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1.
Eur J Med Chem ; 228: 114037, 2022 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-34883290

RESUMO

Off-target toxicity is one of the main challenges faced by anticancer chemotherapeutics. For tumor targeted and precision chemotherapy, we take the advantages of the ligand directed tumor active targeting of small molecule drug conjugates (SMDCs) and the passive tumor targeting of nanoparticles via the enhanced penetration and retention (EPR) effects, put forward a branched small molecule drug conjugate (BSMDC) nanomedicine design concept. In a proof of concept, we used pentaerythritol as the branched moiety, galactosamine (GalN) as the hepatocellular carcinoma (HCC) directing ligands, PTX as a payload, and a stearoyl moiety as the amphiphilic property adjusting group, designed and synthesized BSMDC 1 and prepared its NPs. In cellular level, the BSMDC 1 NPs targeted asialoglycoprotein receptor (ASGPR)-overexpressing HepG2 cells, were effectively taken up in the cells and released in tumor microenvironments, inhibited the HepG2 cell proliferation, arrested HepG2 cell in G2/M phase and induced tumor cell apoptosis. In HepG2 xenograft nude mice, the BSMDC 1 NPs were high specific to target the tumor and demonstrated a higher antitumor efficiency than BSMDC 1, having no apparent influences on mice body weights and major organs, supporting our BSMDC nanomedicine design concept. Therefore, this new strategy may find applications for cancer targeted and precision chemotherapy.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Carcinoma Hepatocelular/tratamento farmacológico , Galactosamina/farmacologia , Neoplasias Hepáticas/tratamento farmacológico , Paclitaxel/farmacologia , Bibliotecas de Moléculas Pequenas/farmacologia , Animais , Antineoplásicos Fitogênicos/química , Apoptose/efeitos dos fármacos , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patologia , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Galactosamina/química , Células Hep G2 , Humanos , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas Experimentais/tratamento farmacológico , Neoplasias Hepáticas Experimentais/metabolismo , Neoplasias Hepáticas Experimentais/patologia , Camundongos , Camundongos Nus , Estrutura Molecular , Nanomedicina , Paclitaxel/química , Bibliotecas de Moléculas Pequenas/química , Relação Estrutura-Atividade
2.
J Med Chem ; 63(23): 14840-14866, 2020 12 10.
Artigo em Inglês | MEDLINE | ID: mdl-33201714

RESUMO

Taking the previously discovered 1-methyl-1,4-dihydroindeno[1,2c]pyrazol derivative LL01 as a lead, systematic structural modifications were made at the phenolic 6- and 7-positions and the aniline at the 3-position of the indenopyrazole core to investigate the SARs and to improve water solubility. Among the designed indenopyrazoles ID01-ID33, a series of potent MTAs were identified. As the hydrochloride salt(s), ID09 and ID33 showed excellent aqueous solubility and favorable Log P value and displayed noteworthily low nanomolar potency against a variety of tumor cells, including those taxol-resistant ones. They inhibited tubulin polymerization, disrupted cellular microtubule networks by targeting the colchicine site, and promoted HepG2 cell cycle arrest and cell apoptosis. In the HepG2 xenograft mouse model, ID09 and ID33 effectively inhibited tumor growth at an oral dose of 25 mg/kg. At an intravenous (iv) injection dose of 10 mg/kg every other day, ID09 suppressed tumor growth by 68% without obvious toxicity.


Assuntos
Antineoplásicos/uso terapêutico , Indenos/uso terapêutico , Neoplasias/tratamento farmacológico , Pirazóis/uso terapêutico , Moduladores de Tubulina/uso terapêutico , Animais , Antineoplásicos/síntese química , Apoptose/efeitos dos fármacos , Movimento Celular/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Pontos de Checagem da Fase G2 do Ciclo Celular/efeitos dos fármacos , Células Hep G2 , Humanos , Indenos/síntese química , Camundongos Endogâmicos BALB C , Estrutura Molecular , Pirazóis/síntese química , Solubilidade , Relação Estrutura-Atividade , Moduladores de Tubulina/síntese química , Água/química , Ensaios Antitumorais Modelo de Xenoenxerto
3.
Eur J Med Chem ; 187: 111968, 2020 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-31865012

