RESUMO
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.
Assuntos
Furanos/química , Elementos de Transição/química , Aminação , Catálise , OxirreduçãoRESUMO
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.
Assuntos
Ácidos Borônicos/farmacologia , Prolina/química , Inibidores de Proteassoma/farmacologia , Ácidos Borônicos/química , Espectroscopia de Ressonância Magnética Nuclear de Carbono-13 , Linhagem Celular Tumoral , Humanos , Inibidores de Proteassoma/síntese química , Inibidores de Proteassoma/química , Espectroscopia de Prótons por Ressonância Magnética , Relação Estrutura-AtividadeRESUMO
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).
Assuntos
Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Desenho de Fármacos , Mostardas de Fosforamida/síntese química , Mostardas de Fosforamida/farmacologia , Quinazolinas/química , Animais , Antineoplásicos/química , Antineoplásicos/farmacocinética , Linhagem Celular Tumoral , Técnicas de Química Sintética , Relação Dose-Resposta a Droga , Humanos , Masculino , Camundongos , Mostardas de Fosforamida/química , Mostardas de Fosforamida/farmacocinética , Ratos , Relação Estrutura-Atividade , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
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.
Assuntos
Ácidos Borônicos/farmacologia , Peptídeos/farmacologia , Inibidores de Proteassoma/química , Animais , Antineoplásicos , Ácidos Borônicos/química , Linhagem Celular Tumoral , Xenoenxertos , Humanos , Camundongos , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Peptídeos/química , Complexo de Endopeptidases do Proteassoma/efeitos dos fármacos , Inibidores de Proteassoma/farmacocinética , Ureia/química , Ureia/farmacologiaRESUMO
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.
Assuntos
Técnicas de Química Sintética , Tiadiazóis/síntese química , Água/químicaRESUMO
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.
Assuntos
Antineoplásicos/farmacologia , Receptores ErbB/antagonistas & inibidores , Quinazolinas/farmacologia , Quinolinas/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Neoplasias do Colo/tratamento farmacológico , Neoplasias do Colo/patologia , Ésteres/síntese química , Ésteres/química , Ésteres/farmacologia , Feminino , Células HCT116 , Humanos , Lapatinib , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Quinazolinas/síntese química , Quinazolinas/química , Quinolinas/síntese química , Quinolinas/química , Relação Estrutura-AtividadeRESUMO
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.
Assuntos
Técnicas de Química Sintética/métodos , Pirimidinas/química , Pirimidinas/síntese química , Água/química , Aldeídos/química , Nitrilas/químicaRESUMO
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).
Assuntos
4-Butirolactona/análogos & derivados , Chalconas/química , 4-Butirolactona/química , Catálise , Cristalografia por Raios X , Modelos Moleculares , EstereoisomerismoRESUMO
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.
Assuntos
Chalcona/química , Ciclopentanos/química , Catálise , Estereoisomerismo , Especificidade por Substrato , TemperaturaRESUMO
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.
Assuntos
Aldeídos/química , Dipeptídeos/química , Cetonas/química , Óxido de Alumínio/química , CatáliseRESUMO
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.
Assuntos
Ácidos Borônicos/síntese química , Desenho de Fármacos , Oligopeptídeos/síntese química , Inibidores de Proteases/síntese química , Inibidores de Proteassoma , Animais , Ácidos Borônicos/farmacologia , Linhagem Celular Tumoral , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Concentração Inibidora 50 , Oligopeptídeos/farmacologia , Inibidores de Proteases/farmacologia , Relação Quantitativa Estrutura-Atividade , CoelhosRESUMO
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.
Assuntos
Analgésicos/química , Analgésicos/síntese química , Piperazinas/química , Piperazinas/síntese química , Compostos de Espiro/química , Analgésicos/farmacologia , Animais , Iodeto de Dimetilfenilpiperazina/química , Iodeto de Dimetilfenilpiperazina/farmacologia , Avaliação Pré-Clínica de Medicamentos , Camundongos , Estrutura Molecular , Medição da Dor , Piperazinas/farmacologia , Sais , Compostos de Espiro/farmacologia , Relação Estrutura-AtividadeRESUMO
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.
