RESUMEN
Scoring changes in enzyme or pathway performance by their effect on growth behavior is a widely applied strategy for identifying improved biocatalysts. While in directed evolution this strategy is powerful in removing non-functional catalysts in selections, measuring subtle differences in growth behavior remains difficult at high throughput, as it is difficult to focus metabolic control on only one or a few enzymatic steps over the entire process of growth-based discrimination. Here, we demonstrate successful miniaturization of a growth-based directed enzyme evolution process. For cultivation of library clones we employed optically clear gel-like microcarriers of nanoliter volume (NLRs) as reaction vessels and used fluorescence-assisted particle sorting to estimate the growth behavior of each of the gel-embedded clones in a highly parallelized fashion. We demonstrate that the growth behavior correlates with the desired improvements in enzyme performance and that we can fine-tune selection stringency by including an antimetabolite in the assay. As a model enzyme reaction, we improve the racemization of ornithine, a possible starting block for the large-scale synthesis of sulphostin, by a broad-spectrum amino acid racemase and confirm the discriminatory power by showing that even moderately improved enzyme variants can be readily identified.
Asunto(s)
Isomerasas de Aminoácido , Antimetabolitos , Evolución Molecular Dirigida , Compuestos Organofosforados , Piperidonas , Ingeniería de Proteínas , Isomerasas de Aminoácido/química , Isomerasas de Aminoácido/genética , Antimetabolitos/síntesis química , Antimetabolitos/química , Compuestos Organofosforados/síntesis química , Compuestos Organofosforados/química , Piperidonas/síntesis química , Piperidonas/químicaRESUMEN
A first synthesis of a new class of novel cytosine thioglycoside analogs from readily available starting materials has been described. The key step of this protocol is the formation of sodium pyrimidine-4-thiolate via condensation of N'-arylidene-2-cyanoacetohydrazides with sodium cyanocarbonimidodithioate salt, followed by coupling with halo sugars to give the corresponding cytosine thioglycoside analogs. Ammonolysis of the latter compounds afforded the free thioglycosides.
Asunto(s)
Antimetabolitos/síntesis química , Citosina/análogos & derivados , Tioglicósidos/síntesis química , Citosina/síntesis químicaRESUMEN
This review first outlines general considerations on phosphinic acids and derivatives as bioisosteric groups. The next sections present key aspects of phosphinic acid-based molecules and include a brief description of the biological pathways involved for their activities. The synthetic aspects and the biological activities of such compounds reported in the literature between 2008 and 2013 are also described.
Asunto(s)
Ácidos Fosfínicos , Animales , Antiinfecciosos/síntesis química , Antiinfecciosos/farmacología , Antimetabolitos/síntesis química , Antimetabolitos/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/farmacología , Antivirales/síntesis química , Antivirales/farmacología , Ácidos Carboxílicos/química , Portadores de Fármacos/síntesis química , Portadores de Fármacos/farmacología , Antagonistas de Aminoácidos Excitadores/síntesis química , Antagonistas de Aminoácidos Excitadores/farmacología , Moduladores del GABA/síntesis química , Moduladores del GABA/farmacología , Herbicidas/síntesis química , Herbicidas/farmacología , Humanos , Ácidos Fosfínicos/síntesis química , Ácidos Fosfínicos/farmacología , Ácidos Fosfóricos/química , Poaceae/efectos de los fármacos , Poaceae/crecimiento & desarrollo , EstereoisomerismoRESUMEN
Recent advances in microbial genomics, synthetic organic chemistry and X-ray crystallography provided opportunities to identify novel antibacterial targets for the development of new classes of antibiotics and to design more potent antimicrobial compounds derived from existing antibiotics in clinical use for decades. The antimetabolites, sulfa drugs and trimethoprim (TMP)-like agents, are inhibitors of three families of enzymes. One family belongs to the carbonic anhydrases, which catalyze a simple but physiologically relevant reaction in all life kingdoms, carbon dioxide hydration to bicarbonate and protons. The other two enzyme families are involved in the synthesis of tetrahydrofolate (THF), i.e. dihydropteroate synthase (DHPS) and dihydrofolate reductase. The antibacterial agents belonging to the THF and DHPS inhibitors were developed decades ago and present significant bacterial resistance problems. However, the molecular mechanisms of drug resistance both to sulfa drugs and TMP-like inhibitors were understood in detail only recently, when several X-ray crystal structures of such enzymes in complex with their inhibitors were reported. Here, we revue the state of the art in the field of antibacterials based on inhibitors of these three enzyme families.
