RESUMEN
A novel series of tricyclic gamma-secretase inhibitors was designed and synthesized via a conformational analysis of literature compounds. The preliminary results have shown that compounds in this new series have much improved in vitro potency and in vivo profiles. More importantly, they have greatly reduced Notch related toxicity that was associated with previous gamma-secretase inhibitors.
Asunto(s)
Secretasas de la Proteína Precursora del Amiloide/antagonistas & inhibidores , Receptores Notch/efectos de los fármacos , Sulfonas/química , Sulfonas/farmacología , Animales , Cristalografía por Rayos X , Diseño de Fármacos , Ratones , Modelos Moleculares , Sulfonas/síntesis químicaRESUMEN
A series of spiro-piperidine azetidinone were synthesized and evaluated as potential TRPV1 antagonists. An important issue of plasma stability was investigated and resolved. Further focused SAR study lead to the discovery of a potent antagonist with good oral pharmacokinetic profile in rat.
Asunto(s)
Azetidinas/síntesis química , Azetidinas/farmacocinética , Química Farmacéutica/métodos , Compuestos de Espiro/síntesis química , Compuestos de Espiro/farmacología , Canales Catiónicos TRPV/antagonistas & inhibidores , Administración Oral , Animales , Diseño de Fármacos , Concentración de Iones de Hidrógeno , Concentración 50 Inhibidora , Modelos Químicos , Ratas , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
[reaction: see text] A highly stereoselective synthesis of beta-amino sulfones and sulfonamides via addition of sulfonyl anions to chiral N-sulfinyl imines is described. The addition reaction proceeds in good yield (75-99%) and stereoselectivity.
RESUMEN
[structure: see text] A highly efficient and practical synthesis of 4,4-Disubstituted-2-Imidazolidinones utilizing a "self-reproduction of the center of chirality" strategy is described.
RESUMEN
Himbacine (1), a complex piperidine alkaloid isolated from the bark of Australian magnolias, is a promising lead in Alzheimer's disease research due to its potent muscarinic receptor antagonist property. We have described here a highly efficient synthetic strategy that resulted in the total synthesis of himbacine (1) in about 10% overall yield and isohimbacine (1a), an unnatural isomer of himbacine, in 18% overall yield. The total synthesis of himbacine was initially approached using an intramolecular Diels-Alder reaction as the key step to generate intermediate 5 followed by a [3 + 2] cycloaddition with nitrone 4 to produce the isoxazolidine derivative 3. Methylation followed by catalytic reduction of 3 gave 12'-hydroxyhimbacine (20), which, upon dehydration, gave isohimbacine (1a) as the sole product. In an alternative approach, an all-encompassing intramolecular Diels-Alder reaction of an appropriately substituted tetraene derivative 31, which bears the entire latent carbon framework and functional group substitution of himbacine, gave the desired advanced tricyclic intermediate 33, which was readily converted to (+)-himbeline (2) and (+)-himbacine (1).
RESUMEN
Using a bioactivity-guided fractionation procedure, five cembranolides, 11-epi-sinulariolide acetate (1), 11-dehydrosinulariolide (2), sinulariolide (3), dihydrosinularin (4), and 3,4:8,11-bisepoxy-7-acetoxycembra-15(17)-en-1,12-olide (5), along with two nucleosides, 2'-deoxyadenosine and thymidine, were isolated from the Formosan soft coral Sinularia flexibilis. Moreover, 7,8-epoxy-11-epi-sinulariolide acetate (1a), 11-sinulariolide acetate (3a), dihydrosinulariolide (3b), 3,4:8,11-bisepoxy-7-hydroxycembra-15(17)-en-1,12-olide (3c), 11-acetoxyl-15(17)-dihydrosinulariolide (3d), 7,8-epoxy-11-sinulariolide acetate (3e), and 3,4:8,11-bisepoxy-7-hydroxycembra-15(17)-dihydro-1,12-olide (3f) were derived from compounds 1 and 3, respectively. These structures were deduced on the basis of physical and chemical evidence. Among them, 1a, 3d, 3e, and 3f are new cembranolide analogues. The structure of compound 1 was further confirmed by X-ray analysis. In addition, the isolated cembranolides and the analogues under went a cytotoxicity assay, and the structure-activity relationship (SAR) of these compounds was studied.
