RESUMEN
A direct C(sp2)-H amination of 2-furanones under metal-free conditions was realized. This unprecedented intermolecular C-H to C-N conversion provides rapid access to 4-amino-furanone derivatives and novel aza-heterocycle fused furanone skeletons. A redox mechanism based on a double-Michael-addition intermediate INT2 is proposed and detected by spectrometry.
Asunto(s)
Furanos/química , Elementos de Transición/química , Aminación , Catálisis , Oxidación-ReducciónRESUMEN
On the basis of the application of proline-boronic acid as pharmacophore in the kinase inhibitors and our previous research results, using proline-boronic acid as warhead, two series of peptide proline-boronic acids, dipeptide proline-boronic acids (I) and tripeptide proline-boronic acids (II), were designed and synthesized. All the synthesized compounds were first evaluated for their biological activity against MGC803 cell, and then, the best compound II-7 was selected to test its anti-tumor spectrum on six human tumor cell lines and proteasome inhibition against three subunits. The results indicated that series II have much better biological activities than series I. The compound II-7 exhibited not only excellent biological activities with IC50 values of nM level in both cell and proteasome models, but also much better subunit selectivity. Thus, proline-boronic acid as warhead is reasonable in the design of proteasome inhibitors.
Asunto(s)
Ácidos Borónicos/farmacología , Prolina/química , Inhibidores de Proteasoma/farmacología , Ácidos Borónicos/química , Espectroscopía de Resonancia Magnética con Carbono-13 , Línea Celular Tumoral , Humanos , Inhibidores de Proteasoma/síntesis química , Inhibidores de Proteasoma/química , Espectroscopía de Protones por Resonancia Magnética , Relación Estructura-ActividadRESUMEN
A novel four-component one-pot approach for the synthesis of 2-amino-1,3,4-thiadiazoles from primary amines, carbon disulfide, hydrazine, and acyl chlorides has been developed. A series of 5-substituted-2-amino-1,3,4-thiadiazoles were synthesized in medium-to-good yields utilizing this newly developed method.
Asunto(s)
Técnicas de Química Sintética , Tiadiazoles/síntesis química , Agua/químicaRESUMEN
Two series of dithiocarbamic acid esters, 4-anilinoquinazoline-6-ylmethylcarbamodithioic acid esters and 3-cyano-4-anilinoquinolin-6-ylmethylcarbamodithioic acid esters, were designed and synthesized. The effect of the synthesized compounds on cell proliferation was evaluated by MTT assay against three human cancer cell lines: MDA-MB-468, SK-BR-3 and HCT-116. Most of the compounds are equally or more potent than the positive control lapatinib. Three compounds (14d, 14h and 14i) were identified as dual inhibitors of the EGFR and ErbB-2 kinases and two compounds (14b and 14c) were identified as multi-target kinase inhibitors, and they are very worthy of further study. Installation of the dithiocarbamic acid ester group at the 6-position of 4-anilinoquinazoline or 3-cyano-4-anilinoquinoline could improve the inhibitory activity. Different dithiocarbamic acid ester groups significantly affect the activities.
Asunto(s)
Antineoplásicos/farmacología , Receptores ErbB/antagonistas & inhibidores , Quinazolinas/farmacología , Quinolinas/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/química , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/patología , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Neoplasias del Colon/tratamiento farmacológico , Neoplasias del Colon/patología , Ésteres/síntesis química , Ésteres/química , Ésteres/farmacología , Femenino , Células HCT116 , Humanos , Lapatinib , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/farmacología , Quinazolinas/síntesis química , Quinazolinas/química , Quinolinas/síntesis química , Quinolinas/química , Relación Estructura-ActividadRESUMEN
A convenient and practical method for the synthesis of 2-alkylthio-4-amino-5-cyano-6-aryl(alkyl)pyrimidines has been developed via a three-component, one-pot reaction from aldehydes, malononitrile and S-alkylisothiouronium salts in water at room temperature. A series of polysubstituted pyrimidines were prepared by this method in moderate to excellent yields. In addition, two kinds of pyrimidine-fused heterocyclic derivatives with potential pharmacological activity were constructed from our 2-alkylthio-4-amino-5-cyano-6-arylpyrimidines.
Asunto(s)
Técnicas de Química Sintética/métodos , Pirimidinas/química , Pirimidinas/síntesis química , Agua/química , Aldehídos/química , Nitrilos/químicaRESUMEN
The direct asymmetric aldol reactions of equivalent molar amounts of aldehydes and ketones were carried out at -20 degrees C over alkaline Al(2)O(3) with 20 mol % of Pro-Trp as catalyst and 20 mol % of N-methylmorpholine or 1,4-diazabicyclo[2.2.2]octane as additive. After simple and environmentally friendly work-up, moderate to high isolated yields (up to 95%), good diastereoselectivities (>99:1), and enantioselectivities (up to 98% ee) have been achieved for the reactions of different kinds of ketones with various aldehydes. The catalytic system could be reused without decrease of activity by addition of 10 mol % catalyst and base in the catalytic system.