Asunto(s)
Antimetabolitos/farmacología , Proteínas Bacterianas/antagonistas & inhibidores , Anhidrasas Carbónicas/química , Dihidropteroato Sintasa/antagonistas & inhibidores , Sulfanilamidas/farmacología , Tetrahidrofolato Deshidrogenasa/química , Trimetoprim/farmacología , Antibacterianos/síntesis química , Antibacterianos/farmacología , Antimetabolitos/síntesis química , Bacterias/efectos de los fármacos , Bacterias/enzimología , Proteínas Bacterianas/química , Inhibidores de Anhidrasa Carbónica/síntesis química , Inhibidores de Anhidrasa Carbónica/farmacología , Dihidropteroato Sintasa/química , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , Antagonistas del Ácido Fólico/síntesis química , Antagonistas del Ácido Fólico/farmacología , Sulfanilamidas/síntesis química , Trimetoprim/análogos & derivados , Trimetoprim/síntesis químicaRESUMEN
Currently available antiviral drugs frequently induce side-effects or selection of drug-resistant viruses. We describe a novel antiviral principle based on targeting the cellular enzyme dihydroorotate dehydrogenase (DHODH). In silico drug design and biochemical evaluation identified Compound 1 (Cmp1) as a selective inhibitor of human DHODH in vitro (IC50 1.5±0.2nM). Crystallization data specified the mode of drug-target interaction. Importantly, Cmp1 displayed a very potent antiviral activity that could be reversed by co-application of uridine or other pyrimidine precursors, underlining the postulated DHODH-directed mode of activity. Human and animal cytomegaloviruses as well as adenoviruses showed strong sensitivity towards Cmp1 in cell culture-based infection systems with IC50 values in the low micromolar to nanomolar range. Particularly, broad inhibitory activity was demonstrated for various types of laboratory and clinically relevant adenoviruses. For replication of human cytomegalovirus in primary fibroblasts, antiviral mode of activity was attributed to the early stage of gene expression. A mouse in vivo model proved reduced replication of murine cytomegalovirus in various organs upon Cmp1 treatment. These findings suggested Cmp1 as drug candidate and validated DHODH as a promising cellular target for antiviral therapy.
Asunto(s)
Antimetabolitos/farmacología , Antivirales/farmacología , Diseño de Fármacos , Evaluación Preclínica de Medicamentos/métodos , Inhibidores Enzimáticos/farmacología , Oxidorreductasas actuantes sobre Donantes de Grupo CH-CH/antagonistas & inhibidores , Pirimidinas/biosíntesis , Adenovirus Humanos/efectos de los fármacos , Animales , Antimetabolitos/síntesis química , Antimetabolitos/química , Antivirales/síntesis química , Antivirales/química , Células Cultivadas , Simulación por Computador , Citomegalovirus/efectos de los fármacos , Dihidroorotato Deshidrogenasa , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Fibroblastos/efectos de los fármacos , Fibroblastos/enzimología , Fibroblastos/virología , Ganciclovir/farmacología , Herpesviridae/efectos de los fármacos , Humanos , Concentración 50 Inhibidora , Ratones , Modelos Moleculares , Estructura Molecular , Organismos Libres de Patógenos Específicos , Relación Estructura-Actividad , Virus Vaccinia/efectos de los fármacos , Cultivo de VirusRESUMEN
