RESUMEN

Graphene quantum dots (GQDs), nanomaterials derived from graphene and carbon dots, are highly stable, soluble, and have exceptional optical properties. Further, they have low toxicity and are excellent vehicles for carrying drugs or fluorescein dyes. Specific forms of GQDs can induce apoptosis and could be used to treat cancers. In this study, three forms of GQDs (GQD (nitrogen:carbon = 1:3), ortho-GQD, and meta-GQD) were screened and tested for their potential to inhibit breast cancer cell (MCF-7, BT-474, MDA-MB-231, and T-47D) growth. All three GQDs decreased cell viability after 72 h of treatment and specifically affected breast cancer cell proliferation. An assay for the expression of apoptotic proteins revealed that p21 and p27 were up-regulated (1.41-fold and 4.75-fold) after treatment. In particular, ortho-GQD-treated cells showed G2/M phase arrest. The GQDs specifically induced apoptosis in estrogen receptor-positive breast cancer cell lines. These results indicate that these GQDs induce apoptosis and G2/M cell cycle arrest in specific breast cancer subtypes and could potentially be used for treating breast cancers.

Asunto(s)

Apoptosis , Neoplasias de la Mama , Grafito , Puntos Cuánticos , Femenino , Humanos , Apoptosis/efectos de los fármacos , Neoplasias de la Mama/tratamiento farmacológico , Puntos de Control del Ciclo Celular , Grafito/farmacología , Grafito/uso terapéutico

RESUMEN

Herein, we report the identification, design, and synthesis of a series of 4-substituted 2-amino-3,4-dihydroquinazolines with hairpin turn side chains as novel inhibitors of BACE-1. The dihydroquinazoline derivatives were rationally designed by modifying the amide group and relocating the α -hydrophobic substituent on the hairpin turn side chain of lead compound 2 to the C4-position on the 3,4-dihydroquinazoline scaffold to facilitate interactions with the S1, S2 and S1' subsites of BACE-1. Among these derivatives, two compounds exhibited potent BACE-1 inhibitory activity: 4-methyl-substituted (22a, BACE-1 CFA IC50 = 0.38 µM; BACE-1 WCA IC50 = 0.14 µM) and 4-cyclohexylmethyl-substituted (22b, BACE-1 CFA IC50 = 0.49 µM; BACE-1 WCA IC50 = 0.14 µM) 2-amino-3,4-dihydroquinazoline, each bearing a side chain of N-cyclohexyl-N-((1-methyl-1H-pyrazol-4-yl)methyl amide. The results suggest that the structural modifications maintain the hairpin turn topology similar to that of compound 2 and provide an additional interaction with the S2 subsite.

Asunto(s)

Secretasas de la Proteína Precursora del Amiloide/antagonistas & inhibidores , Ácido Aspártico Endopeptidasas/antagonistas & inhibidores , Inhibidores Enzimáticos/farmacología , Secretasas de la Proteína Precursora del Amiloide/metabolismo , Ácido Aspártico Endopeptidasas/metabolismo , Línea Celular Tumoral , Relación Dosis-Respuesta a Droga , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Humanos , Modelos Moleculares , Conformación Molecular , Quinazolinas/síntesis química , Quinazolinas/farmacología , Relación Estructura-Actividad

RESUMEN

We demonstrate that the acrylamide group can be used to improve the drug-like properties of potential drug candidates. In the EGFR inhibitor development, both the solubility and membrane permeability properties of compounds 6a and 7, each containing an acrylamide group, were substantially better than those of gefitinib (1) and AZD3759 (2), respectively. We demonstrated that incorporation of an acrylamide moiety could serve as a good strategy for improving drug-like properties.

RESUMEN

Alzheimer's disease is a neurodegenerative disorder characterized by deposition of ß-amyloid (Aß) fibrils accompanied with progressive neurite loss. None of the clinically approved anti-Alzheimer's agents target both pathological processes. We hypothesized that conjugation of a metal chelator to destabilize Aß fibrils (fAßs) and a long-chain fatty alcohol to induce neurite outgrowth may generate a novel molecular scaffold that targets both pathologies. The hydroxyalkylquinoline J2326 was designed and synthesized by joining an 11-carbon alcohol to 5-chloro-8-methoxyquinoline at the 2-position and its anti-neurodegenerative potentials in vitro and in vivo were characterized. It attenuated fAß formation and disaggregated the existing fAß zinc-dependently as well as zinc-independently. It also triggered extracellular signal-regulated kinase-dependent neurite outgrowth and increased synaptic activity in neuronal cells. In fAß-driven neurodegeneration in vitro, J2326 reversed neurite collapse and neurotoxicity. These roles of J2326 were also demonstrated in vivo and were pivotal to the observed improvement in memory of mice with hippocampal fAß lesions. These results show that the effectiveness of J2326 on fAß-driven neurodegeneration is ascribed to its novel scaffold. This might give clues to evolving attractive therapy for future clinical trials.

