímeros/síntese química , Uridina/síntese química , Uridina/químicaRESUMO
In this study we report the synthesis of C5/C6-fused uridine phosphonates that are structurally related to earlier reported allosteric P2Y2 receptor ligands. A silyl-Hilbert-Johnson reaction of six quinazoline-2,4-(1H,3H)-dione-like base moieties with a suitable ribofuranosephosphonate afforded the desired analogues after full deprotection. In contrast to the parent 5-(4-fluoropheny)uridine phosphonate, the present extended-base uridine phosphonates essentially failed to modulate the P2Y2 receptor.
Assuntos
Organofosfonatos/síntese química , Agonistas do Receptor Purinérgico P2Y/síntese química , Receptores Purinérgicos P2Y2/metabolismo , Uridina/síntese química , Regulação Alostérica , Astrócitos/citologia , Astrócitos/efeitos dos fármacos , Astrócitos/metabolismo , Linhagem Celular Tumoral , Humanos , Ligantes , Organofosfonatos/farmacologia , Agonistas do Receptor Purinérgico P2Y/farmacologia , Quinazolinas/química , Uridina/análogos & derivados , Uridina/farmacologiaRESUMO
A small library of ninety four uridine antibiotic analogs was synthesized, under the Pilot Scale Library (PSL) Program of the NIH Roadmap initiative, from amine 2 and carboxylic acids 33 and 77 in solution-phase fashion. Diverse aldehyde, sulfonyl chloride, and carboxylic acid reactant sets were condensed to 2, leading after acid-mediated hydrolysis, to the targeted compounds 3-32 in good yields and high purity. Similarly, treatment of 33 with diverse amines and sulfonamides gave 34-75. The coupling of the amino terminus of d-phenylalanine methyl ester to the free 5'-carboxylic acid moiety of 33 followed by sodium hydroxide treatment led to carboxylic acid analog 77. Hydrolysis of this material gave analog 78. The intermediate 77 served as the precursor for the preparation of novel dipeptidyl uridine analogs 79-99 through peptide coupling reactions to diverse amine reactants. None of the described compounds show significant anticancer or antimalarial acivity. A number of samples exhibited a variety of promising inhibitory, agonist, antagonist, or activator properties with enzymes and receptors in primary screens supplied and reported through the NIH MLPCN program.
Assuntos
Antibacterianos/química , Técnicas de Química Combinatória , Bibliotecas de Moléculas Pequenas/química , Uridina/análogos & derivados , Antibacterianos/síntese química , Antibacterianos/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/farmacologia , Humanos , Malária Falciparum/tratamento farmacológico , Plasmodium falciparum/efeitos dos fármacos , Bibliotecas de Moléculas Pequenas/síntese química , Bibliotecas de Moléculas Pequenas/farmacologia , Uridina/síntese química , Uridina/farmacologiaRESUMO
The insufficient penetration through the cell membranes is one of the major drawbacks of chemotherapeutics such as 5-fluorouracil (5-FU; 1). To improve the penetration, a useful strategy is the attachment of lipophilic moieties. Thus, we have synthesized a series of nucleolipid derivatives of 5-fluorouridine (5-FUrd; 2a), carrying lipophilic moieties at N(3) and/or at the 2',3'-O position, i.e., 3a, 3b, 4-7, and tested their cytostatic/cytotoxic activities towards three carcinoma cell lines (colon (HT-29), hepatocellular (HepG2), and renal (RENCA)) in comparison with 5-FU (1) and 5-FUrd (2a). After 48â h of incubation, four derivatives, 3a, 3b, 5, and 7, showed inhibitory effects on the survival of HT-29, HepG2, and RENCA cells. Additionally, to differentiate between anticancer and side-effects, we tested the cytotoxicity of the derivatives in human macrophages. Interestingly, the derivatives 4, 5, and 6 did not exhibit any effects on survival of THP-1 macrophages. Furthermore, we investigated the apoptosis induction of compound 1 and 2a, and the above-mentioned derivatives in HT-29 cells. Derivative 5 showed the highest significant (p<0.05; p<0.01) increase of the apoptosis at 80â µM after 2-h or 4-h treatment, as well as after 6-h incubation at 40â µM (p<0.05). Real-time PCR revealed that 40-µM derivative 5 showed a 1.8-fold increase of the pro-apoptotic caspase-3 gene and a twofold significant increase (p<0.01 and p<0.05 vs. control and 1, resp.) of the tumor suppressor TP53 gene, whereas the other compounds did not show any effect. We demonstrated that some 5-FUrd derivatives such as compound 5 are more effective than 5-FU or 5-FUrd concerning a cytotoxic (vs. cytostatic (5-FU, 5-FUrd)) effect on different cancer cell lines, but without cytotoxic side-effects on differentiated macrophages. Thus, compound 5 is suggested as a novel potent cytotoxic multi-anti-cancer drug.