Atherosclerosis is a condition resulting from the accumulation of oxidized low-density lipoproteins (oxLDLs) in arterial walls. Previously developed macromolecules consisting of alkyl chains and polyethylene glycol (PEG) on a mucic acid backbone, termed nanolipoblockers (NLBs) are hypothesized to mitigate the uptake of oxLDL by macrophage scavenger receptors. In this work, we developed a coarse grained model to characterize the interactions between NLBs with a segment of human scavenger receptor A (SR-A), a key receptor domain that regulates cholesterol uptake and foam cell conversion of macrophages, and studied NLB ability to block oxLDL uptake in PBMC macrophages. We focused on four different NLB configurations with variable molecular charge, charge location, and degree of NLB micellization. Kinetic studies showed that three of the four NLBs form micelles within 300 ns and of sizes comparable to literature results. In the presence of SR-A, micelle-forming NLBs interacted with the receptor primarily in an aggregated state rather than as single unimers. The model showed that incorporation of an anionic charge near the NLB mucic acid head resulted in enhanced interaction with the proposed binding pocket of SR-A compared to uncharged NLBs. By contrast, NLBs with an anionic charge located at the PEG tail showed no interaction increase as NLB aggregates were predominately observed to interact away from the oxLDL binding site. Additionally, using two different methods to assess the number of contacts that each NLB type formed with SR-A, we found that the rank order of contacts coincided with our experimental flow cytometry results evaluating the ability of the different NLBs to block the uptake of oxLDL.
Asunto(s)
Antimetabolitos/farmacología , Lipoproteínas LDL/metabolismo , Macrófagos/metabolismo , Simulación de Dinámica Molecular , Polietilenglicoles/farmacología , Receptores Depuradores de Clase A/química , Antimetabolitos/síntesis química , Sitios de Unión , Células Cultivadas , Evaluación Preclínica de Medicamentos , Humanos , Lipoproteínas LDL/antagonistas & inhibidores , Macrófagos/efectos de los fármacos , Micelas , Conformación Molecular , Polietilenglicoles/síntesis química , Unión Proteica , Receptores Depuradores de Clase A/metabolismo , Azúcares Ácidos/síntesis química , Azúcares Ácidos/farmacologíaRESUMEN
A novel anti-proliferative macromolecular conjugate, CS-g-MMCs, was synthesized in order to decrease the cytotoxicity of Mitomycin C (MMC) which was a traditional anti-proliferative agent of fibroblast in trabeculectomy. The structure of CS-g-MMCs was characterized by (1)H NMR, FT-IR spectroscopy and GPC analysis. The grafting degree (dg) of MMC onto chitosan (CS) was determined to be in the range of 2.8-11.3%, which could be controlled by variation of the molar ratios of MMC to oxidized chitosan (CS-CHO). In the drug release profiles of CS-g-MMCs in vitro, an initial burst followed by slow leakage was observed, and addition of acid or lysozyme obviously accelerated the MMC release. The MTS assay indicated that CS-CHO of 8 mg/ml has no cytotoxicity against human Tenon's capsule fibroblasts (HTCFs). The inhibition of HTCFs proliferation by CS-g-MMCs increased along with increasing the dg of conjugate. The CS-g-MMCs also caused the apoptosis of HTCFs and interfered in the active DNA synthesis in HTCFs. Furthermore, the expression of a-SMA at gene and protein levels were obviously lower when HTCFs were treated with CS-g-MMCs, as compared to MMC or blend of MMC/CS-CHO (p<0.05). Our results primarily demonstrated that the CS-g-MMCs conjugates have low cytotoxicity and have the effect to inhibit fibroblast proliferation.