Asunto(s)

Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/patología , Amiloide/metabolismo , Antipsicóticos/química , Antipsicóticos/uso terapéutico , Diseño de Fármacos , Modelos Moleculares , Neuritas/efectos de los fármacos , Animales , Cloruros/farmacología , Modelos Animales de Enfermedad , Alcoholes Grasos/farmacología , Ratones , Quinolinas/farmacología , Ratas , Transducción de Señal/efectos de los fármacos , Zinc/metabolismo , Compuestos de Zinc/farmacología

RESUMEN

A series of 6-acylureido derivatives containing a 3-(pyrrol-2-ylmethylidene)indolin-2-one scaffold were synthesized as potential dual Aurora B/FLT3 inhibitors by replacing the 6-arylureido moiety in 6-arylureidoindolin-2-one-based multi-kinase inhibitors. (Z)-N-(2-(pyrrolidin-1-yl)ethyl)-5-((6-(3-(2-fluoro-4-methoxybenzoyl)ureido)-2-oxoindolin-3-ylidene)methyl)-2,4-dimethyl-1H-pyrrole-3-carboxamide (54) was identified as a dual Aurora B/FLT3 inhibitor (IC50 = 0.4 nM and 0.5 nM, respectively). Compound 54 also exhibited potent cytotoxicity with single-digit nanomolar IC50 values against the FLT3 mutant-associated human acute myeloid leukemia (AML) cell lines MV4-11 (FLT3-ITD) and MOLM-13 (FLT3-ITD). Compound 54 also specifically induced extrinsic apoptosis by inhibiting the phosphorylation of the Aurora B and FLT3 pathways in MOLM-13 cells. Compound 54 had a moderate pharmacokinetic profile. The mesylate salt of 54 efficiently inhibited tumor growth and reduced the mortality of BALB/c nude mice (subcutaneous xenograft model) that had been implanted with AML MOLM-13 cells. Compound 54 is more potent than sunitinib not only against FLT3-WT AML cells but also active against sunitinib-resistant FLT3-ITD AML cells. This study demonstrates the significance of dual Aurora B/FLT3 inhibitors for the development of potential agents to treat AML.

Asunto(s)

Aurora Quinasa B/antagonistas & inhibidores , Diseño de Fármacos , Indoles/química , Indoles/farmacología , Leucemia Mieloide Aguda/tratamiento farmacológico , Tirosina Quinasa 3 Similar a fms/antagonistas & inhibidores , Animales , Antineoplásicos/síntesis química , Antineoplásicos/química , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Línea Celular Tumoral , Chlorocebus aethiops , Humanos , Indoles/síntesis química , Indoles/uso terapéutico , Masculino , Ratones , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/uso terapéutico , Células Vero , Ensayos Antitumor por Modelo de Xenoinjerto

RESUMEN

Bioisosteric replacement of acylureido moiety in 6-acylureido-3-pyrrolylmethylidene-2-oxoindoline derivatives resulted in a series of malonamido derivatives with indolin-2-one scaffold (11-14). Further conformational restrictions of the malonamido moiety led to 2-oxo-1,2-dihydropyridine (21-25) or a 4-oxo-1,4-dihydropyridine derivatives (31-36). 4-Oxo-1,4-dihydropyridine derivatives were more potent Aurora B inhibitors than their 2-oxo-1,2-dihydropyridine counterparts and demonstrated cytotoxicities against A549 and HepG2 cells in the submicromolar range. In A549 cells, 31h decreased phosphorylation of histone H3, triggered polyploidy, induced expression of pro-apoptotic Fas and FasL with subsequent activation of caspase 8, resulting into apoptosis. In a Huh7-xenograft mouse model, 31h demonstrated potent in vivo efficacy with a daily dose of 5 mg/kg.