Assuntos
Antineoplásicos/química , Uridina/análogos & derivados , Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Caspase 3/genética , Caspase 3/metabolismo , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Células HT29 , Células Hep G2 , Humanos , RNA Mensageiro/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Uridina/síntese química , Uridina/química , Uridina/farmacologiaRESUMO
The cancerostatic 5-fluorouridine (5-FUrd; 1) was sequentially sugar-protected by introduction of a 2',3'-O-heptylidene ketal group (â2), followed by 5'-O-monomethoxytritylation (â3). This fully protected derivative was submitted to Mitsunobu reactions with either phytol ((Z and E)-isomer) or nerol ((Z)-isomer) to yield the nucleoterpenes 4a and 4b. Both were 5'-O-deprotected with 2% Cl2 CHCOOH in CH2 Cl2 to yield compounds 5a and 5b, respectively. These were converted to the 5'-O-cyanoethyl phosphoramidites 6a and 6b, respectively. Moreover, the 2',3'-O-(1-nonyldecylidene) derivative, 7a, of 5-fluorouridine was resynthesized and labelled at C(5') with an Eterneon-480 fluorophor(®) (â7b). The resulting nucleolipid was studied with respect to its incorporation in an artificial bilayer, as well as to its aggregate formation. Additionally, two oligonucleotides carrying terminal phytol-alkylated 5-fluorouridine tags were prepared, one of which was studied concerning its incorporation in an artificial lipid bilayer.
Assuntos
Materiais Biocompatíveis/química , DNA/metabolismo , Fitol/química , Terpenos/química , Uridina/análogos & derivados , Monoterpenos Acíclicos , Materiais Biocompatíveis/metabolismo , DNA/química , Isomerismo , Bicamadas Lipídicas/química , Bicamadas Lipídicas/metabolismo , Oligonucleotídeos/química , Oligonucleotídeos/metabolismo , Uridina/síntese química , Uridina/químicaRESUMO
One of the major drawbacks of chemotherapeutics is their insufficient penetration through cell membranes due to a high hydrophobicity. Thus, we have synthesized a series of selected nucleolipid derivatives of 5-fluorouridine (5-FUrd; 2a), carrying lipophilic moieties at N(3) and/or in the 2',3'-O-position (i.e., 3a-7a and 3c), and tested their cytostatic/cytotoxic activities using HT-29 human colon carcinoma cells, in comparison with, e.g., 5-FU (1) and 5-FUrd (2a). Incorporation and intracellular localization of the substances under test were performed after conjugation with the fluorochrome Atto 425. We showed that all 5'-O-labelled Atto 425 derivatives were incorporated by the human HT-29 cells and accumulated in their cytoplasm. Moreover, after 24-h treatment of HT-29 human colon carcinoma cells, 1 or 2a (10, 20, 40, or 80â µM) revealed a significant (14-23 or 33-45%, resp.) decrease of the viability in comparison with the (negative) control. Interestingly, derivatives 3a and 3c (40 and 80â µM) led to a significant (77-95 or 89-96%, resp.) inhibition of survival of human HT29 cells, i.e., these two substances were ca. 63-72% or ca. 75%, respectively more effective than 5-FU (1; positive control). Furthermore, derivative 5a showed a significant, i.e., 30 and 86%, inhibition of the survival at 40 and 80â µM, respectively in comparison with the (negative) control. Some synthesized 5-FUrd derivatives turned out to be more effective than 5-FU (1) or 5-FUrd (2a).
Assuntos
Antineoplásicos/síntese química , Uridina/análogos & derivados , Antineoplásicos/química , Antineoplásicos/toxicidade , Sobrevivência Celular/efeitos dos fármacos , Neoplasias do Colo/metabolismo , Neoplasias do Colo/patologia , Células HT29 , Humanos , Microscopia Confocal , Uridina/síntese química , Uridina/química , Uridina/toxicidadeRESUMO
Steroid based cancer chemotherapeutic agents of the type 2'-amino-3'-cyanocholest-6-eno[5,7-de]4H-pyrans (1c-3c) have been synthesized and characterized by the various spectroscopic and analytical techniques. The DNA binding studies of compounds (1c-3c) with CT DNA were carried out by UV-vis and fluorescence spectroscopy and gel electrophoresis. The compounds (1c-3c) bind to DNA preferentially through electrostatic and hydrophobic interactions with Kb values found to be 5.4 × 10(3), 2.3 × 10(3)M(-1) and 1.97 × 10(3)M(-1), respectively indicating the higher binding affinity of compound (1c) towards DNA. The molecular docking study suggested that the electrostatic interaction of compounds (1c-3c) in between the nucleotide base pairs is due to the presence of pyran moiety in steroid molecule. All the compounds (1c-3c) cleave supercoiled pBR322 DNA via hydrolytic pathway, as validated by T4 DNA ligase assay. The compounds (1c-3c) were screened for in vitro cytotoxicity against the cancer and non-cancer cells SW480, A549, HepG2, HeLa, MCF-7, HL-60, DU-145, NL-20, HPC and HPLF by MTT assay. The compounds (1c-3c) were tested for genotoxicity (comet assay) involving apoptotic degradation of DNA and was analyzed by agarose gel electrophoresis and visualized by ethidium bromide staining. The results revealed that compound (1c) has better prospectus to act as cancer chemotherapeutic candidate which warrants further in vivo anticancer investigations.