Asunto(s)
Antimetabolitos/farmacología , Proliferación Celular/efectos de los fármacos , Quitosano/farmacología , Portadores de Fármacos , Fibroblastos/efectos de los fármacos , Mitomicina/farmacología , Cápsula de Tenon/efectos de los fármacos , Actinas/genética , Actinas/metabolismo , Adolescente , Adulto , Antimetabolitos/síntesis química , Antimetabolitos/toxicidad , Apoptosis/efectos de los fármacos , Movimiento Celular/efectos de los fármacos , Células Cultivadas , Química Farmacéutica , Quitosano/análogos & derivados , Quitosano/síntesis química , Quitosano/toxicidad , Cromatografía en Gel , Replicación del ADN/efectos de los fármacos , Preparaciones de Acción Retardada , Relación Dosis-Respuesta a Droga , Femenino , Fibroblastos/patología , Regulación de la Expresión Génica , Humanos , Concentración de Iones de Hidrógeno , Cinética , Espectroscopía de Resonancia Magnética , Masculino , Persona de Mediana Edad , Mitomicina/síntesis química , Mitomicina/toxicidad , Muramidasa/química , Solubilidad , Espectroscopía Infrarroja por Transformada de Fourier , Tecnología Farmacéutica/métodos , Cápsula de Tenon/patología , Adulto JovenRESUMEN
The oligopeptide transporter PEPT1 is considered as a valuable target for prodrug design, but its 3D structure and substrate specificity of PEPT1 are not fully understood. In this study, we designed a focused dipeptide conjugated azidothymidine (AZT) library and described a convenient and efficient solid phase synthesis scheme based on click chemistry. Over 60 candidate structures containing various dipeptide sequences were obtained with high purity, and screened in a PEPT1 overexpressing cell model for their abilities to compete with the known ligand cephalexin. Some of the compounds selected to have medium or high affinity were tested for their in vivo transport in a single-pass intestinal perfusion experiment. Results showed that the designed library contained some new structure features that have high affinities toward PEPT1 and could be further explored for their application in prodrug design and development.
Asunto(s)
Antimetabolitos/química , Dipéptidos/química , Dipéptidos/metabolismo , Simportadores/metabolismo , Zidovudina/química , Antimetabolitos/síntesis química , Antimetabolitos/metabolismo , Dipéptidos/síntesis química , Células HeLa , Humanos , Transportador de Péptidos 1 , Técnicas de Síntesis en Fase Sólida , Zidovudina/síntesis química , Zidovudina/metabolismoRESUMEN
A murine P388 leukemia line fully resistant to thiarabine was obtained after five courses of intraperitoneal treatment (daily for nine consecutive days). The subline was sensitive as was the parental P388/0 line to 5-fluorouracil, gemcitabine, cyclophosphamide, cisplatin, melphalan, BCNU, mitomycin C, doxorubicin, mitoxantrone, etoposide, irinotecan, vincristine, and paclitaxel, but was cross resistant (at least marginally) to three antimetabolites: palmO-ara-C, fludarabine phosphate, and methotrexate. The deoxycytidine kinase activity in the subline was comparable to that for P388/0, whereas the dCMP deaminase activity was 43% of that for P388/0. No deoxycytidine deaminase activity was detected in either of the leukemias. There appeared to be little, if any, difference in the metabolism of deoxycytidine, cytidine, or thiarabine in the two leukemias.
Asunto(s)
Antimetabolitos/administración & dosificación , Antineoplásicos/administración & dosificación , Arabinonucleotidos/administración & dosificación , Línea Celular Tumoral/efectos de los fármacos , Resistencia a Antineoplásicos/efectos de los fármacos , Animales , Antimetabolitos/síntesis química , Antineoplásicos/química , Arabinonucleotidos/síntesis química , Línea Celular Tumoral/citología , Línea Celular Tumoral/enzimología , DCMP Desaminasa/metabolismo , Desoxicitidina Quinasa/metabolismo , Femenino , Leucemia P388 , Ratones , Trasplante de Neoplasias , Trasplante HeterólogoRESUMEN
A set of hydroxamate derivatives of folic acid and methotrexate (MTX) was synthesized and evaluated for the inhibitory activity against histone deacetylase (HDAC) and dihydrofolate reductase (DHFR), two enzymes overexpressed in metastasizing tumors. The synthesized compounds were further screened for their antiproliferative activity in two human cancer cell lines, A549 (non-small cell lung carcinoma) and PC-3 (prostate adenocarcinoma). All derivatives showed significant inhibitory activity against HDACs (micromolar range) while only the MTX derivative was reasonably effective in DHFR inhibition. A docking study provided insight into the binding mode of the most potent inhibitor in the active sites of the enzymes, allowing rationalization of the bioassays. The MTX-based compound could be of interest for testing against metastasizing tumors in an animal model. The studied derivatives represent promising molecular templates for further development of dual activity anti-cancer drugs.