RESUMO

Tubulin inhibitors that bind to the colchicine site are widely studied anticancer agents. In continuous our researches, we designed a series of novel indazole derivatives as microtubule-targeting agents (MTAs). The structure-activity relationships (SARs) investigations indicated that a 3,4,5-trimethoxyphenyl moiety and a methyl or methoxy substitution were preferred for the better antiproliferative activity. The indazole derivatives 3c and 3f showed noteworthy low nanomolar potency against HepG2, HCT116, SW620, HT29 and A549 tumor cells. In mechanism studies, 3c and 3f were proved to target the colchicine site, inhibited tubulin polymerization and disrupted cellular microtubule networks, arrested HCT116 cell in G2/M phase and induced cell apoptosis. In the HCT116 xenografts mouse model, 3c and 3f suppressed tumor growth by 45.3% and 58.9% at an orally dose of 25 mg/kg without causing obvious weight loss. The indazole 3f may serve as a good lead or drug candidate for colorectal cancer therapy.


Assuntos
Antineoplásicos/farmacologia , Colchicina/farmacologia , Descoberta de Drogas , Indazóis/farmacologia , Moduladores de Tubulina/farmacologia , Tubulina (Proteína)/metabolismo , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Sítios de Ligação/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Colchicina/síntese química , Colchicina/química , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Indazóis/síntese química , Indazóis/química , Camundongos , Camundongos Nus , Modelos Moleculares , Estrutura Molecular , Polimerização/efeitos dos fármacos , Relação Estrutura-Atividade , Moduladores de Tubulina/síntese química , Moduladores de Tubulina/química
4.
Invest New Drugs ; 38(1): 29-38, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-30887253

RESUMO

Through rational drug design, we previously identified an indenoprazole derivative, 2-(6-ethoxy-3-(3-ethoxyphenylamino)-1-methyl-1,4-dihydroindeno[1,2-c]pyrazol-7-yloxy)acetamide (LL01), as a potent tubulin polymerization inhibitor targeting the tubulin colchicine binding site. In this study, we further demonstrated that LL01 was not a P-gp substrate. It potently inhibited the growth of a variety of tumor cells, including those with multidrug resistance, with GI50 values in the low nanomole ranges. In vitro liver microsome stability assay, LL01 was modest stable in the liver microsomes of human, mouse and rat, but was fast metabolized in dog. After single oral administration of LL01 at a dose of 10 mg/kg in SD male rats, LL01 showed acceptable PK properties with a mean bioavailability of 41%. In human HepG2 hepatoma xenograft, at the oral doses of 25 mg/kg/day and 12.5 mg/kg/day, LL01 inhibited the tumor growth by 61.27%, and 43.74%, respectively, which is much better than the positive drug sorafenib (29.45%; 30 mg/kg/day). Therefore, LL01 might be a potential drug candidate for further investigation for hepatocellular carcinoma therapy.


Assuntos
Antineoplásicos/farmacologia , Carcinoma Hepatocelular/tratamento farmacológico , Colchicina/metabolismo , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Neoplasias Hepáticas/tratamento farmacológico , Moduladores de Tubulina/farmacologia , Tubulina (Proteína)/metabolismo , Animais , Antineoplásicos/química , Apoptose , Sítios de Ligação , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patologia , Proliferação de Células , Resistência a Múltiplos Medicamentos , Feminino , Humanos , Técnicas In Vitro , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Ratos , Ratos Sprague-Dawley , Moduladores de Tubulina/química , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
5.
Molecules ; 24(16)2019 Aug 12.
Artigo em Inglês | MEDLINE | ID: mdl-31408939

RESUMO

In the present study, we aimed to develop a novel fermented tea (NFT) product and to evaluate their in vitro antioxidant potential and chemical composition. We found that NFT contained a high level of total phenolic compounds (102.98 mg gallic acid equivalents/g extract) and exhibited diverse antioxidant activities, such as scavenging of 1,1-diphenyl-2-picryl-hydrazyl (DPPH) and hydroxyl radicals, as well as reducing power. The total catechins in NFT were comparable to those of Lipton black tea (LBT), but lower than those of Boseong green tea (BGT) or Tieguanyin oolong tea (TOT). Among all catechins tested, epigallocatechin (EGC) and epigallocatechin-3-O-gallate (EGCG) were the predominant compounds in NFT. In particular, the contents of total theaflavins (TFs), theaflavin (TF), theaflavin-3-gallate (TF3G), and theaflavin-3'-gallate (TF3'G) in NFT were significantly higher than that of BGT, TOT, or LBT. NFT had the highest level of total essential amino acid and γ-aminobutyric acid (GABA) compared with BGT, TOT and LBT. Furthermore, the sensory evaluation results showed that NFT had satisfactory color, aroma, taste, and overall acceptability scores. Our results highlight the potential usefulness of this novel fermented tea as a nutraceutical food/ingredient with special functional activities.