Asunto(s)
Antozoos/química , Diterpenos/aislamiento & purificación , Diterpenos/toxicidad , Diterpenos/química , Humanos , Pruebas de Toxicidad , Células Tumorales CultivadasRESUMEN
In the present paper, design, synthesis, X-ray crystallographic analysis, and HIV-1 protease inhibitory activities of a novel class of compounds are disclosed. Compounds 28-30, 32, 35, and 40 were synthesized and found to be inhibitors of the HIV-1 protease. The crucial step in their synthesis involved an unusual endo radical cyclization process. Absolute stereochemistry of the three asymmetric centers in the above compounds have been established to be (4S,2'R,3'S) for optimal potency. X-ray crystallographic analysis has been used to determine the binding mode of the inhibitors to the HIV-1 protease.
Asunto(s)
Carbamatos/síntesis química , Inhibidores de la Proteasa del VIH/síntesis química , Proteasa del VIH/química , Modelos Moleculares , Tiazepinas/síntesis química , Carbamatos/química , Cristalografía por Rayos X , Diseño de Fármacos , Inhibidores de la Proteasa del VIH/química , Estructura Molecular , Unión Proteica , Conformación Proteica , Estereoisomerismo , Relación Estructura-Actividad , Tiazepinas/químicaRESUMEN
HCV infection affects more than 170 million people worldwide and many of those patients will reach the end stage complications of the disease which include hepatocarcinoma and liver failure. The success rate for treatment of patients infected with genotype-1 is about 40%. Therefore, novel treatments are needed to combat the infection. The HCV NS3 protease inhibitor Boceprevir (1) was reported by our research group and efforts continue for the discovery of more potent compounds with improved pharmacokinetic profiles. A new series of HCV NS3 protease inhibitors having a cyclic sulfone P3-cap have been discovered. Compounds 43 and 44 showed K(i)* values in the single-digit nM range and their cellular potency was improved by 10-fold compared to 1. The pharmacokinetic profiles of 43 and 44 in rats and monkeys were also improved to achieve higher plasma levels after oral administration.
Asunto(s)
Hepacivirus/enzimología , Oligopéptidos/síntesis química , Inhibidores de Serina Proteinasa/síntesis química , Sulfonas/síntesis química , Administración Oral , Animales , Cristalografía por Rayos X , Haplorrinos , Modelos Moleculares , Oligopéptidos/farmacocinética , Oligopéptidos/farmacología , Ratas , Inhibidores de Serina Proteinasa/farmacocinética , Inhibidores de Serina Proteinasa/farmacología , Estereoisomerismo , Relación Estructura-Actividad , Sulfonas/farmacocinética , Sulfonas/farmacologíaRESUMEN
The synthesis and biological activity of a novel series of thrombin receptor antagonists is described. This series of compounds showed excellent in vitro and in vivo potency. The most potent compound 40 had an IC(50) of 7.6 nM and showed robust inhibition of platelet aggregation in a cynomolgus monkey model after oral administration.
Asunto(s)
Alcaloides/farmacología , Química Farmacéutica/métodos , Furanos/farmacología , Naftalenos/farmacología , Parasimpatolíticos/farmacología , Piperidinas/farmacología , Receptores de Trombina/antagonistas & inhibidores , Administración Oral , Alcaloides/química , Animales , Área Bajo la Curva , Furanos/química , Concentración 50 Inhibidora , Ligandos , Macaca fascicularis , Modelos Químicos , Naftalenos/química , Parasimpatolíticos/química , Piperidinas/química , Agregación Plaquetaria/efectos de los fármacos , Unión Proteica , Ratas , Trombina/químicaRESUMEN
Attachment of the cyclopropylcarbamate group to the piperidine core of gamma-secretase inhibitors leads to a dramatic increase of their in vitro potency. Strategies for subsequent improvement of the in vivo pharmacokinetic profile of the series are discussed. Resulting compounds significantly reduce Abeta levels in TgCRND8 mice after a single PO dosing at 30 mpk.