Asunto(s)
Aldehídos/química , Dipéptidos/química , Cetonas/química , Óxido de Aluminio/química , CatálisisRESUMEN
A series of tripeptide boronate proteasome inhibitors were designed and synthesized on the basis of our previously built tripeptide aldehyde 3D-QSAR models. All the synthesized compounds were evaluated for their proteasome-inhibitory activities in an isolated 20S rabbit proteasome, and selected compounds were evaluated for their antitumor activities in vitro against four human cancer cell lines. Biological results showed bulky and negative substituents at P(2) position improved the proteasome-inhibitory potency obviously, which completely conformed to the theoretical models, while those at P(3) position thoroughly deviated from the 3D-QSAR model. Most of the screened compounds showed less than 1 nM inhibitory potency and high selectivity against 20S proteasome, of which 7f is the most potent (IC(50)=0.079 nM) and twofold more active than bortezomib (IC(50)=0.161 nM). Cell viability indicated hydrophilic 4-hydroxyphenyl substituent at P(2) or P(3) position was not favorable to the cellular activities. Especially for the two hematologic cancer cell lines, HL-60 and U266, 7f inhibited them at the level of less than 10 nM and was more potent than the control bortezomib. It is being considered a promising new lead to be developed for the treatment of various cancers.
Asunto(s)
Ácidos Borónicos/síntesis química , Diseño de Fármacos , Oligopéptidos/síntesis química , Inhibidores de Proteasas/síntesis química , Inhibidores de Proteasoma , Animales , Ácidos Borónicos/farmacología , Línea Celular Tumoral , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Concentración 50 Inhibidora , Oligopéptidos/farmacología , Inhibidores de Proteasas/farmacología , Relación Estructura-Actividad Cuantitativa , ConejosRESUMEN
A series of novel compounds with phosphoramide mustard functionality incorporated into the quinazoline scaffold of EGFR/HER2 inhibitors were designed and synthesized as multi-target-directed ligands against tumor cells. In vitro assays showed that tumor cell lines with high HER2 level were more sensitive to the compounds than tumor cells with low HER2 level. Compound 10d (EMB-3) was one of the most potent inhibitors with IC50 of 7.4 nM and 82 nM against EGFR and HER2, respectively. The mechanism studies were also supported by the effect of 10d-induced DNA damage in MDA-MB-468 cells. In vivo efficacy study showed that 10d could significantly inhibit H522 tumor xenograft model with a TGI of 68% at dose of 100 mg/kg (QDx28, p.o.) and no significant body weight loss was observed. MTD study indicated that compound 10d had no acute toxicity to mice at doses up to 900 mg/kg (single dose).
Asunto(s)
Antineoplásicos/síntesis química , Antineoplásicos/farmacología , Diseño de Fármacos , Mostazas de Fosforamida/síntesis química , Mostazas de Fosforamida/farmacología , Quinazolinas/química , Animales , Antineoplásicos/química , Antineoplásicos/farmacocinética , Línea Celular Tumoral , Técnicas de Química Sintética , Relación Dosis-Respuesta a Droga , Humanos , Masculino , Ratones , Mostazas de Fosforamida/química , Mostazas de Fosforamida/farmacocinética , Ratas , Relación Estructura-Actividad , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
A novel class of urea-containing peptide boronic acids as proteasome inhibitors was designed by introducing a urea scaffold to replace an amido bond. Compounds were synthesized and their antitumor activities were evaluated. After two rounds of optimizations, the compound I-14 was found to be a potent proteasome inhibitor. Compared with Bortezomib, I-14 showed higher potency against the chymotrypsin-like activity of human 20S proteasome (IC50 < 1 pM), similar potency against four different cancer cell lines (IC50 < 10 nM), and better pharmacokinetic profile. Furthermore, I-14 significantly inhibited tumor growth in Bel7404 mouse xenograft model. The excellent proteasome inhibition by I-14 was rationalized through docking and molecular dynamics studies.