Assuntos
Antioxidantes/isolamento & purificação , Camellia sinensis/química , Flavonoides/isolamento & purificação , Chá/química , Antioxidantes/química , Biflavonoides/química , Biflavonoides/isolamento & purificação , Compostos de Bifenilo/antagonistas & inibidores , Catequina/análogos & derivados , Catequina/química , Catequina/isolamento & purificação , Cor , Fermentação , Flavonoides/química , Flavonoides/classificação , Ácido Gálico/análogos & derivados , Ácido Gálico/química , Ácido Gálico/isolamento & purificação , Humanos , Radical Hidroxila/antagonistas & inibidores , Odorantes/análise , Picratos/antagonistas & inibidores , Paladar/fisiologia , Ácido gama-Aminobutírico/química , Ácido gama-Aminobutírico/isolamento & purificação
6.
Molecules ; 24(2)2019 Jan 13.
Artigo em Inglês | MEDLINE | ID: mdl-30642134

RESUMO

To find novel antitumor agents, a series of 1H-benzofuro[3,2-c]pyrazole derivatives 4a-e were designed and synthesized. The treatment of 6-methoxybenzofuran-3(2H)-one 3 with LiHMDS in anhydrous tetrahydrofuran (THF) followed by reaction with 3-substitued phenyl isothiocyanate gave the thioamide intermediates, which underwent condensation with hydrazine monohydrate in dioxane/EtOH (1:1) to provide the benzofuropyrazole derivatives 4a⁻e as well as the unexpected pyrazole derivatives 5a⁻e. In tumor cell growth inhibitory assay, all the benzofuropyrazole derivatives were not active against the breast tumor MCF-7 cell, only 4a was highly active and more potent than ABT-751 against the leukemia K562 (GI50 = 0.26 µM) and lung tumor A549 cells (GI50 = 0.19 µM), while other benzofuropyrazoles showed very weak inhibitory activity. In contrast, the pyrazoles 5a-e were in general more potent than the benzofuropyrazoles 4a⁻e. Compound 5a exhibited a similar tendency to that of 4a with high potency against K562 and A549 cells but weak effects on MCF-7 cell. Both pyrazoles 5b and 5e exhibited high inhibitory activities against K562, MCF-7 and A549 cells. The most active compound 5b was much more potent than ABT-751 against K562 and A549 cells with GI50 values of 0.021 and 0.69 M, respectively. Moreover, 5b was identified as a novel tubulin polymerization inhibitor with an IC50 of 7.30 M.


Assuntos
Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Pirazóis/síntese química , Pirazóis/farmacologia , Animais , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Humanos , Pirazóis/química , Moduladores de Tubulina/química , Moduladores de Tubulina/farmacologia
7.
Expert Opin Ther Pat ; 28(8): 647-651, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30073889

RESUMO

INTRODUCTION: There are great potential in the development of selective HDAC6 inhibitors for the treatment of infectious diseases, neoplasms, endocrine diseases, and other diseases associated with HDAC6 activity. Areas covered: The application claims 1,3,4-oxadiazole sulfamide derivatives as selective HDAC6 inhibitors for the treatment of infectious diseases, neoplasms, endocrine, nutritional, and metabolic diseases; mental and behavioral disorders; neurological diseases; diseases of the eye and adnexa; cardiovascular diseases; respiratory diseases; digestive diseases; diseases of the skin and subcutaneous tissue; disease of the musculoskeletal system and connective tissue; or congenital malformations, deformations and chromosomal abnormalities. Many of the exemplified compounds showed nanomole potency against HDAC6 and were more than 5000-fold selectivity for HDAC6 over HDAC1. Expert opinion: These 1,3,4-oxadiazole sulfamide derivatives have a unique zinc-binding group (ZBG) that provide good leads for the discovery of potent selective HDAC6 inhibitors for the treatment of a variety of diseases associated with HDAC6 activity.