Asunto(s)

Antineoplásicos/farmacología , Aurora Quinasa B/antagonistas & inhibidores , Dihidropiridinas/farmacología , Inhibidores Enzimáticos/farmacología , Indoles/química , Piridonas/química , Amidas/química , Antineoplásicos/síntesis química , Antineoplásicos/química , Apoptosis/efectos de los fármacos , Aurora Quinasa B/metabolismo , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Dihidropiridinas/síntesis química , Dihidropiridinas/química , Relación Dosis-Respuesta a Droga , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Células Hep G2 , Humanos , Malonatos/química , Estructura Molecular , Relación Estructura-Actividad , Urea/análogos & derivados , Urea/química , Ensayos Antitumor por Modelo de Xenoinjerto

RESUMEN

The metal ion chelating ß-N-hydroxy-γ-ketocarboxamide pharmacophore was integrated into a quinazolinone scaffold, leading to N-arylalkyl-3-hydroxy-4-oxo-3,4-dihydroquinazolin-2-carboxamide derivatives as hepatitis C virus (HCV) NS5B polymerase inhibitors. Lead optimization led to the identification of N-phenylpropyl carboxamide 9 k (IC(50) =8.8 µM). Compound 9 k possesses selectivity toward HCV1b replicon Ava.5 cells (EC(50) =17.5 µM) over parent Huh-7 cells (CC(50) =187.5 µM). Compound 9 k effects a mixed mode of NS5B inhibition, with NTP-competitive displacement properties. The interaction between 9 k and NS5B is stabilized by the presence of magnesium ions. Docking studies showed that the binding orientation of 9 k occupies the central portions of both magnesium-mediated and NTP-ribose-response binding sites within the active site region of NS5B. As a result, 3-hydroxy-4-oxo-3,4-dihydroquinazolin-2-carboxamide derivatives are disclosed herein as novel, mainly active site inhibitors of HCV NS5B polymerase.

Asunto(s)

Antivirales/química , Descubrimiento de Drogas , Hepacivirus , Quinazolinonas/química , Proteínas no Estructurales Virales/antagonistas & inhibidores , Antivirales/farmacología , Dominio Catalítico , Humanos , Modelos Moleculares , Estructura Molecular , Reacción en Cadena de la Polimerasa , Quinazolinonas/farmacología , Relación Estructura-Actividad

RESUMEN

3-(4-Bromophenyl)-6-nitrobenzo[1.3.2]dithiazolium ylide 1,1-dioxide (5) was discovered as a new prototype for dual inhibitors of cyclooxygenase-2 (COX-2) and 5-lipoxygenase (5-LOX). Thus, the structure-activity relationships of benzo[1.3.2]dithiazolium ylide 1,1-dioxide skeleton were carried out. The 6-NO(2) group played an essential role in the inhibitory activity. In addition, moderate-sized lipophilic substituents at the para-position of the 3-aryl moiety were required for dual COX-2/5-LOX inhibitory activity. Among the identified potent dual inhibitors, 3-(4-tbutylphenyl) derivative 30c (IC(50) values of 0.27 µM and 0.30 µM against COX-2 and 5-LOX, respectively) and 3-(4-biphenyl) derivative 30f (IC(50) values of 0.50 µM and 0.15µM against COX-2 and 5-LOX, respectively) were the most potent dual COX-2/5-LOX inhibitors. Intraperitoneal administration of 30c at 100mg/kg demonstrated potent acute anti-inflammatory activity. As a result, benzo[1.3.2]dithiazolium ylide 1,1-dioxide represented a novel scaffold for the exploitation in developing dual COX-2/5-LOX inhibitors.

Asunto(s)

Antiinflamatorios/química , Inhibidores de la Ciclooxigenasa 2/química , Inhibidores de la Lipooxigenasa/química , Tiazoles/química , Tiazoles/farmacología , Animales , Antiinflamatorios/síntesis química , Antiinflamatorios/farmacología , Araquidonato 5-Lipooxigenasa/metabolismo , Ciclooxigenasa 2/metabolismo , Inhibidores de la Ciclooxigenasa 2/síntesis química , Inhibidores de la Ciclooxigenasa 2/farmacología , Edema/tratamiento farmacológico , Humanos , Concentración 50 Inhibidora , Inhibidores de la Lipooxigenasa/síntesis química , Inhibidores de la Lipooxigenasa/farmacología , Espectroscopía de Resonancia Magnética , Masculino , Espectrometría de Masas , Estructura Molecular , Ratas , Ratas Wistar , Relación Estructura-Actividad , Tiazoles/síntesis química