Asunto(s)
Ácidos Borónicos/farmacología , Péptidos/farmacología , Inhibidores de Proteasoma/química , Animales , Antineoplásicos , Ácidos Borónicos/química , Línea Celular Tumoral , Xenoinjertos , Humanos , Ratones , Simulación del Acoplamiento Molecular , Simulación de Dinámica Molecular , Péptidos/química , Complejo de la Endopetidasa Proteasomal/efectos de los fármacos , Inhibidores de Proteasoma/farmacocinética , Urea/química , Urea/farmacologíaRESUMEN
Four new pregnane glycosides, stelmatocryptonoside A, B, C, and D (1-4), were isolated from the stems of Stelmatocrypton khasianum. On the basis of chemical and spectral data, the structures of 1-4 were established as 3beta, 16alpha-dihydroxy-pregn-5-en-20-one-16-O-beta-D-glucopyranosyl-(1-->2)-[beta-D-glucopyranosyl-(1-->6)]-beta-D-glucopyranosyl-(1-->6)-beta-D-glucopyranoside; 3beta, 20-dihydroxy-pregn-5-en-20-beta-D-glucopyranosyl-(1-->6)-beta-D-glucopyranosyl-(1-->6)-beta-D-glucopyranosyl-(1-->2)-beta-D-digitalopyranoside; 3beta, 16alpha-dihydroxy-pregn-5-en-20-one-16-O-beta-D-glucopyranosyl-(1-->2)-beta-D-glucopyranosyl-(1-->6)-beta-D-glucopyranoside; and 3beta, 16alpha-dihydroxy-pregn-5-en-20-one-16-O-beta-D-glucopyranosyl-(1-->6)-beta-D-glucopyranosyl-(1-->6)-beta-D-glucopyranoside. This is the first report of pregnane glycosides with sugar chains linked at C-16 of the aglycone.
Asunto(s)
Glicósidos/aislamiento & purificación , Extractos Vegetales/química , Plantas Medicinales/química , Pregnanos/aislamiento & purificación , Glicósidos/química , Espectroscopía de Resonancia Magnética , Modelos Químicos , Estructura Molecular , Pregnanos/químicaRESUMEN
The free-radical addition of 2,3,4,6-tetra-O-acetyl-beta-D-galactopyranosyl-(1-->4)-2,3,6-tri-O-acetyl-1-thio-beta-D-glucopyranose to the allyl ether functions of p-methoxyphenyl per-O-allyl-D-galactopyranoside, D-glucopyranoside, and lactoside provides a concise and effective route for synthesis of glycoside clusters, of use for exploring anti-metastatic activity.
Asunto(s)
Glicósidos/síntesis química , Galactosa/química , Glicósidos/química , Espectroscopía de Resonancia MagnéticaRESUMEN
OBJECTIVE: To study the chemical constituents from the leaves of Eucommia ulmoides. METHOD: The constituents were isolated by chromatography method and the structures were identified on the basis of spectral analysis. RESULT: Six compounds, ursolic acid(1), beta-sitosterol(2), p-coumaric(3), caffeic acid ethyl ester(4), chlorogenic acid(5) and syringin(6) were obtained. CONCLUSION: Compound 3, 4, 5 were obtained from the plant for the first time.
Asunto(s)
Ácidos Cafeicos/aislamiento & purificación , Ácido Clorogénico/aislamiento & purificación , Ácidos Cumáricos/aislamiento & purificación , Eucommiaceae/química , Plantas Medicinales/química , Ácidos Cafeicos/química , Ácido Clorogénico/química , Ácidos Cumáricos/química , Hojas de la Planta/química , PropionatosRESUMEN
The highly efficient asymmetric Michael addition reactions of cyclopentanone with chalcones were catalyzed by a simple and commercially available chiral 1,2-diaminocyclohexane-hexanedioic acid, and exhibited good yields (up to 92%) and excellent enantioselectivities (up to 99% ee). A new di-iminium mechanism for the reaction was proposed.
Asunto(s)
Chalcona/química , Ciclopentanos/química , Catálisis , Estereoisomerismo , Especificidad por Sustrato , TemperaturaRESUMEN
The first direct organocatalytic asymmetric vinylogous Michael addition reactions of gamma-butenolides to chalcones have been developed by using chiral 1,2-diaminocyclohexane as a novel organocatalyst via a di-iminium transition state to provide syn-Michael products with good yields, high diastereoselectivities and enantioselectivities (up to 78% yield, >99 : 1 dr and 96% ee).
Asunto(s)
4-Butirolactona/análogos & derivados , Chalconas/química , 4-Butirolactona/química , Catálisis , Cristalografía por Rayos X , Modelos Moleculares , EstereoisomerismoRESUMEN
Two novel classes of monospirocyclopiperazinium salts were designed, synthesized, and evaluated for their in vivo analgesic activities. Some interesting structure-activity relationships are revealed: (1) Spirocyclopiperazinium moiety is favorable to improve the analgesic activity; (2) The size and conformation of spirocyclopiperazinium moiety significantly affects the analgesic activity; (3) Phenylethyl group of 3d is a crucial pharmacophore. Among the compounds synthesized, 3d exhibited the most potent activity with low toxicity. Further antinociceptive mechanism studies of 3d showed that these compounds will be a new kind of analgesics.
