RESUMO
Glycogen synthase kinase 3ß (GSK-3ß) is a potential therapeutic target for the treatment of a variety of human diseases. Here, we report the design and synthesis of a series of thieno[3,2-c]pyrazol-urea derivatives and evaluation of their GSK-3ß inhibitory activity. Among these analogues, the compound without substitution on terminal phenyl ring (3a) was found to be the most potent GSK-3ß inhibitor with an IC50 of 74.4 nM, while substitution on the terminal phenyl (3b-3p) led to decreased potency, independent of the position, size, or electronic properties of the substituents. Kinase selectivity assay revealed that 3a showed good selectivity over a panel of kinases, but was less selective over CDK1, CDK2 and CDK5. Additionally, the pharmacological properties of the synthesized compounds were investigated computationally by the SwissADME and the results showed that most of the compounds have good ADME profiles.
RESUMO
Glycogen synthase kinase 3ß (GSK-3ß) is a potential target for anti-Alzheimer's disease (AD) drug development. In this study, a series of novel thieno[3,2-c]pyrazol-3-amine derivatives was synthesized and evaluated as potential GSK-3ß inhibitors by structure-based drug design. The thieno[3,2-c]pyrazol-3-amine derivative 54 with a 4-methylpyrazole moiety which interacted with Arg141 by π-cation interaction was identified as a potent GSK-3ß inhibitor with an IC50 of 3.4 nM and an acceptable kinase selectivity profile. In the rat primary cortical neurons, compound 54 showed neuroprotective effects on Aß-induced neurotoxicity. Western blot analysis indicated that 54 inhibited GSK-3ß by up-regulating the expression of phosphorylated GSK-3ß at Ser9 and down-regulating the expression of phosphorylated GSK-3ß at Tyr216. Meanwhile, 54 decreased tau phosphorylation at Ser396 in a dose-dependent way. In astrocytes and microglia cells, 54 inhibited the expression of inducible nitric oxide synthase (iNOS), indicating that 54 showed an anti-neuroinflammatory effect. In the AlCl3-induced zebrafish AD model, 54 significantly ameliorated the AlCl3-induced dyskinesia, demonstrating its anti-AD activity in vivo.
Assuntos
Doença de Alzheimer , Proteínas tau , Ratos , Animais , Proteínas tau/metabolismo , Glicogênio Sintase Quinase 3 beta/metabolismo , Peixe-Zebra/metabolismo , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/metabolismo , FosforilaçãoRESUMO
ß-D-N4-hydroxycytidine (NHC, EIDD-1931) is a nucleoside analogue that exhibits broad spectrum antiviral activity against a variety of RNA viruses. Herein, we report the synthesis of a series of lipid prodrugs of NHC and a novel 3'-fluoro modified NHC analogue, and evaluation of their antiviral activity against five variants of SARS-CoV-2. All lipid prodrugs showed potent antiviral activity against the tested SARS-CoV-2 variants with EC50 values in the range of 0.31-3.51 µM, which were comparable to those of NHC or higher than those of remdesivir and molnupiravir. An increase in the cytostatic activity of the lipid prodrugs was found, but prodrug 2d proved equally selective as molnupinavir. The 3'-F analogue of NHC (6) only displayed minor antiviral activity against the SARS-CoV-2 Omicron variant (EC50 = 29.91 µM), while no activity was found for other variants at the highest concentration tested. The promising antiviral data of the lipid prodrugs of NHC suggest that they deserve further investigation as new anti-SARS-CoV-2 drugs.
Assuntos
COVID-19 , Pró-Fármacos , Humanos , SARS-CoV-2 , Pró-Fármacos/farmacologia , Antivirais/farmacologia , Antivirais/uso terapêutico , LipídeosRESUMO
BU-4664L is a naturally occurring N-farnesylated dibenzodiazepinone with important biological activities. Herein, we report the synthesis and antitumor evaluation of two series of BU-4664L derivatives bearing different substituent patterns on the dibenzodiazepinone core and with diverse side chains. All of the derivatives displayed micromolar activity against the human prostate cancer PC-3 cells, while lower or no activity against the human lung H460 cells. The most active derivatives were 10a and 16c which exerted antiproliferative activity against PC-3 cells with GI50 values of 5.66 and 5.94 µM, respectively, and thus represent promising lead compounds for further development.