RESUMEN

Mutations in the gene encoding the mitochondrial protein high temperature requirement A2 (HTRA2) are inconsistently associated with a risk of Parkinson's disease (PD). We assessed the presence of HTRA2 mutations among patients with PD and performed functional assay of identified mutations or variants. Among the total 1,373 subjects, the entire HTRA2 coding region was sequenced in 113 early-onset PD (EOPD), 20 familial PD patients and 150 control subjects. An additional 390 sporadic late-onset PD patients and 700 controls were subsequently screened to validate possible mutations found in the first set. We identified two novel heterozygous variants, c.427C > G (Pro143Ala) and c.906 +3 G > A, in 2 (1.5%) EOPD patients. The missense variant, Pro143Ala, was also observed in one late-onset PD patient but was absent in total 850 control subjects (relative risk 2.3, 95% CI 1.5-2.8, P = 0.04). Expressing Pro143Ala variant of HTRA2 in primary dopaminergic neurons causes neurite degeneration. Following exposure to rotenone, the ultra-structural mitochondrial abnormality, the percentage of mitochondrial dysfunction and apoptosis in cells carrying the HTRA2 Pro143Ala variant was significantly higher than wild-type cells. Mechanistically, protein level of phosphorylated HTRA2 was increased in cells carrying the Pro143Ala variant, suggesting Pro143Ala variant promotes HTRA2 phosphorylation with resultant mitochondrial dysfunction. Our results support a biologically relevant role of HTRA2 in PD susceptibility in Taiwanese. Further large-scale association studies are warranted to confirm the role of HTRA2 Pro143Ala variant in the risk of PD.

Asunto(s)

Mitocondrias/genética , Proteínas Mitocondriales/genética , Enfermedad de Parkinson/genética , Serina Endopeptidasas/genética , Adulto , Edad de Inicio , Apoptosis/genética , Pueblo Asiatico , Estudios de Casos y Controles , Neuronas Dopaminérgicas/patología , Salud de la Familia , Femenino , Predisposición Genética a la Enfermedad , Heterocigoto , Serina Peptidasa A2 que Requiere Temperaturas Altas , Humanos , Masculino , Persona de Mediana Edad , Mitocondrias/metabolismo , Proteínas Mitocondriales/metabolismo , Mutación , Enfermedad de Parkinson/epidemiología , Enfermedad de Parkinson/metabolismo , Enfermedad de Parkinson/patología , Fosforilación , Polimorfismo de Nucleótido Simple , Análisis de Secuencia/métodos , Análisis de Secuencia de ADN/métodos , Serina Endopeptidasas/metabolismo

Asunto(s)

Antineoplásicos/síntesis química , Indoles/síntesis química , Microtúbulos/química , Sulfonamidas/química , Sulfonamidas/síntesis química , Moduladores de Tubulina/síntesis química , Antineoplásicos/química , Antineoplásicos/toxicidad , División Celular , Línea Celular Tumoral , Ensayos de Selección de Medicamentos Antitumorales , Fase G2 , Humanos , Indoles/química , Indoles/toxicidad , Masculino , Microtúbulos/metabolismo , Neoplasias de la Próstata/tratamiento farmacológico , Neoplasias de la Próstata/metabolismo , Relación Estructura-Actividad , Sulfonamidas/toxicidad , Moduladores de Tubulina/química , Moduladores de Tubulina/toxicidad , Bencenosulfonamidas

RESUMEN

Comprehensive studies support the notion that selective inhibitors of cyclooxygenase-2 (COX-2) display anticancer activities in numerous types of cancer cells, including prostate cancers. Our previous study showed that the benzodithiazolium-based compound CX9051 selectively inhibited COX-2 activity. We now show that CX9051 inhibits cell proliferation and induces apoptosis in numerous human cancer cell types. Biochemical analyses, including flow cytometry, showed that CX9051 induced apoptosis in the absence of cell cycle checkpoint arrest and down-regulated the expression of Bcl-2, Bcl-x(L), and Mcl-1, but up-regulated tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) expression, leading to proteolytic activation of caspase-8, -9, -7, and -3. These data suggest that CX9051 functions in both mitochondria-mediated intrinsic and death receptor-induced extrinsic apoptosis pathways. Moreover, confocal microscopy demonstrated that CX9051 induced nuclear translocation of nuclear factor-kappa B (NF-kappaB) at initial stage and then caused a marked decrease of total cellular NF-kappaB at later stage in both PC-3 and DU145 cells. Taken together, our data suggest that CX9051 induces TRAIL up-regulation and activation of extrinsic apoptotic signaling, which in turn activates mitochondria-mediated intrinsic apoptotic signaling, leading to cancer cell apoptosis.