Asunto(s)
Antineoplásicos/síntesis química , Inhibidores Enzimáticos/síntesis química , Antagonistas del Ácido Fólico/síntesis química , Ácido Fólico/síntesis química , Ácidos Hidroxámicos/síntesis química , Proteínas Represoras/antagonistas & inhibidores , Antimetabolitos/síntesis química , Antimetabolitos/química , Antimetabolitos/farmacología , Antineoplásicos/química , Antineoplásicos/metabolismo , Antineoplásicos/farmacología , Línea Celular Tumoral , Ensayos de Selección de Medicamentos Antitumorales , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/metabolismo , Inhibidores Enzimáticos/farmacología , Ácido Fólico/análogos & derivados , Ácido Fólico/química , Ácido Fólico/metabolismo , Ácido Fólico/farmacología , Antagonistas del Ácido Fólico/química , Antagonistas del Ácido Fólico/metabolismo , Antagonistas del Ácido Fólico/farmacología , Células HeLa , Histona Desacetilasas/química , Histona Desacetilasas/metabolismo , Humanos , Ácidos Hidroxámicos/química , Ácidos Hidroxámicos/metabolismo , Ácidos Hidroxámicos/farmacología , Masculino , Metotrexato/análogos & derivados , Metotrexato/química , Metotrexato/farmacología , Terapia Molecular Dirigida , Neoplasias/tratamiento farmacológico , Neoplasias/fisiopatología , Relación Estructura-Actividad , Tetrahidrofolato Deshidrogenasa/química , Tetrahidrofolato Deshidrogenasa/metabolismoRESUMEN
De acordo com a Organização Mundial da Saúde, AIDS, malária e tuberculose são as três maiores doenças infectantes do mundo, atingindo principalmente crianças. Regiões paupérrimas e de clima tropical, como a África sub-saariana, são as mais atingidas. Este quadro agrava-se com a disseminação de cepas do Plasmodium falcíparum resistentes à cloroquina e multi-resistentes. Além disso, alguns fármacos utilizados na terapêutica da malária apresentam vários efeitos adversos, comprometendo o tratamento. Trata-se de um grande desafio e o seu enfrentamento requer estratégias. O desenvolvimento de novos quimioterápicos deve fundamentar-se em diferenças bioquímicas e morfológicas entre as células do hospedeiro e do parasita. A biossíntese de fosfolipídeos de membrana em parasitas do grupo Apicomplexa é de extrema importância para a maturação e a reprodução do parasita e constitui-se em bom alvo para novos antimaláricos, uma vez que é encontrada somente em parasitas. Hemácias infectadas têm sua absorção modificada em relação aos eritrócitos não-infectados, conferindo seletividade a substâncias como lipídeos. O trabalho em questão propõe a síntese de antimetabólitos da serina, visando à inibição das enzimas fosfatidilserina síntase e serina descarboxilase, fundamentais para a biossíntese de fosfolipídeos de membrana desses parasitas. Cinco derivados heterocíclicos da serine foram sintetizados: derivados diidroimidazólico, diidroxazólico, diidroxazínico, diidropirimidínico e diidrooxatiólico. Também, o transportador fosfolipídico com o ácido esteárico foi sintetizado. Os antimetabólitos serão acoplados a esse e outros fosfolípídeos, obtendo-se fármacos dirigidos específicos direcionados seletivamente a eritrócitos infectados...