Assuntos
Antineoplásicos/farmacologia , Dibenzazepinas/farmacologia , Sesquiterpenos/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Dibenzazepinas/síntese química , Dibenzazepinas/química , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Estrutura Molecular , Sesquiterpenos/síntese química , Sesquiterpenos/química , Relação Estrutura-AtividadeRESUMO
Glycogen synthase kinase 3ß (GSK-3ß) catalyses the hyperphosphorylation of tau protein in the Alzheimer's disease (AD) pathology. A series of novel thieno[3,2-c]pyrazol-3-amine derivatives were designed and synthesised and evaluated as potential GSK-3ß inhibitors by structure-guided drug rational design approach. The thieno[3,2-c]pyrazol-3-amine derivative 16b was identified as a potent GSK-3ß inhibitor with an IC50 of 3.1 nM in vitro and showed accepted kinase selectivity. In cell levels, 16b showed no toxicity on the viability of SH-SY5Y cells at the concentration up to 50 µM and targeted GSK-3ß with the increased phosphorylated GSK-3ß at Ser9. Western blot analysis indicated that 16b decreased the phosphorylated tau at Ser396 in a dose-dependent way. Moreover, 16b effectively increased expressions of ß-catenin as well as the GAP43, N-myc, and MAP-2, and promoted the differentiated neuronal neurite outgrowth. Therefore, the thieno[3,2-c]pyrazol-3-amine derivative 16b could serve as a promising GSK-3ß inhibitor for the treatment of AD.
Assuntos
Doença de Alzheimer , Aminas , Glicogênio Sintase Quinase 3 beta , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/metabolismo , Aminas/síntese química , Aminas/farmacologia , Inibidores Enzimáticos/farmacologia , Glicogênio Sintase Quinase 3 beta/antagonistas & inibidores , Humanos , Fosforilação , Proteínas tau/metabolismoRESUMO
A series of novel 3-(1-benzotriazole)-nor-ß-lapachones 5a-5l were synthesized as the NQO1-targeted anticancer agents. Most of these compounds displayed good antiproliferative activity against the breast cancer MCF-7, lung cancer A549 and hepatocellular carcinoma HepG2 cells in agreements with their NQO1 activity. Among them, compound 5k was identified as a favorable NQO1 substrate. It could activate the ROS production in a NQO1-dependent manner, arrest tumor cell cycle at G0/G1 phase, promote tumor cell apoptosis, and decrease the mitochondrial membrane potential. In HepG2 xenograft models, 5k significantly suppressed the tumor growth with no influences on animal body weights. Therefore, 5k could be a good lead for further anticancer drug developments.
Assuntos
Antineoplásicos/farmacologia , Benzofuranos/farmacologia , Desenho de Fármacos , Inibidores Enzimáticos/farmacologia , NAD(P)H Desidrogenase (Quinona)/antagonistas & inibidores , Naftoquinonas/farmacologia , Triazóis/farmacologia , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Benzofuranos/síntese química , Benzofuranos/química , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Humanos , Neoplasias Hepáticas Experimentais/tratamento farmacológico , Neoplasias Hepáticas Experimentais/metabolismo , Neoplasias Hepáticas Experimentais/patologia , Camundongos , Camundongos Nus , Modelos Moleculares , Estrutura Molecular , NAD(P)H Desidrogenase (Quinona)/metabolismo , Naftoquinonas/síntese química , Naftoquinonas/química , Relação Estrutura-Atividade , Triazóis/síntese química , Triazóis/química , Células Tumorais CultivadasRESUMO
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 XenoenxertoRESUMO
The clinical application of mitoxantrone (MTZ), a DNA-intercalating topoisomerase II (topo II) poison, has been largely limited by the risk of secondary tumor and severe myelosuppression. To develop more effective antineoplastic agents with less toxicity, a spectrum of anthraquinone analogues of MTZ were herein designed and synthesized based on the concept of 'enhancing protein backbone-binding', by rationally introducing hydrophobic long fatty acid chain (LFC) and hydrophilic polyamine (PA) components, which are reported to function as effective tumor-targeting tethers. The SAR exploration implicated that in our synthesized molecules, the introduction of both lipophilic LFC and hydrophilic PA fragment is plausibly beneficial to the anti-proliferative potency, with a certain degree of selectivity between the hematopoietic and solid malignant cells, which still need to be further accurately confirmed. Meanwhile, many compounds, the LFC-tethered 5d2 and PA-bridged 8c in particular, provided satisfactory topo IIα inhibition by acting as DNA non-intercalators, largely attributable to their strong adaptability to three binding regions (pocket I, II and III) and also the generated H-bonding interactions between inhibitors and key residues of topo IIα. In brief, 5d2 and 8c might be promising hits for further exploitation of more potent topo IIα inhibitors.
