RESUMO
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
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
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 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.
Assuntos
Glicosídeos/síntese química , Galactose/química , Glicosídeos/química , Espectroscopia de Ressonância MagnéticaRESUMO
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.