Asunto(s)
Antimaláricos/síntesis química , Antimaláricos/uso terapéutico , Antimetabolitos/síntesis química , Fosfolípidos/biosíntesis , Técnicas In Vitro , Malaria/epidemiología , Malaria/tratamiento farmacológico , Plasmodium falciparum/genética , Serina/farmacocinética , Serina/síntesis química , Química Farmacéutica , Cromatografía/métodos , Cromatografía , Relación Estructura-ActividadRESUMEN
A potential radiopharmaceutical and HSV1-TK substrate, 3-((1,3-dihydroxypropan-2-yloxy)-methyl)-6-(4-(3-((2-mercaptoethyl)(2-(2-mercaptoethyl-amino)-ethyl)amino)propoxy)phenyl)-3H-imidazopurin-9(5H)-one-oxo-technetium(V), was synthesized via a converging approach and its chemical structure was comparatively characterized with a non-radioactive analog. The final radiochemical purity and yield were 97 and 73%, respectively.
Asunto(s)
Antimetabolitos/síntesis química , Ganciclovir/análogos & derivados , Genes Reporteros/genética , Compuestos de Organotecnecio/síntesis química , Radiofármacos/síntesis química , Cromatografía Líquida de Alta Presión , Ganciclovir/síntesis química , Expresión Génica , Herpesvirus Humano 1/enzimología , Indicadores y Reactivos , Espectroscopía de Resonancia Magnética , Espectrometría de Masas , Tecnecio/química , Timidina Quinasa/metabolismoRESUMEN
The first synthesis of 1'-fluoronucleosides, which has long been synthetic targets as the potential antimetabolites, was achieved. Electrophilic fluorination of the 1'-position of a 1'-ketouridine derivative, followed by reduction of the 2'-keto-moiety, gave the protected 1'-fluorouridine derivative and its arabino-type congener. Alternatively, nucleophilic fluorination of a 1'-phenyselenouridine derivative with DAST/NBS produced the protected 1'-fluorouridine and its alpha-anomer.
Asunto(s)
Antimetabolitos/síntesis química , Flúor/química , Uridina/análogos & derivados , Antimetabolitos/química , Uridina/síntesis química , Uridina/químicaRESUMEN
Pyrazole nucleosides and condensed pyrazole nucleosides exhibit various biological activities. This article describes recent synthetic approaches to their preparation, chemical properties, biological activities, and structure-activity relationships, with emphasis to selected drugs or drug candidates. Two pyrazole C-nucleoside compounds pyrazofurin (pyrazomycin) and its alpha-epimer pyrazofurin B are active components of potent antivirals approved for therapeutic use in human medicine aimed against various diseases caused by DNA viruses.
Asunto(s)
Antimetabolitos/síntesis química , Antivirales/síntesis química , Virus ADN , Pirazoles/síntesis química , Ribonucleósidos/síntesis química , Virosis/tratamiento farmacológico , Amidas , Antimetabolitos/química , Antimetabolitos/uso terapéutico , Antivirales/química , Antivirales/uso terapéutico , Pirazoles/química , Pirazoles/uso terapéutico , Ribonucleósidos/química , Ribonucleósidos/uso terapéutico , Ribosa , Relación Estructura-ActividadRESUMEN
In an attempt to improve the AzA selectivity of the 2-(aryl)alkylthio derivatives of adenosine, we planned the synthesis of the corresponding derivatives of the 5-N-ethylcarboxamidoadenosine (NECA). For this purpose, we designed the synthesis of 2-mercapto-NECA to be pursued by means of an opening-closure method We obtained the open AICAR analog; however, ring closure efforts failed to give the desired compound. The newly synthesized AICAR derivative could potentially be endowed with antiviral or antitumoral activity.