Assuntos
Antineoplásicos/farmacologia , Ditiocarb/química , Ditiocarb/farmacologia , Antineoplásicos/síntese química , Química Farmacêutica/métodos , Ditiocarb/síntese química , Desenho de Fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Ésteres , Células HL-60 , Humanos , Concentração Inibidora 50 , Modelos QuímicosRESUMO
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.
Assuntos
Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Ciclofosfamida/síntese química , Ciclofosfamida/farmacologia , Piperazinas/síntese química , Piperazinas/farmacologia , Compostos de Espiro/síntese química , Compostos de Espiro/farmacologia , Animais , Ciclofosfamida/análogos & derivados , Concentração Inibidora 50 , Camundongos , Pró-Fármacos , Relação Estrutura-AtividadeRESUMO
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.
Assuntos
Analgésicos/síntese química , Analgésicos/farmacologia , Azetidinas/síntese química , Azetidinas/farmacologia , Piridinas/síntese química , Piridinas/farmacologia , Analgésicos/química , Animais , Azetidinas/química , Isomerismo , Piridinas/química , Ratos , Relação Estrutura-AtividadeRESUMO
Hydrochloride derivatives 5a-c and quaternary ammonium derivatives 6a-c of epibatidine incorporated with amino acid ester were synthesized and evaluated for their in vivo analgesic activity and toxicity. Among all tested compounds, compound 6c has the most potent analgesic activity. The quaternary ammonium salts 6a and 6c showed better analgesic activity than the corresponding hydrochlorides 5a and 5c. Both 5a-c and 6a-c showed significantly lower toxicity than epibatidine itself.
Assuntos
Analgésicos não Narcóticos/síntese química , Compostos Bicíclicos Heterocíclicos com Pontes/síntese química , Piridinas/síntese química , Compostos de Amônio Quaternário/síntese química , Aminoácidos , Analgésicos não Narcóticos/química , Analgésicos não Narcóticos/farmacologia , Animais , Compostos Bicíclicos Heterocíclicos com Pontes/química , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Relação Dose-Resposta a Droga , Ácido Clorídrico/farmacologia , Camundongos , Dor/prevenção & controle , Piridinas/química , Piridinas/farmacologia , Compostos de Amônio Quaternário/química , Compostos de Amônio Quaternário/farmacologia , Relação Estrutura-AtividadeRESUMO
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.
Assuntos
Analgésicos/síntese química , Compostos Heterocíclicos com 2 Anéis/síntese química , Analgésicos/química , Analgésicos/uso terapêutico , Animais , Ciclização , Modelos Animais de Doenças , Compostos Heterocíclicos com 2 Anéis/química , Compostos Heterocíclicos com 2 Anéis/uso terapêutico , Camundongos , Estrutura Molecular , Dor/tratamento farmacológico , Relação Estrutura-AtividadeRESUMO
Three series of spirocyclopiperazinium derivatives 5a-d, 6a-f and 17a-d were synthesized and evaluated for their in vivo analgesic activities. Compounds 5a, 17a and 17b exhibited excellent analgesic activity. Two important structure-activity relationships were observed from this study: (1) the quaternary ammonium functionality is a critical pharmacophore for analgesic activity; (2) it is important to adjust the lipophilic property of compounds to improve analgesic activity.
Assuntos
Analgésicos/síntese química , Piperazinas/síntese química , Piperazinas/farmacologia , Analgésicos/administração & dosagem , Analgésicos/farmacologia , Animais , Relação Dose-Resposta a Droga , Interações Hidrofóbicas e Hidrofílicas , Hipnóticos e Sedativos/síntese química , Hipnóticos e Sedativos/farmacologia , Dose Máxima Tolerável , Camundongos , Piperazinas/administração & dosagem , Sais , Compostos de Espiro , Relação Estrutura-AtividadeRESUMO
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.
Assuntos
Alcenos/síntese química , Analgésicos/síntese química , Piperazinas/síntese química , Compostos de Espiro/síntese química , Alcenos/química , Alcenos/farmacologia , Analgésicos/química , Analgésicos/farmacologia , Animais , Hipnóticos e Sedativos/síntese química , Hipnóticos e Sedativos/química , Hipnóticos e Sedativos/farmacologia , Indicadores e Reagentes , Camundongos , Atividade Motora/efeitos dos fármacos , Medição da Dor , Piperazinas/química , Piperazinas/farmacologia , Compostos de Espiro/química , Compostos de Espiro/farmacologia , Relação Estrutura-AtividadeRESUMO
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.