Assuntos
Antraquinonas/química , Antineoplásicos/farmacologia , Desenho de Fármacos , Mitoxantrona/análogos & derivados , Inibidores da Topoisomerase II/farmacologia , Antineoplásicos/química , Linhagem Celular Tumoral , Humanos , Mitoxantrona/química , Mitoxantrona/farmacologia , Relação Estrutura-Atividade , Inibidores da Topoisomerase II/químicaRESUMO
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 4aâ»e as well as the unexpected pyrazole derivatives 5aâ»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 4aâ»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 ïM, respectively. Moreover, 5b was identified as a novel tubulin polymerization inhibitor with an IC50 of 7.30 ïM.
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/farmacologiaRESUMO
In previous work, we applied the rotation-limiting strategy and introduced a substituent at the 3-position of the pyrazolo [3,4-d]pyrimidin-4-amine as the affinity element to interact with the deeper hydrophobic pocket, discovered a series of novel quinazolinones as potent PI3Kδ inhibitors. Among them, the indole derivative 3 is one of the most selective PI3Kδ inhibitors and the 3,4-dimethoxyphenyl derivative 4 is a potent and selective dual PI3Kδ/γ inhibitor. In this study, we replaced the carbonyl group in the quinazolinone core with a sulfonyl group, designed a series of novel 2H-benzo[e][1,2,4]thiadiazine 1,1-dioxide derivatives as PI3Kδ inhibitors. After the reduction of nitro group in N-(2,6-dimethylphenyl)-2-nitrobenzenesulfonamide 5 and N-(2,6-dimethylphenyl)-2-nitro-5-fluorobenzenesulfonamide 6, the resulting 2-aminobenzenesulfonamides were reacted with trimethyl orthoacetate to give the 3-methyl-2H-benzo[e][1,2,4]thiadiazine 1,1-dioxide derivatives. After bromination of the 3-methyl group, the nucleophilic substitution with the 3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine provided the respective iodide derivatives, which were further reacted with a series of arylboronic acids via Suzuki coupling to furnish the 2H-benzo[e][1,2,4]thiadiazine 1,1-dioxide derivatives 15a-J and 16a-d. In agreement with the quinazolinone derivatives, the introduction of a 5-indolyl or 3,4-dimethoxyphenyl at the affinity pocket generated the most potent analogues 15a and 15b with the IC50 values of 217 to 266 nM, respectively. In comparison with the quinazolinone lead compounds 3 and 4, these 2H-benzo[e][1,2,4]thiadiazine 1,1-dioxide derivatives exhibited much decreased PI3Kδ inhibitory potency, but maintained the high selectivity over other PI3K isoforms. Unlike the quinazolinone lead compound 4 that was a dual PI3Kδ/γ inhibitor, the benzthiadiazine 1,1-dioxide 15b with the same 3,4-dimethoxyphenyl moiety was more than 21-fold selective over PI3Kγ. Moreover, the introducing of a fluorine atom at the 7-position of the 2H-benzo[e][1,2,4]thiadiazine 1,1-dioxide core, in general, was not favored for the PI3Kδ inhibitory activity. In agreement with their high PI3Kδ selectivity, 15a and 15b significantly inhibited the SU-DHL-6 cell proliferation.
Assuntos
Classe I de Fosfatidilinositol 3-Quinases/antagonistas & inibidores , Inibidores de Proteínas Quinases/síntese química , Quinazolinonas/química , Tiadiazinas/síntese química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Classe I de Fosfatidilinositol 3-Quinases/química , Desenho de Fármacos , Humanos , Simulação de Acoplamento Molecular , Neoplasias/tratamento farmacológico , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Quinazolinonas/síntese química , Quinazolinonas/farmacologia , Relação Estrutura-Atividade , Tiadiazinas/química , Tiadiazinas/farmacologiaRESUMO
The design, synthesis, and biological evaluation of a series of six HIV-1 protease inhibitors incorporating isosorbide moiety as novel P2 ligands are described. All the compounds are very potent HIV-1 protease inhibitors with IC50 values in the nanomolar or picomolar ranges (0.05-0.43 nM). Molecular docking studies revealed the formation of an extensive hydrogen-bonding network between the inhibitor and the active site. Particularly, the isosorbide-derived P2 ligand is involved in strong hydrogen bonding interactions with the backbone atoms.
