RESUMO
Two series of 2,4-diarylaminopyrimidine derivatives containing sulfonamide moiety were designed and synthesized for screening as inhibitors of focal adhesion kinase (FAK). Most compounds significantly inhibited the enzymatic activities of FAK, and the best compound was 7b (IC50 = 0.27 nM). A majority of aminoethyl sulfonamide derivatives could effectively inhibit the proliferation of human cancer cell lines (HCT116, A549, MDA-MB-231 and Hela) expressing high levels of FAK. Particularly, compounds 7b, 7c, and 7o exhibited more significant efficacy against all of four cancer cell lines within concentrations of 1.5 µM. Furthermore, these three compounds displayed higher selectivity of cancer cells over normal cells (SI value > 14), compared to the positive control TAE226 (SI value = 1.63). Interestingly, introduction of dithiocarbamate moiety to the aminoethyl sulfonamide derivatives can indeed improve the antiproliferative activities against A549 cells. Especially, compound 8d demonstrated most significant cytotoxicity activity against A549 cells with an IC50 value of 0.08 µM, which is 20-fold superior to parent compound 7k. Additionally, compound 7b, which display the best anti-FAK potency, can inhibit the clone formation and migration of HCT-116 cells, and cause cell cycle arrest at G2/M phase, inducing apoptosis by promoting ROS production. Overall, these results suggest that 7b is a valuable FAK inhibitor that deserves further optimization to improve its druggability.
Assuntos
Antineoplásicos , Humanos , Antineoplásicos/farmacologia , Apoptose , Linhagem Celular Tumoral , Proliferação de Células , Ensaios de Seleção de Medicamentos Antitumorais , Proteína-Tirosina Quinases de Adesão Focal , Simulação de Acoplamento Molecular , Estrutura Molecular , Inibidores de Proteínas Quinases/farmacologia , Relação Estrutura-Atividade , Sulfonamidas/farmacologia , Pirimidinas/química , Pirimidinas/farmacologiaRESUMO
The approved small-molecule inhibitors of anaplastic lymphoma kinase (ALK) have shown remarkable efficacy in some subset of cancer patients. However, the numerous ALK mutants or fusion partners are resistant to such drugs, greatly limiting their application in clinic. Despite the drug design strategy of proteolysis-targeting chimera (PROTAC) holds great potential to overcome drug resistance in theory, there are obvious disadvantages for the reported PROTACs that include high molecular weight, long linkers, difficult synthesis routes as well as insufficient evidence in activity for diverse ALK mutants. In this study, we designed and synthesized a miniaturized PROTAC of ALK named AP-1 following the principle of minimalist design. Two simple chemical units of ligands and a minimized linker with only two atoms were selected for synthesis of AP-1. At cellular level, AP-1 successfully degraded three types of ALK mutants including NPM-ALK, EML4-ALK and F1174L mutation ALK form with potent activity, high selectivity in ALK-positive cells. In xenograft mouse model, AP-1 showed the stronger antitumor efficacy than ceritinib as well as ALK degraders reported in literatures. AP-1 with an extremely simple PROTAC structure can be served as an effective candidate drug for therapy of various types of ALK-positive cancers. And the design principle of AP-1 has a good guiding significance for overcoming the disadvantages such as excessive molecular weight and poor solubility of PROTAC.
Assuntos
Antineoplásicos , Neoplasias , Quimera de Direcionamento de Proteólise , Animais , Humanos , Camundongos , Antineoplásicos/química , Linhagem Celular Tumoral , Desenho de Fármacos , Resistencia a Medicamentos Antineoplásicos , Mutação , Neoplasias/tratamento farmacológico , Inibidores de Proteínas Quinases/química , Fator de Transcrição AP-1 , Quimera de Direcionamento de Proteólise/química , Quimera de Direcionamento de Proteólise/farmacologiaRESUMO
The serine-threonine protein phosphatase 2A (PP2A) is a heterotrimeric enzyme complex that regulates many fundamental cellular processes. PP2A is involved in tumorigenesis because mutations in the scaffold subunit, PPP2R1B, were found in several types of cancers. However, the biological function of PPP2R1B remains largely unknown. We report here that homozygous deletion of Ppp2r1b in Mus musculus impairs meiotic recombination and causes meiotic arrest in spermatocytes. Consistently, male mice lacking Ppp2r1b are characterized with infertility. Furthermore, heterozygous missense mutations in the Homo sapiens PPP2R1B gene, which encodes PPP2R1B, are identified in azoospermia patients with meiotic arrest. We found that PPP2R1B mutants are susceptible to degradation by an E3 ligase CRL4ADCAF6 , and resistant to de-polyubiquitylation by ubiquitin-specific protease 5 (USP5). In addition, heterozygous mutations in PPP2R1B reduce stability of the wild-type PPP2R1B. Our results demonstrate an essential role of PPP2R1B in spermatogenesis and identify upstream regulators of PPP2R1B.