Assuntos
Inibidores de Histona Desacetilases/farmacologia , Oxidiazóis/farmacologia , Sulfonamidas/farmacologia , Desenho de Fármacos , Descoberta de Drogas/métodos , Desacetilase 6 de Histona/antagonistas & inibidores , Inibidores de Histona Desacetilases/síntese química , Inibidores de Histona Desacetilases/química , Humanos , Oxidiazóis/síntese química , Oxidiazóis/química , Patentes como Assunto , Sulfonamidas/síntese química , Sulfonamidas/química
8.
Eur J Med Chem ; 151: 9-17, 2018 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-29601991

RESUMO

PI3Kδ and PI3Kγ regulate immune cell signaling. Selective PI3Kδ or PI3Kγ inhibitors and dual PI3Kδ/γ inhibitors have the potential for the treatment of immune cell-mediated diseases and hematological malignancies. Based on the quinazolinone pharmacophore, we used a pyrazolo[3,4-d]pyrimidin-4-amine portion as the hinge region binding moiety, an aromatic or a heteroaromatic substituent at the 3-position of the pyrazolo[3,4-d]pyrimidine core as the affinity element, and designed novel 2-tolyl and 2,6-dimethylphenyl quinazolinone derivatives as potential PI3Kδ inhibitors. Most of these compounds displayed high inhibitory rates (89-97%) against PI3Kδ at the concentration of 1 µM, with the IC50 values of 8.4 nM-106 nM. Among the 3-(2,6-dimethylphenyl)quinazolinone series, the introduction of an indol-5-yl substituent at the pyrazolo[3,4-d]pyrimidine 3-position led to a potent and selective PI3Kδ (IC50 = 8.6 nM) inhibitor 10d, that was more than 3630-fold, 390-fold and 40-fold selective for PI3Kδ over PI3Kα, ß and γ, while the substitution with a 3,4-dimethoxyphenyl resulted in a potent and selective dual PI3Kδ/γ inhibitor 10e with IC50 values of 8.4 nM and 62 nM against PI3Kδ and PI3Kγ, respectively. Compound 10e was also more than 1400-fold, 820-fold selective for PI3Kδ over PI3Kα and PI3Kß. In agreement with their remarkable PI3Kδ inhibitory activity, compounds 10d and 10e showed high antiproliferative activity against human B-cell SU-DHL-6 cells. Moreover, the dual PI3Kδ/γ inhibitor 10e had reasonable pharmacokinetic profiles with a good plasma exposure, low clearance, low volume distribution, and an acceptable oral bioavailability of 34.9%.


Assuntos
Classe I de Fosfatidilinositol 3-Quinases/antagonistas & inibidores , Inibidores de Fosfoinositídeo-3 Quinase , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Quinazolinonas/química , Quinazolinonas/farmacologia , Animais , Linfócitos B/efeitos dos fármacos , Linfócitos B/enzimologia , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Classe I de Fosfatidilinositol 3-Quinases/metabolismo , Classe Ib de Fosfatidilinositol 3-Quinase/metabolismo , Descoberta de Drogas , Humanos , Masculino , Camundongos , Simulação de Acoplamento Molecular , Inibidores de Proteínas Quinases/farmacocinética , Quinazolinonas/farmacocinética , Ratos Sprague-Dawley
9.
J Med Chem ; 59(11): 5341-55, 2016 06 09.
Artigo em Inglês | MEDLINE | ID: mdl-27172319

RESUMO

By targeting a new binding region at the interface between αß-tubulin heterodimers at the colchicine binding site, we designed a series of 7-substituted 1-methyl-1,4-dihydroindeno[1,2-c]pyrazoles as potential tubulin polymerization inhibitors. Among the compounds synthesized, 2-(6-ethoxy-3-(3-ethoxyphenylamino)-1-methyl-1,4-dihydroindeno[1,2-c]pyrazol-7-yloxy)acetamide 6a and 2-(6-ethoxy-3-(3-ethoxyphenylamino)-1-methyl-1,4-dihydroindeno[1,2-c]pyrazol-7-yloxy)-N-hydroxyacetamide 6n showed noteworthy low nanomolar potency against HepG2, Hela, PC3, and MCF-7 cancer cell lines. In mechanism studies, 6a inhibited tubulin polymerization and disorganized microtubule in A549 cells by binding to tubulin colchicine binding site. 6a arrested A549 cells in G2/M phase that was related to the alterations in the expression of cyclin B1 and p-cdc2. 6a induced A549 cells apoptosis through the activation of caspase-3 and PARP. In addition, 6a inhibited capillary tube formation in a concentration-dependent manner. In nonsmall cell lung cancer xenografts mouse model, 6a suppressed tumor growth by 59.1% at a dose of 50 mg/kg (ip) without obvious toxicity, indicating its in vivo potential as anticancer agent.