Asunto(s)
Analgésicos/química , Analgésicos/síntesis química , Piperazinas/química , Piperazinas/síntesis química , Compuestos de Espiro/química , Analgésicos/farmacología , Animales , Yoduro de Dimetilfenilpiperazina/química , Yoduro de Dimetilfenilpiperazina/farmacología , Evaluación Preclínica de Medicamentos , Ratones , Estructura Molecular , Dimensión del Dolor , Piperazinas/farmacología , Sales (Química) , Compuestos de Espiro/farmacología , Relación Estructura-ActividadRESUMEN
A novel class of cyclophosphamide spiropiperaziniums was synthesized and evaluated for their in vivo anti-cancer activities against S180 and H22. Most of them exhibited definite activities. Especially, compounds 8b and 8k showed good anti-cancer activities, meanwhile, 8k also showed much lower toxicity than CP. Several interesting structure-activity relationships were revealed.
Asunto(s)
Antineoplásicos/síntesis química , Antineoplásicos/farmacología , Ciclofosfamida/síntesis química , Ciclofosfamida/farmacología , Piperazinas/síntesis química , Piperazinas/farmacología , Compuestos de Espiro/síntesis química , Compuestos de Espiro/farmacología , Animales , Ciclofosfamida/análogos & derivados , Concentración 50 Inhibidora , Ratones , Profármacos , Relación Estructura-ActividadRESUMEN
A variety of 4-N atom substituted derivatives were synthesized and evaluated for their in vitro anticancer activities using 4-methylpiperazine-1-carbodithioic acid 3-cyano-3,3-diphenyl-propyl ester 4 as lead compound. Among them, compound 6a without any substituent on 4-N atom (R(1) = H) was found to be the most active anticancer agent with IC(50) = 5.3 microM against HL-60 and IC(50) = 11.5 microM against Bel-7402, respectively. Increase in the polarity and/or introduction of suitable acyl groups at the 4-N atom of the lead compound 4 are favorable for the improvement of activity.
Asunto(s)
Antineoplásicos/farmacología , Ditiocarba/química , Ditiocarba/farmacología , Antineoplásicos/síntesis química , Química Farmacéutica/métodos , Ditiocarba/síntesis química , Diseño de Fármacos , Ensayos de Selección de Medicamentos Antitumorales , Ésteres , Células HL-60 , Humanos , Concentración 50 Inhibidora , Modelos QuímicosRESUMEN
A series of highly sterically hindered secondary amine analogues of pyridylmethylamine (7a-f, 8a-c) and positional isomeric analogues of ABT-594 (9a-c) were synthesized and evaluated for their in vivo analgesic activity. The compounds 7a and 7d show potent analgesic activity and lower toxicity. Some interesting structure-activity relationships have been revealed.
Asunto(s)
Analgésicos/síntesis química , Analgésicos/farmacología , Azetidinas/síntesis química , Azetidinas/farmacología , Piridinas/síntesis química , Piridinas/farmacología , Analgésicos/química , Animales , Azetidinas/química , Isomerismo , Piridinas/química , Ratas , Relación Estructura-ActividadRESUMEN
Based on the structure characteristics of the lead compounds, 1, 1' octanedioyl-4, 4'-dimethyl-4, 4'-dibenzyl dipiperazinium dibromide (2) and 3, 8-disubstituted-3, 8-diazabicyclo [3.2.1]octanes (DBO), di-(3, 8-diazabicyclo [3.2.1]octane) diquaternary ammonium salts 3 a-c were designed and synthesized through a highly practical procedure. Target compounds 3 a-c and the hydrochloride salts of their precursors 10 a-c were evaluated for their in vivo analgesic and sedative activities. Interestingly, the introduction of an endoethylenic bridge in the piperazine of lead compound 2 causes loss of the analgesic activity and increases the toxicity dramatically. This result shows that the flexible conformation of piperazine in compound 2 is favorable for interaction with the receptor, and the quaternization of compounds 10 a-c is the main reason for the toxicity increase.
Asunto(s)
Analgésicos/síntesis química , Compuestos Heterocíclicos con 2 Anillos/síntesis química , Analgésicos/química , Analgésicos/uso terapéutico , Animales , Ciclización , Modelos Animales de Enfermedad , Compuestos Heterocíclicos con 2 Anillos/química , Compuestos Heterocíclicos con 2 Anillos/uso terapéutico , Ratones , Estructura Molecular , Dolor/tratamiento farmacológico , Relación Estructura-ActividadRESUMEN
Based on the structure of compound 3, two series of spirocyclopiperazinium derivatives 7a-n and 10a-h were synthesized and evaluated for their in vivo analgesic and sedative activities. Compounds 7f and 10c were discovered to exhibit excellent analgesic activity. Structure-activity relationships revealed that anion of the quaternary salt affected the analgesic and sedative activity significantly; the allyl group is a most effective group among the compounds 7a-n; the electron-released substitute on the aromatic ring is favorable to increase the analgesic activity.