Assuntos
Infertilidade Masculina/patologia , Mutação , Proteína Fosfatase 2/metabolismo , Proteína Fosfatase 2/fisiologia , Espermatogênese , Testículo/patologia , Ubiquitinação , Animais , Família , Feminino , Homozigoto , Humanos , Infertilidade Masculina/etiologia , Infertilidade Masculina/metabolismo , Masculino , Meiose , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteína Fosfatase 2/genética , Testículo/metabolismoRESUMO
Pyruvate kinase M2 isoform (PKM2) plays a key role in cancer progression through both metabolic and non-metabolic functions, thus it is recognized as a potential target for cancer diagnosis and treatment. In this study, we discovered a sulfonamide-dithiocarbamate compound 8a as a novel PKM2 activator from a random screening of an in-house compound library. Then, a series of lead compound 8a analogs were designed and synthesized for screening as potent PKM2 activators. Among them, compound 8b (AC50 = 0.136 µM) and 8k (AC50 = 0.056 µM) showed higher PKM2 activation activities than positive control NZT (AC50 = 0.228 µM), and they (IC50 < 1 µM) exhibited more significant anti-proliferative activities against human tumor cell lines than NZT (IC50 > 10 µM). Especially, compound 8k inhibited the proliferation of multiple cancer cells, but showed little toxicity on normal cells. In addition, we found that compound 8k inhibit the colony formation of MCF7 cells. Western blot analysis demonstrated that 8k could reduce PKM2 nuclear localization and block the downstream signaling pathway of PKM2, resulting in suppression of tumor cell proliferation. Overall, compound 8k may be a promising candidate for further mechanistic investigation of PKM2 and cancer therapy.
Assuntos
Antineoplásicos/farmacologia , Proteínas de Transporte/antagonistas & inibidores , Proteínas de Membrana/antagonistas & inibidores , Piperazina/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Sulfonamidas/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Proteínas de Transporte/metabolismo , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Proteínas de Membrana/metabolismo , Estrutura Molecular , Piperazina/química , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Relação Estrutura-Atividade , Sulfonamidas/síntese química , Sulfonamidas/química , Hormônios Tireóideos/metabolismo , Proteínas de Ligação a Hormônio da TireoideRESUMO
A new type of spirocyclic bisoxindole-based C2-symmetric diols (SBIDOLs) was designed and synthesized. A series of racemic SBIDOL derivatives (6a-6g) were readily synthesized from commercially available 2-halo-5-methoxyanilines 1 (X = Cl or Br) through N-mono alkylation, acylation, oxidation, double intramolecular Friedel-Crafts reaction, and demethylation reactions. The optical resolution of racemic 6b was achieved via fractional crystallization of their bis-l-menthoxycarboxylates. Further modifications of SBIDOLs were investigated, leading to 5,5'-diaryl SBIDOL derivatives (11a and 11b) through Pd-catalyzed Suzuki coupling and DM-SBIDOL 12 by Pd/C-catalyzed hydrogenative dechlorination reactions.
RESUMO
Bruton's tyrosine kinase (BTK) has emerged as an attractive target related to B-lymphocytes dysfunctions, especially hematologic malignancies and autoimmune diseases. In our study, a series of diphenylaminopyrimidine derivatives bearing dithiocarbamate moieties were designed and synthesized as novel BTK inhibitors for treatment of B-cell lymphoma. Among all these compounds, 30ab (IC50â¯=â¯1.15⯱â¯0.19â¯nM) displays similar or more potent inhibitory activity against BTK than spebrutinib (IC50â¯=â¯2.12⯱â¯0.32â¯nM) and FDA approved drug ibrutinib (IC50â¯=â¯3.89⯱â¯0.57â¯nM), which is attributed to close binding of 30ab with BTK predicted by molecular docking. In particular, 30ab exhibits enhanced anti-proliferative activity against B-lymphoma cell lines at the IC50 concentration of 0.357⯱â¯0.02⯵M (Ramos) and 0.706⯱â¯0.05⯵M (Raji), respectively, almost 10-fold better than ibrutinib and spebrutinib. In addition, 30ab displays stronger selectivity on B-cell lymphoma over other cancer cell lines than spebrutinib. Furthermore, 30ab efficiently blocks BTK downstream pathways and results in apoptosis of cancer cells. In vivo xenograft model evaluation demonstrates the significant efficacy and broad safety margin of 30ab in treatment of B-cell lymphoma. We propose that compound 30ab is a candidate for further study and development based on our current findings.