Assuntos
Antineoplásicos/farmacologia , Colchicina/metabolismo , Desenho de Fármacos , Pirazóis/farmacologia , Moduladores de Tubulina/farmacologia , Tubulina (Proteína)/metabolismo , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Sítios de Ligação/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Colchicina/química , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Camundongos , Camundongos Nus , Modelos Moleculares , Estrutura Molecular , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/patologia , Pirazóis/síntese química , Pirazóis/química , Relação Estrutura-Atividade , Tubulina (Proteína)/química , Moduladores de Tubulina/síntese química , Moduladores de Tubulina/química
10.
Eur J Med Chem ; 85: 569-75, 2014 Oct 06.
Artigo em Inglês | MEDLINE | ID: mdl-25127149

RESUMO

Two new analogues of the steroid hormone 1α,25-dihydroxyvitamin D3 with aromatic side chains attached at C-17 were designed to investigate their effects on VDR, HL-60 cell differentiation and tumor cell proliferation. These analogues were prepared by the classical photochemical ring opening approach. After the protection of both the 1α- and 3ß-hydroxyl in 1α-hydroxydehydroepiandrosterone with TBS groups, followed by bromination with NBS and debromination in the presence of γ-collidine, the diene intermediate was obtained. Hydrazone formation followed by iodine oxidation gave a vinyl iodide. The aromatic side chain at C-17 was introduced via the Negishi coupling of the resulting intermediate with an in situ generated zinc reagent with the substituted aryl bromide (CD-side chain) in the presence of catalytic amount of Pd(PPh3)4. After the removal of the TBDMS and MOM protective groups, followed by UV irradiation and the subsequent thermal reaction, the 1α,25-(OH)2-D3 analogues with a substituted phenyl ring attached at C-17 to replace the C-20 and C-21 were prepared. In the VDR competitive binding assay, compounds 2 and 3 almost lost their binding ability, and were only 0.01% and 0.015% as potent as the 1α,25-dihydroxyvitamin D3. However, compounds 2 and 3 were as potent as 1α,25-(OH)2-D3 in inducing HL-60 cell differentiation at concentrations of 30, 100, 300, 1000 nM, respectively. Moreover, compounds 2 and 3 exhibited similar or better antiproliferative potency against MCF-7 human breast cancer cells, the IC50 values for analogues 2, 3 and the natural hormone were 7.08, 7.56, and 12.5 µM, respectively.


Assuntos
Vitamina D/análogos & derivados , Diferenciação Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Técnicas de Química Sintética , Células HL-60 , Humanos , Células MCF-7 , Modelos Moleculares , Conformação Molecular , Estereoisomerismo , Relação Estrutura-Atividade , Vitamina D/síntese química , Vitamina D/química , Vitamina D/farmacologia
11.
Bioorg Med Chem Lett ; 23(11): 3314-9, 2013 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-23601711

RESUMO

The small chemical compound 8-ethoxy-2-(4-fluorophenyl)-3-nitro-2H-chromene (S14161) was recently identified as an inhibitor of the phosphoinositide 3-kinase (PI3K). In the present study, we designed a novel synthesis of S14161 and prepared a series of its analogues via the oxa-Michael-Henry reaction in the presence of catalytic amounts of l-proline and triethylamine. Further structural simplification led to the identification of 6-bromo-8-ethoxy-3-nitro-2H-chromene (BENC-511) that exhibited potent antiproliferative activities against a panel of 12 tumor cell lines. Compared with S14161, BENC-511 was more potent in blocking the AKT phosphorylation and inducing cancer cell apoptosis. BENC-511 also displayed more potent effects on human umbilical vein epithelial cells (HUVEC) migration, suggesting its anti-angiogenesis activity.