Asunto(s)
Aminoimidazol Carboxamida/análogos & derivados , Antimetabolitos/síntesis química , Ribonucleótidos/síntesis química , Adenosina-5'-(N-etilcarboxamida)/síntesis química , Adenosina-5'-(N-etilcarboxamida)/farmacología , Aminoimidazol Carboxamida/síntesis química , Aminoimidazol Carboxamida/farmacología , Antimetabolitos/farmacología , Antineoplásicos/síntesis química , Antivirales/síntesis química , Química Farmacéutica/métodos , Diseño de Fármacos , Modelos Químicos , Ribonucleótidos/farmacologíaRESUMEN
In order to obtain new compounds with potential antibacterial activity some new (sulfonamidophenyl)-amide derivatives of N-(m-nitrobenzoil)-D,L-asparagine have been synthesized. The compounds have been obtained by decyclization reaction of 2-(m-nitrophenyl)-4-(beta-amidomethyl)-delta2-oxazolinone with various sulfonamides. A toxicity study with determination of DL50 value has also been realized.
Asunto(s)
Asparagina/síntesis química , Asparagina/toxicidad , Sulfonamidas/síntesis química , Sulfonamidas/toxicidad , Animales , Antibacterianos/síntesis química , Antibacterianos/farmacología , Antimetabolitos/síntesis química , Antimetabolitos/farmacología , Asparagina/análogos & derivados , Dosificación Letal Mediana , Masculino , Ratones , Modelos AnimalesRESUMEN
Purine antimetabolites have been very successful therapeutic agents against a host of infectious diseases and malignancies. Success of the treatment relies as much on the efficient accumulation by the target cell or organism as it does on selective action on a vital biochemical pathway of the target cell. Here we compare the ability of a new class of tricyclic purine antimetabolites to interact with transporters from human erythrocytes or Trypanosoma brucei. We show that these compounds display a remarkable selectivity for the parasite's transporters. The adenine analogue showed greater trypanocidal activity than the hypoxanthine or guanine analogues in vitro.
Asunto(s)
Antimetabolitos/metabolismo , Purinas/metabolismo , Alopurinol/farmacología , Animales , Antimetabolitos/síntesis química , Transporte Biológico , Relación Dosis-Respuesta a Droga , Eritrocitos/metabolismo , Humanos , Cinética , Modelos Químicos , Proteínas de Transporte de Nucleobases/química , Oxazinas/farmacología , Purinas/química , Ratas , Trypanosoma brucei brucei , Xantenos/farmacologíaRESUMEN
A series of potentially biologically active fluorinated uracil derivatives has been prepared in three steps from oxazolines and fluorinated nitriles with good chemical yields.
Asunto(s)
Uracilo/análogos & derivados , Antimetabolitos/síntesis química , Hidrocarburos Fluorados/química , Nitrilos/química , Oxazoles/química , Uracilo/síntesis químicaRESUMEN
N-nicotinyl-2-(5-fluorouracil-1-yl)-D,L-glycine (NFG) and N-isonicotinyl-2-(5-fluorouracil-1-yl)-D,L-glycine (INFG) were synthesized as colon-specific prodrugs of 5-fluorouracil (5-FU). As N-aromatic acyl amides of glycine, they are expected to be stable in the upper intestine and delivered to the colon as an intact form if they are nonabsorbable. Microbial hydrolysis of amide bond in the colon will give 2-(5-fluorouracil)-D,L-glycine, which releases 5-FU by spontaneous decomposition. NFG and INFG were soluble in water and stable in pH 1.2 and 7.4 buffer solutions. The apparent partition coefficient of NFG or INFG in 1-octanol/pH 7.4 phosphate buffer solution at 37 degrees was 0.025 or 0.024, respectively. On incubation with cecal contents of rats, conversion of NFG or INFG proceeded only 9 or 5% in 8 h, respectively, producing 5-FU and a metabolite. The metabolite formation was inhibited in the presence of diazouracil, a dihydrouracil dehydrogenase inhibitor. The HPLC retention time of the metabolite from the incubation of 5-FU, NFG, or INFG with cecal contents was identical to dihydro-5-fluorouracil (dihydro-5FU). When N-nicotinyl-2-hydroxy-D,L-glycine methyl ester (NHGM) was incubated with the cecal contents, the extent of amide bond hydrolysis was 85% in 24 h. The result suggested that steric hindrance imposed by 5-FU at 2-position of glycine retarded the hydrolysis of the amide bond in NFG or INFG and suppressed the prodrug conversion.