Assuntos
Desenho de Fármacos , Inibidores da Protease de HIV/farmacologia , Protease de HIV/metabolismo , HIV-1/enzimologia , Isossorbida/farmacologia , Relação Dose-Resposta a Droga , Inibidores da Protease de HIV/síntese química , Inibidores da Protease de HIV/química , HIV-1/efeitos dos fármacos , Isossorbida/síntese química , Isossorbida/química , Ligantes , Modelos Moleculares , Conformação Molecular , Relação Estrutura-AtividadeRESUMO
3-Nitro-2H-chromenes have recently been identified as a novel class of potent antitumor agents. In view of the favorable effects shown by sulfonylhydrazones and acylhydrazones, we designed and synthesized a series of sulfonylhydrazone- and acylhydrazone-substituted 8-ethoxy-3-nitro-2H-chromene derivatives, and evaluated their cell growth inhibition activities against A549, KG-1, A2780, and K562 cells. All the tested compounds exhibited more potent antiproliferative activity than BENC-511 against KG-1 cells. These compounds displayed IC50 values in the nanomolar range against A2780 cells. Compound 7d showed prominent cytotoxicity against K562 cells with an IC50 of 0.11 µM, which was comparable to that of BENC-511. Compound 7d arrested K562 cells at the G1 phase at high concentrations and induced apoptosis in K562 cells. Furthermore, 7d increased the levels of cleaved caspase-3, decreased the expression of bcl-2 and induced the cleavage of poly(ADP-ribose) polymerase in K562 cells. Thus, this study provides the development of a series of novel compounds as effective antitumor agents with apoptotic death ability.
Assuntos
Antineoplásicos/síntese química , Apoptose/efeitos dos fármacos , Benzopiranos/síntese química , Proliferação de Células/efeitos dos fármacos , Hidrazonas/química , Antineoplásicos/química , Antineoplásicos/farmacologia , Benzopiranos/química , Benzopiranos/farmacologia , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Citometria de Fluxo , Humanos , Concentração Inibidora 50 , Células K562 , Estrutura MolecularRESUMO
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/metabolismoRESUMO
Epothilone B (Epo B) is a potent antitumor natural product with sub-nanomolar anti-proliferation action against several human cancer cells. However, poor selectivity to tumor cells and unacceptable therapeutic windows of Epo B and its analogs are the major obstacles to their development into clinical drugs. Herein, we present self-assembled nanomicelles based on an amphiphilic carbohydrate-Epo B conjugate that is inactive until converted to active Epo B within the tumor. Four Epo B-Rhamnose conjugates linked via two linkers containing a disulfide bond that is sensitive to GSH were synthesized. Conjugate 34 can self-assemble into nanomicelles with a high concentration of Rha on the surface, allowing for better tumor targeting. After internalization by cancer cells, the disulfide bond can be cleaved in the presence of high levels of GSH to release active Epo B, thereby exhibiting significant anticancer efficiency and selectivity in vitro and in vivo.
Assuntos
Epotilonas , Nanopartículas , Neoplasias , Humanos , Neoplasias/tratamento farmacológico , Carboidratos/uso terapêutico , Dissulfetos , Linhagem Celular Tumoral , Nanopartículas/químicaRESUMO
The epigenetic reader BRD4 is involved in chromatin remodelling and transcriptional regulation, making it a promising therapeutic target. However, over the past decades, many BRD4 inhibitors that entered clinical trials were, in the main, unsatisfactory, due to some therapeutic limitations such as off-target effects and drug resistance. Combining a BRD4 inhibitor with another drug was expected to be an ideal option to overcome these hurdles and to improve therapeutic outcomes. However, such combination therapy could trigger toxicity caused by drug-drug interactions, complex pharmacokinetics, and additive effects. Recently, the application of dual-target drugs targeting BRD4 and other kinases has become an attractive approach to remedy the defects of a single BRD4 inhibitor. This review focuses on recent advances in the discovery of dual BRD4-kinase inhibitors, with an emphasis on their co-crystal structures and structure-activity relationships (SARs), as well as future perspectives in this field.