Assuntos
Antineoplásicos/síntese química , Benzopiranos/química , Benzopiranos/síntese química , Inibidores de Fosfoinositídeo-3 Quinase , Antineoplásicos/química , Antineoplásicos/toxicidade , Benzopiranos/farmacologia , Sítios de Ligação , Catálise , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Avaliação Pré-Clínica de Medicamentos , Ensaios de Seleção de Medicamentos Antitumorais , Células Endoteliais da Veia Umbilical Humana , Humanos , Simulação de Acoplamento Molecular , Neovascularização Fisiológica/efeitos dos fármacos , Fosfatidilinositol 3-Quinases/metabolismo , Fosforilação/efeitos dos fármacos , Piperazinas/química , Prolina/química , Estrutura Terciária de Proteína , Proteínas Proto-Oncogênicas c-akt/metabolismo
12.
Curr Med Chem ; 20(15): 1997-2016, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23317165

RESUMO

Rheumatoid arthritis (RA) and other chronic inflammatory diseases are always the major therapeutic challenges. Recent research efforts provided new insights into the molecular basis of these diseases and new opportunities for developing improved anti-inflammatory drugs. The p38 mitogen-activated protein (MAP) kinase plays a central role in the regulation of the biosynthesis and release of several proinflammatory cytokines including tumor necrosis factor alpha (TNF-α) and interleukin-1 beta (IL-1ß). Hence, inhibition of the p38 MAP kinase is regarded as a promising therapeutic strategy for controlling inflammatory diseases. A diverse range of p38α MAP kinase inhibitors have been developed as potential anti-inflammatory agents, and some of them have entered the phase II clinical trials. The imidazole derivatives are known as competitive inhibitors at the ATP binding site of the p38α MAP kinase. Modifications on the imidazole scaffold have led to a large amount of potent p38α MAP kinase inhibitors. This review will summarize the developments of small molecule p38α MAP kinase inhibitors based on the imidazole core scaffolds in recent 10 years. Variations at the N1, C2, C4 and C5 positions of imidazole were introduced, and the structure-activity relationships of these imidazole inhibitors were also discussed.


Assuntos
Anti-Inflamatórios/química , Artrite Reumatoide/tratamento farmacológico , Imidazóis/química , Proteína Quinase 14 Ativada por Mitógeno/antagonistas & inibidores , Inibidores de Proteínas Quinases/química , Bibliotecas de Moléculas Pequenas/química , Animais , Anti-Inflamatórios/farmacologia , Artrite Reumatoide/enzimologia , Descoberta de Drogas , Humanos , Imidazóis/farmacologia , Proteína Quinase 14 Ativada por Mitógeno/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Bibliotecas de Moléculas Pequenas/farmacologia , Relação Estrutura-Atividade
13.
Anticancer Agents Med Chem ; 12(4): 391-406, 2012 May.
Artigo em Inglês | MEDLINE | ID: mdl-22043991

RESUMO

Progress in identifying and understanding the molecular and cellular causes of cancer has led to the discovery of anomalies that characterize cancer cells and that represent targets for the development of cancer therapeutics. One such target is the epidermal growth factor receptor (EGFR), a transmembrane protein that is frequently dysregulated in cancer cells and associated with the development, progression and aggressiveness of a number of malignancies. Inhibition of EGFR signaling has thus been identified as an attractive strategy in control of tumor proliferation, and over a decade of intense activity in the field has culminated in the discoveries and subsequent approvals of gefitinib and erlotinib for the treatment of non-small cell lung cancer. However, the drug's resistance to gefitinib and erlotinib has been clinically observed. Therefore, intensive efforts have been made in the discovery of novel potent and selective EGFR inhibitors. This review will focus on the developments of small molecule EGFR inhibitors based on the quinazoline core scaffolds in recent 5 years. Diverse EGFR inhibitors are classified as 4-anilinoquinazolines and 4-nonanilininoquinazolines, their biological data are described, and the structure-activity relationships (SARs) are discussed.


Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Receptores ErbB/antagonistas & inibidores , Neoplasias/tratamento farmacológico , Quinazolinas/química , Quinazolinas/farmacologia , Animais , Antineoplásicos/uso terapêutico , Descoberta de Drogas , Receptores ErbB/metabolismo , Humanos , Quinazolinas/uso terapêutico , Bibliotecas de Moléculas Pequenas/química , Bibliotecas de Moléculas Pequenas/farmacologia , Bibliotecas de Moléculas Pequenas/uso terapêutico , Relação Estrutura-Atividade
14.
Bioorg Med Chem Lett ; 21(12): 3730-3, 2011 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-21555220

RESUMO

A series of new HIV-1 protease inhibitors with the hydroxyethylamine core and different hydroxyprolinamide P2 ligands were designed and synthesized. Variation of substitutions at the P2 significantly affected the enzyme inhibitory potency of the inhibitors. Compounds 2a and 2d showed excellent enzyme inhibitory activity with IC(50) values in the nanomolar range. An active site binding model for inhibitors 2a and 2d was suggested based upon the computational-docking results of the ligand with HIV-1 protease. This model offers molecular insights regarding ligand-binding site interactions of the hydroxyprolinamide-derived novel P2-ligand.


Assuntos
Amidas/síntese química , Inibidores da Protease de HIV/síntese química , HIV-1/enzimologia , Hidroxiprolina/síntese química , Amidas/química , Amidas/farmacologia , Sítios de Ligação , Darunavir , Desenho de Fármacos , Inibidores da Protease de HIV/química , Inibidores da Protease de HIV/farmacologia , HIV-1/efeitos dos fármacos , Humanos , Hidroxiprolina/química , Hidroxiprolina/farmacologia , Concentração Inibidora 50 , Ligantes , Estrutura Molecular , Sulfonamidas/química , Sulfonamidas/farmacologia
15.
Med Chem ; 7(6): 561-71, 2011 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-22313296

RESUMO

A practical synthesis of 2,3-diarylated 2H-benzo[e][1,2]thiazine 1,1-dioxides and their 3,4-dihydro derivatives was developed. ortho-Methyl lithiation of N-aryl-o-toluenesulfonamide followed by reaction with aryl aldehydes gave carbinol sulfonamides, which were either converted directly, or first oxidized to their ketones and converted, to 2,3-diarylated six-membered benzosultams via a TMSCl-NaI-MeCN mediated cyclization. A library of benzosultams was synthesized and evaluated for inhibitory activity against MCF-7 cells. Compound 3 in the 3,4-dihydro (saturated) series and compound 8 in the unsaturated series exhibited the highest potencies with growth inhibition (GI50) values of 0.8 and 18.0 µM, respectively. Molecular modeling studies suggest that these compounds can associate with the colchicine binding site on microtubules. However, experimental assessments of that and other mechanistic possibilities are still ongoing.


Assuntos
Antineoplásicos/farmacologia , Neoplasias da Mama/patologia , Tiazinas/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Modelos Moleculares , Relação Estrutura-Atividade , Tiazinas/síntese química , Tiazinas/química
16.
Biochem Biophys Res Commun ; 341(1): 82-7, 2006 Mar 03.
Artigo em Inglês | MEDLINE | ID: mdl-16431216

RESUMO

A patient with severe hypertriglyceridemia and recurrent pancreatitis was found to have significantly decreased lipoprotein lipase (LPL) activity and normal apolipoprotein C-II concentration in post-heparin plasma. DNA analysis of the LPL gene revealed two mutations, one of which was a novel homozygous G-->C substitution, resulting in the conversion of a translation initiation codon methionine to isoleucine (LPL-1). The second was the previously reported heterozygous substitution of glutamic acid at residue 242 with lysine (LPL-242). In vitro expression of both mutations separately or in combination demonstrated that LPL-1 had approximately 3% protein mass and 2% activity, whereas LPL-242 had undetectable activity but normal mass. The combined mutation LPL-1-242 exhibited similar changes as for LPL-1, with markedly reduced mass, and for LPL-242, with undetectable activity. These results suggest that the homozygous initiator codon mutation rather than the heterozygous LPL-242 alteration was mainly responsible for the patient phenotypes.


Assuntos
Códon de Iniciação/genética , Hiperlipoproteinemia Tipo IV/genética , Hiperlipoproteinemia Tipo I/genética , Lipase Lipoproteica/genética , Pancreatite/genética , Adolescente , Análise Mutacional de DNA , Humanos , Hiperlipoproteinemia Tipo I/enzimologia , Hiperlipoproteinemia Tipo IV/enzimologia , Lipase Lipoproteica/deficiência , Mutação , Pancreatite/enzimologia , Biossíntese de Proteínas/genética , Recidiva
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