Asunto(s)
Enfermedad de Alzheimer/tratamiento farmacológico , Secretasas de la Proteína Precursora del Amiloide/antagonistas & inhibidores , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/uso terapéutico , Péptidos beta-Amiloides/antagonistas & inhibidores , Péptidos beta-Amiloides/biosíntesis , Precursor de Proteína beta-Amiloide/metabolismo , Animales , Área Bajo la Curva , Cristalografía por Rayos X , Inhibidores Enzimáticos/farmacocinética , Humanos , Indicadores y Reactivos , Espectroscopía de Resonancia Magnética , Ratones , Ratones Transgénicos , Modelos Moleculares , Conformación Molecular , Ratas , Relación Estructura-ActividadRESUMEN
Two novel chemokine receptor CCR-5 inhibitors, Sch 210971 (1) and Sch 210972 (2), were isolated from the fungal fermentation broth of Chaetomium globosum by normal- and reversed-phase HPLC purifications. The structure determination of 1 and 2 was accomplished on the basis of UV, MS, and NMR spectral data analyses including COSY, NOESY, HMQC, and HMBC experiments. The structure and relative configuration of 2 were determined unequivocally by X-ray crystallographic analysis. The major component 2 demonstrated a potent inhibitory activity of IC(50) = 79 nM in the CCR-5 receptor in vitro binding assay.
Asunto(s)
Fármacos Anti-VIH/farmacología , Antagonistas de los Receptores CCR5 , Chaetomium/química , Compuestos Heterocíclicos de 4 o más Anillos/farmacología , Fármacos Anti-VIH/química , Fármacos Anti-VIH/aislamiento & purificación , Arizona , Cristalografía por Rayos X , Compuestos Heterocíclicos de 4 o más Anillos/química , Compuestos Heterocíclicos de 4 o más Anillos/aislamiento & purificación , Humanos , Concentración 50 Inhibidora , Estructura Molecular , Hojas de la Planta/química , Espectrometría de Masa por Ionización de ElectrosprayRESUMEN
The structure-activity relationship (SAR) of the lactone ring of himbacine derived thrombin receptor (PAR-1) antagonists (e.g., 2-5) is described. The effect of the lactone carbonyl group on binding to PAR-1 is dependent on the substitution pattern of the pyridine ring. A stereoselective intramolecular Michael addition reaction to the vinyl pyridine group was observed for these pyridine analogs of himbacine in basic conditions at elevated temperature.
Asunto(s)
Alcaloides/química , Furanos/química , Lactonas/química , Naftalenos/química , Piperidinas/química , Receptor PAR-1/antagonistas & inhibidores , Concentración 50 Inhibidora , Estructura Molecular , Receptor PAR-1/metabolismo , Relación Estructura-ActividadRESUMEN
Conformational and stereochemical analysis of six new symmetrical dimers was performed using proton-proton vicinal coupling measured from (1)H NMR and (13)C satellites of (1)H NMR signals, natural abundance (13)C-edited nuclear overhauser effect (NOE) experiments, comprehensive NOE analysis and molecular modeling. The (13)C satellite analysis and (13)C-edited NOE experiments were carried out to extract spectral information between equivalent protons. Molecular modeling was applied for estimations of three-dimensional parameters of the studied dimers, which were subsequently used to generate a set of theoretical NOE for each possible conformation. The J-coupling, (13)C-edited NOE and quantitative NOE analyses showed the predominance of gauche conformation for three dimers, whereas a mixture of gauche and anti conformations (45:55) for three other dimers was established by quantitative NOE analysis. X-ray crystallographic study confirmed the stereochemistry of one of the dimers and revealed a discrepancy in conformation stability between liquid and solid states.
Asunto(s)
Cristalografía/métodos , Hidrocarburos/química , Espectroscopía de Resonancia Magnética/métodos , Modelos Moleculares , Isótopos de Carbono , Simulación por Computador , Dimerización , Hidrocarburos/análisis , Conformación Molecular , ProtonesRESUMEN
A novel synthesis of cis and trans substituted 4-tert-butoxycarbonyl cyclohexylglycines via asymmetric aminohydroxylation of vinyl styrene followed by reduction of the aromatic ring and subsequent oxidation is reported.