Asunto(s)

Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Benzotiazoles/farmacología , Óxidos S-Cíclicos/farmacología , Inhibidores de la Ciclooxigenasa 2/farmacología , Ciclooxigenasa 2/metabolismo , FN-kappa B/fisiología , Neoplasias de la Próstata/enzimología , Antineoplásicos/química , Benzotiazoles/química , Western Blotting , Caspasas/metabolismo , Técnicas de Cultivo de Célula , Línea Celular Tumoral , Núcleo Celular/efectos de los fármacos , Núcleo Celular/metabolismo , Proliferación Celular/efectos de los fármacos , Óxidos S-Cíclicos/química , Inhibidores de la Ciclooxigenasa 2/química , Fragmentación del ADN/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Ensayo de Inmunoadsorción Enzimática , Citometría de Flujo , Humanos , Etiquetado Corte-Fin in Situ , Masculino , FN-kappa B/metabolismo , Neoplasias de la Próstata/metabolismo , Neoplasias de la Próstata/patología , Receptores de Muerte Celular/metabolismo , Ligando Inductor de Apoptosis Relacionado con TNF/metabolismo

RESUMEN

A series of new ureidoindolin-2-one derivatives were synthesized and evaluated as inhibitors of receptor tyrosine kinases. Investigation of structure-activity relationships at positions 5, 6, and 7 of the oxindole skeleton led to the identification of 6-ureido-substituted 3-pyrrolemethylidene-2-oxindole derivatives that potently inhibited both the vascular endothelial growth factor receptor (VEGFR) and platelet-derived growth factor receptor (PDGFR) families of receptor tyrosine kinases. Several derivatives showed potency against the PDGFR inhibiting both its enzymatic and cellular functions in the single-digit nanomolar range. Among them, compound 35 was a potent inhibitor against tyrosine kinases, including VEGFR and PDGFR families, as well as Aurora kinases. Inhibitor 36 (non-substituted on the pyrrole or phenyl ring) had a moderate pharmacokinetic profile and completely inhibited tumor growth initiated with the myeloid leukemia cell line, MV4-11, in a subcutaneous xenograft model in BALB/c nude mice.

Asunto(s)

Receptores ErbB/antagonistas & inhibidores , Indoles/química , Inhibidores de Proteínas Quinasas/síntesis química , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Pirroles/química , Receptores del Factor de Crecimiento Derivado de Plaquetas/antagonistas & inhibidores , Urea/análogos & derivados , Animales , Aurora Quinasas , Sitios de Unión , Línea Celular Tumoral , Simulación por Computador , Ensayos de Selección de Medicamentos Antitumorales , Receptores ErbB/metabolismo , Humanos , Indoles/uso terapéutico , Indoles/toxicidad , Leucemia Mieloide/tratamiento farmacológico , Ratones , Oxindoles , Inhibidores de Proteínas Quinasas/uso terapéutico , Inhibidores de Proteínas Quinasas/toxicidad , Proteínas Serina-Treonina Quinasas/metabolismo , Pirroles/uso terapéutico , Pirroles/toxicidad , Receptores del Factor de Crecimiento Derivado de Plaquetas/metabolismo , Relación Estructura-Actividad , Trasplante Heterólogo , Urea/química , Urea/uso terapéutico , Urea/toxicidad

RESUMEN

Hepatitis C virus nonstructural protein 3 (HCV NS3) helicase is believed to be essential for viral replication and has become an attractive target for the development of antiviral drugs. A fluorescence resonant energy transfer helicase assay was established for fast screening of putative inhibitors selected from virtual screening using the program DOCK. Soluble blue HT (1) was first identified as a novel HCV helicase inhibitor. Crystal structure of the NS3 helicase in complex with soluble blue HT shows that the inhibitor bears a significantly higher binding affinity mainly through a 4-sulfonatophenylaminophenyl group, and this is consistent with the activity assay. Subsequently, fragment-based searches were utilized to identify triphenylmethane derivatives for more potent inhibitors. Lead optimization resulted in a 3-bromo-4-hydroxyl substituted derivative 12 with an EC(50) value of 2.72 microM to Ava.5/Huh-7 cells and a lower cytotoxicity to parental Huh-7 cells (CC(50) = 10.5 microM), and it indeed suppressed HCV replication in the HCV replicon cells. Therefore, these inhibitors with structural novelty may serve as a useful scaffold for the discovery of new HCV NS3 helicase inhibitors.