Assuntos
Antineoplásicos , Proteínas de Ciclo Celular , Neoplasias , Fatores de Transcrição , Antineoplásicos/farmacologia , Proteínas de Ciclo Celular/antagonistas & inibidores , Humanos , Neoplasias/tratamento farmacológico , Proteínas Nucleares , Polifarmacologia , Fatores de Transcrição/antagonistas & inibidoresRESUMO
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-AtividadeRESUMO
Brartemicin is a trehalose-based inhibitor of tumor cell invasion produced by the actinomycete of the genus Nonomuraea. In order to explore the preliminary structure-activity relationship and obtain more potent inhibitors, a series of brartemicin analogs were synthesized through the Mitsunobu coupling of the secondary hydroxyls benzyl protected α,α-D-trehalose with benzoic acid derivatives, followed by modification of functional groups and deprotection. These compounds were evaluated for their inhibitory activity against invasion of murine colon 26-L5 carcinoma cells in vitro. Among the synthetic analogs tested, 6,6'-bis(2,3-dimethoxybenzoyl)-α,α-D-trehalose (5e) was found to be the most potent anti-invasive agent, exhibited a 2.6-fold improvement with regard to the parent natural product brartemicin, and it is considered to be a promising lead molecule for the anti-metastasis.
Assuntos
Antineoplásicos/síntese química , Trealose/análogos & derivados , Animais , Antineoplásicos/química , Antineoplásicos/uso terapêutico , Linhagem Celular Tumoral , Camundongos , Relação Estrutura-Atividade , Trealose/síntese química , Trealose/química , Trealose/uso terapêuticoRESUMO
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/farmacologiaRESUMO
BACKGROUND: The casein kinase 1 (CK1) family is involved in regulating many cellular processes, including membrane trafficking, DNA damage repair, cytoskeleton dynamics, cytoskeleton maintenance and apoptosis. CK1 isoforms, especially CK1δ and CK1ε have emerged as important therapeutic targets for severe disorders such as Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), familial advanced sleep phase syndrome and cancer. Due to the importance of CK1 for the pathogenesis of disorders, there are great interests in the development of CK1 inhibitors. METHODS: Using SciFinder® as a tool, the publications about the biology of CK1 and the recent developments of CK1 inhibitors were surveyed with an exclusion of those published as patents. RESULTS: This review presents the current state of knowledge on the development of CK1 inhibitors, including both synthetic small molecular inhibitors that were divided into 7 categories according to structural features, and the natural compounds. An overview of the advancement of CK1 inhibitors was given, with the introduction of various existing CK1 inhibitors, their inhibitory activities, and the structure-activity relationships. CONCLUSION: Through physicochemical characterization and biological investigations, it is possible to understand the structure-activity relationship of CK1 inhibitors, which will contribute to better design and discovery of potent and selective CK1 inhibitors as potential agents for severe disorders such as AD, ALS and cancer.
Assuntos
Caseína Quinase I , Neoplasias , Apoptose , Caseína Quinase I/metabolismo , Humanos , Neoplasias/tratamento farmacológico , Isoformas de Proteínas , Relação Estrutura-AtividadeRESUMO
RET is a proto-oncogene encoding a receptor tyrosine kinase. RET regulates key aspects of cellular proliferation, differentiation and survival. The activation of RET via gene fusions or point mutations is closely related to lung, thyroid and other cancers. This review summarizes the developments of a diversity of small molecule RET protein kinase inhibitors in the past 10 years. These RET inhibitors are classified according to their hinge binder chemotypes as: pyrimidines, including the pyrazolopyrimidines, pyrimidine oxazines, quinazolines, 4-aminopyrimidines and 4-aminopyridines; indolinones; 5-aminopyrazole-4-carboxamides; 3-trifluoromethylanilines; imidazopyridines, imidazopyridazines and pyrazopyridines; nicotinonitriles; pyridones and 1,2,4-triazoles. In each section, the biological activities of the inhibitors, their structure-activity relationships and possible binding modes with the RET kinase are introduced.