Asunto(s)
Glicina/análogos & derivados , Glicina/síntesis química , Catálisis , Química Orgánica/métodos , Cristalografía por Rayos X , Ciclización , Conformación Molecular , Estructura Molecular , Resonancia Magnética Nuclear Biomolecular , Oxidación-Reducción , Estereoisomerismo , Estirenos/química , Compuestos de Vinilo/químicaRESUMEN
The synthesis of a biaryl ether containing macrocyclic depsipeptide 1 was achieved in 6% overall yield. The desired macrocycle was constructed by cyclization of a phenol into eta(6)-ruthenium complex. The ruthenium metal was subsequently photolytically deprotected to obtain the macrocycle 1.
Asunto(s)
Péptidos Cíclicos/síntesis química , Rutenio/química , Catálisis , Cromatografía en Capa Delgada , Técnicas Químicas Combinatorias/métodos , Cristalografía por Rayos X , Ciclización , Ésteres/síntesis química , Éteres/síntesis química , Resonancia Magnética Nuclear BiomolecularRESUMEN
N-Acetylcolchinol methyl ether 1 served as the starting material to prepare the chloroacetamide (3) and epoxide (5) analogues. Both 3 and 5 were potent inhibitors of tubulin polymerization in vitro. Compound 3 was also 4-fold more cytotoxic than colchicine against the 1A9 tumor cell line and showed a unique cross-resistance profile.
Asunto(s)
Antineoplásicos/síntesis química , Antineoplásicos/farmacología , Colchicina/análogos & derivados , Colchicina/síntesis química , Colchicina/farmacología , Tubulina (Proteína)/efectos de los fármacos , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Indicadores y Reactivos , Modelos Moleculares , Conformación Molecular , Células Tumorales CultivadasRESUMEN
A novel primase inhibitor, Sch 642305 (1), was isolated from the fermentation broth of the fungal culture Penicillium verrucosum. The structure of 1 was elucidated on the basis of MS and NMR spectroscopic data as a new and unusual bicyclic 10-membered macrolide. The absolute configuration of the asymmetric centers was determined by X-ray crystallographic analysis of the p-bromobenzoate derivative (3). Compound 1 exhibited inhibitory activity against bacterial DNA primase enzyme with an EC(50) of 70 microM.
Asunto(s)
ADN Primasa/antagonistas & inhibidores , Inhibidores Enzimáticos/aislamiento & purificación , Inhibidores Enzimáticos/farmacología , Macrólidos/aislamiento & purificación , Macrólidos/farmacología , Penicillium/química , Arizona , Cristalografía por Rayos X , Inhibidores Enzimáticos/química , Fermentación , Macrólidos/química , Conformación Molecular , Estructura Molecular , Resonancia Magnética Nuclear BiomolecularRESUMEN
In a continuing study to isolate novel antitumor agents from rainforest plants, three new isopropenylfurano-beta-naphthoquinones, designated lantalucratins A (1), B (2), and C (3), and three new isoprenyl-alpha-naphthoquinones, designated lantalucratins D (4), E (5), and F (6), were isolated from Lantana involucrata. Their structures were determined on the basis of NMR and X-ray crystallographic analyses. Compounds 1 and 2 showed cytotoxic activities against various human tumor cell lines, including drug-resistant variants, with IC50 values of 1.0-4.9 microM.
Asunto(s)
Antineoplásicos Fitogénicos/aislamiento & purificación , Lantana/química , Naftoquinonas/aislamiento & purificación , Plantas Medicinales/química , Antineoplásicos Fitogénicos/química , Antineoplásicos Fitogénicos/farmacología , Resistencia a Antineoplásicos , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Concentración 50 Inhibidora , Estructura Molecular , Naftoquinonas/química , Naftoquinonas/farmacología , Resonancia Magnética Nuclear Biomolecular , Puerto Rico , Células Tumorales CultivadasRESUMEN
The synthesis and binding affinity for hNK(1) and hNK(2) receptors of a series of diacyl substituted 2-aryl piperazines are described. SAR evaluation led to the racemic derivative 11g as an apparent dual inhibitor. Chiral chromatographic separation of 11g led to the observation that NK(1) activity was shown by one enantiomer (13a) and NK(2) activity was shown by the other enantiomer (13b). X-ray crystallographic analysis of the crystalline di-BOC derivative of the NK(2) active piperazine (15) showed that the 2R configuration was associated with NK(2) activity. Further derivatization indicated that dual NK(1)/NK(2) activity could be built into the 2R series.