Assuntos
Tirosina Quinase da Agamaglobulinemia/antagonistas & inibidores , Inibidores de Proteínas Quinases/uso terapêutico , Pirimidinas/metabolismo , Humanos , Estrutura Molecular , Inibidores de Proteínas Quinases/farmacologiaRESUMO
The M2 isoform of pyruvate kinase (PKM2) is a potential antitumor therapeutic target. In this study, we designed and synthesised a series of 2, 3-didithiocarbamate substituted naphthoquinones as PKM2 inhibitors based on the lead compound 3k that we previously reported. Among them, compound 3f (IC50 = 1.05 ± 0.17 µM) and 3h (IC50 = 0.96 ± 0.18 µM) exhibited potent inhibition of PKM2, and their inhibitory activities are superior to compound 3k (IC50 = 2.95 ± 0.53 µM) and the known PKM2 inhibitor shikonin (IC50 = 8.82 ± 2.62 µM). In addition, we evaluated in vitro antiproliferative effects of target compounds using MTS assay. Most target compounds exhibited dose-dependent cytotoxicity with IC50 values in nanomolar concentrations against HCT116, MCF7, Hela, H1299 and B16 cells. These small molecule PKM2 inhibitors not only provide candidate compounds for cancer therapy, but also offer a tool to probe the biological effects of PKM2 inhibition on cancer cells.
Assuntos
Antineoplásicos/farmacologia , Inibidores Enzimáticos/farmacologia , Naftoquinonas/farmacologia , Piruvato Quinase/antagonistas & inibidores , Antineoplásicos/síntese química , Antineoplásicos/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 , Estrutura Molecular , Naftoquinonas/síntese química , Naftoquinonas/química , Piruvato Quinase/metabolismo , Relação Estrutura-Atividade , Células Tumorais CultivadasRESUMO
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
In this study we investigated the antitumor activity of the novel dual dithiocarbamatic acid ester LRD-22 in vitro and in vivo. Several cancer cell lines were employed to determine the effect of LRD-22 on cell growth, and the MTT assay showed there was a significant decrease in viable tumor cell numbers in the presence of LRD-22, especially in the HepG2 cell line. Colony formation assay also showed LRD-22 strongly inhibits HepG2 cell growth. Evaluation of the mechanism involved showed that inhibitory effects of LRD-22 on cell growth are due to induction of apoptosis and G2/M arrest. LRD-22 inhibited Aurora-A phosphorylation at Thr288 and subsequently impaired p53 phosphorylation at Ser315 which was associated with the proteasome degradation pathway. Tumor suppressor protein p53 is stabilized by this mechanism and accumulates through inhibition of Aurora-A kinase activity via treatment with LRD-22. In vivo study of HepG2 xenograft in nude mice also shows LRD-22 suppresses tumor growth at a concentration of 5 mg/kg without animals suffering loss of body weight. In conclusion, our results demonstrate LRD-22 acts as an Aurora-A kinase inhibitor to induce apoptosis and inhibit proliferation in HepG2 cells, and should be considered as a promising targeting agent for HCC therapy.