Assuntos
Antineoplásicos/síntese química , Colestanos/síntese química , DNA/metabolismo , Piranos/química , Esteroides/química , Uridina/análogos & derivados , Antineoplásicos/metabolismo , Antineoplásicos/toxicidade , Apoptose/efeitos dos fármacos , Sítios de Ligação , Linhagem Celular Tumoral , Colestanos/metabolismo , Colestanos/toxicidade , Ensaio Cometa , DNA/química , Clivagem do DNA/efeitos dos fármacos , Células HL-60 , Células HeLa , Células Hep G2 , Humanos , Interações Hidrofóbicas e Hidrofílicas , Células MCF-7 , Simulação de Acoplamento Molecular , Conformação de Ácido Nucleico , Plasmídeos/química , Plasmídeos/metabolismo , Piranos/síntese química , Piranos/metabolismo , Piranos/toxicidade , Espécies Reativas de Oxigênio/metabolismo , Eletricidade Estática , Esteroides/síntese química , Esteroides/toxicidade , Uridina/síntese química , Uridina/metabolismo , Uridina/toxicidadeRESUMO
The 2',3'-O-levulinic acid derivative 2b of the cancerostatic 5-fluorouridine as well as its N(3)-farnesylated nucleolipid 2d were synthesized and coupled to H2 O-soluble chitosanes of different molecular weight and at various pH values (3.5-5.5) leading to 6 and 7. In addition, the coumarine fluorophore ATTO-488 N(9)-butanoate was bound to the biopolymer by a sequential-coupling technique to afford 9 and 10. Moreover, chitosan foils were prepared, to which 2b was coupled. Their degradation by chitosanase (from Streptomyces sp. N174) was studied UV-spectrophotometrically in a Franz diffusion cell.
Assuntos
Quitosana/química , Uridina/análogos & derivados , Concentração de Íons de Hidrogênio , Ácidos Levulínicos/química , Prenilação , Espectrofotometria Ultravioleta , Uridina/síntese química , Uridina/químicaRESUMO
In the present study, we carried out a structure-activity analysis in Trichomonas vaginalis of a series of adenosine and uridine analogues. The most potent compounds were found to be 2' and 3' modified adenosine analogues some of which are potent inhibitors of S-adenosylhomocysteine hydrolase. The 9-(2-deoxy-2-fluoro-ß,D-arabinofuranosyl)adenine compound was more potent than metronidazole, a current FDA approved and commonly prescribed drug for treatment of trichomoniasis. Its IC(50) was 0.09 µM compared to 0.72 µM for metronidazole.
Assuntos
Adenosina/análogos & derivados , Adenosina/síntese química , Adenosil-Homocisteinase/antagonistas & inibidores , Antiprotozoários/síntese química , Inibidores Enzimáticos/síntese química , Proteínas de Protozoários/antagonistas & inibidores , Trichomonas vaginalis/efeitos dos fármacos , Uridina/síntese química , Adenosina/farmacologia , Adenosil-Homocisteinase/metabolismo , Animais , Antiprotozoários/farmacologia , Células CHO , Técnicas de Cultura de Células , Sobrevivência Celular/efeitos dos fármacos , Cricetinae , Inibidores Enzimáticos/farmacologia , Humanos , Concentração Inibidora 50 , Metronidazol/farmacologia , Proteínas de Protozoários/metabolismo , Relação Estrutura-Atividade , Trichomonas vaginalis/crescimento & desenvolvimento , Uridina/análogos & derivados , Uridina/farmacologiaRESUMO
We synthesized various pH-responsive fluorescent deoxyuridine derivatives (1a-g). These fluorescent nucleosides exhibited distinctive fluorescence at 470-600 nm in aqueous solvents containing methanol only at acidic to neutral pH values. In particular, 1f exhibited strong fluorescence only at pH range of 3.1-7.2 with a pK(a) of 6.1. Such pH-sensitive fluorescent nucleosides can be used as 'on-off' fluorescence switch for monitoring pH change in biological systems, particularly for cancer cell detection.