Asunto(s)

Descubrimiento de Drogas , Hepacivirus/enzimología , Inhibidores de Proteasas/química , Inhibidores de Proteasas/farmacología , Compuestos de Tritilo/química , Compuestos de Tritilo/farmacología , Proteínas no Estructurales Virales/antagonistas & inhibidores , Sitios de Unión , Línea Celular , Proliferación Celular/efectos de los fármacos , Evaluación Preclínica de Medicamentos , Hepacivirus/efectos de los fármacos , Modelos Moleculares , Replicón/efectos de los fármacos , Programas Informáticos , Proteínas no Estructurales Virales/química

RESUMEN

Derivatives of indolo[2,1-b]quinazolinone containing aminoalkylamino side chains were synthesized as specific DNA triplex stabilizing agents. The aminoalkylamino side chains are essential for triplex stabilization. The position-8 fluorine atom or a methyl group to the nitrogen adjacent to the planar core can enhance triplex stability by 6 degrees C and the effect is additive. Conformational analysis reveals that the orientation of the side chain underlies the ability of this compound to stabilize a DNA triplex.

Asunto(s)

ADN/química , ADN/efectos de los fármacos , Indoles/síntesis química , Indoles/farmacología , Quinazolinas/síntesis química , Quinazolinas/farmacología , Fenómenos Químicos , Química Física , Dicroismo Circular , Ligandos , Conformación de Ácido Nucleico/efectos de los fármacos , Espectrofotometría Ultravioleta

RESUMEN

A convenient and nonreductive deiodination is reported for the ortho-iodo-hydroxylated arenes including derivatives of quinolinol, phenol, and naphthol. Tertiary amines pyridine, triethylamine, and N-methylmorpholine in the presence of water initiated deiodination of ortho-iodo-hydroxylated arenes without affecting para-iodine and other reduction-susceptible groups. This reported method also works efficiently for polyiodinated systems. Simplicity, short reaction times, and absence of reducing catalyst are features of this method.

Asunto(s)

Aminas/química , Hidrocarburos Aromáticos/química , Yodo/química , Hidroxilación , Estructura Molecular , Oxidación-Reducción

RESUMEN

The Mitsunobu reaction was applied to prepare, in one step, purine N(3),5'-cyclonucleosides 10a-d. A subsequent ring opening in the ribose moiety of the resultant N(3),5'-nucleosides by sodium periodate led to the corresponding N(3),5'-cyclo-2',3'-seconucleosides. These products consist of 5-, 6-, and 7-membered tricyclic system which is the basic skeleton of TIBO derivatives, known antiviral agents.

Asunto(s)

Nucleósidos de Purina/síntesis química , Benzodiazepinas/síntesis química , Benzodiazepinas/química , Formicinas/química , Imidazoles/síntesis química , Imidazoles/química

RESUMEN

The omega-chloroalkylation of 2-substituted quinazolin-4(3H)-one derivatives 1 and 2 with Br-(CH(2))(n)-Cl (n = 2-4) and the intramolecular imidate-amide rearrangement of the alkylated products are described. At room temperature, the 2-phenyl substituent promoted O-alkylation, whereas the less steric 2-benzyl group led to a higher ratio of N-alkylation. The investigation of the O-alkylated products, 4-omega-chloroalkoxyquinazolines, revealed that the migration of omega-chloroethyl and omega-chloropropyl groups from oxygen to nitrogen should be intramolecular via five- and six-membered cyclic 1,3-azaoxonium intermediates, respectively. Competition between rearrangement and nucleophilic substitution results in the formation of 7a,b and 8a,b from the nucleophilic substitution of 4a,b and 6a,b, respectively.

Asunto(s)

Técnicas Químicas Combinatorias , Quinazolinas/química , Alquilación , Indicadores y Reactivos , Nitrógeno/química , Oxígeno/química , Estereoisomerismo , Temperatura