Assuntos
Apoptose/efeitos dos fármacos , Aurora Quinase A/antagonistas & inibidores , Benzodioxóis/farmacologia , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Tiocarbamatos/farmacologia , Animais , Antineoplásicos/farmacologia , Aurora Quinase A/metabolismo , Proliferação de Células/efeitos dos fármacos , Feminino , Células Hep G2/efeitos dos fármacos , Humanos , Camundongos Nus , Fosforilação/efeitos dos fármacos , Inibidores de Proteínas Quinases/farmacologia , Tiocarbamatos/química , Proteína Supressora de Tumor p53/antagonistas & inibidores , Proteína Supressora de Tumor p53/metabolismo , Redução de Peso/efeitos dos fármacos , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Pyruvate kinase M2 (PKM2) is a key protein responsible for cancer's Warburg effect. Activation of PKM2 may alter aberrant metabolism in cancer cells, which suggests PKM2 as a tumor selective therapeutic target. In this paper, the lead compound 8 was first discovered as a new kind of PKM2 activator from a random screening of an in-house compound library. Then, a series of lead compound 8 analogs were designed, synthesized and evaluated for their activation of PKM2 and anticancer activities. 7-Azaindole analog 32 was identified as the most potent PKM2 activator. Compounds with potent enzyme activity also exhibited selective anti-proliferation activity on cancer cell lines HCT116, Hela and H1299 compared with non-tumor cell line BEAS-2B. The structure-activity relationships of these compounds were supported by molecular docking results. Preliminary pharmacological studies also showed that compound 32 arrests the cell cycle at the G2/M phase in HCT116 cell line.
Assuntos
Antineoplásicos/química , Piruvato Quinase/metabolismo , Tiocarbamatos/química , Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Sítios de Ligação , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Ésteres , Pontos de Checagem da Fase G2 do Ciclo Celular/efeitos dos fármacos , Células HCT116 , Células HeLa , Humanos , Pontos de Checagem da Fase M do Ciclo Celular/efeitos dos fármacos , Simulação de Acoplamento Molecular , Isoformas de Proteínas/antagonistas & inibidores , Isoformas de Proteínas/metabolismo , Estrutura Terciária de Proteína , Piruvato Quinase/antagonistas & inibidores , Relação Estrutura-Atividade , Tiocarbamatos/síntese química , Tiocarbamatos/farmacologiaRESUMO
While protein aggregation's association with aging and age-related diseases is well-established, the specific proteins involved and whether dissolving them could alleviate aging remain unclear. Our research addresses this gap by uncovering the role of PKM2 aggregates in aging. We find that PKM2 forms aggregates in senescent cells and organs from aged mice, impairing its enzymatic activity and glycolytic flux, thereby driving cells into senescence. Through a rigorous two-step small molecule library screening, we identify two compounds, K35 and its analog K27, capable of dissolving PKM2 aggregates and alleviating senescence. Further experiments show that treatment with K35 and K27 not only alleviate aging-associated signatures but also extend the lifespan of naturally and prematurely aged mice. These findings provide compelling evidence for the involvement of PKM2 aggregates in inducing cellular senescence and aging phenotypes, and suggest that targeting these aggregates could be a promising strategy for anti-aging drug discovery.
Assuntos
Envelhecimento , Senescência Celular , Proteínas de Ligação a Hormônio da Tireoide , Animais , Envelhecimento/metabolismo , Camundongos , Humanos , Proteínas de Membrana/metabolismo , Proteínas de Membrana/genética , Proteínas de Transporte/metabolismo , Glicólise , Hormônios Tireóideos/metabolismo , Agregados Proteicos , Piruvato Quinase/metabolismo , Camundongos Endogâmicos C57BL , MasculinoRESUMO
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
BACKGROUND: Cerebrotendinous xanthomatosis (CTX) is a rare autosomal recessive lipid-storage disorder caused by mutations in CYP27A1. Psychiatric manifestations in CTX are rare and nonspecific, and they often lead to considerable diagnostic and treatment delay. CASE SUMMARY: A 33-year-old female patient admitted to the psychiatric ward for presentation of delusions, hallucinations, and behavioral disturbance is reported. The patient presented with cholestasis, cataract, Achilles tendon xanthoma, and cerebellar signs in adulthood and with intellectual disability and learning difficulties in childhood. After the characteristic CTX findings on imaging were obtained, a pathological examination of the Achilles tendon xanthoma was refined. Re-placement therapy was then initiated after the diagnosis was clarified by genetic analysis. During hospitalization in the psychiatric ward, the nonspecific psychiatric manifestations of the patient posed difficulty in diagnosis. After the patient's history of CTX was identified, the patient was diagnosed with organic schizophrenia-like disorder, and psychotic symptoms were controlled by replacement therapy combined with antipsychotic medication. CONCLUSION: Psychiatrists should be aware of CTX, its psychiatric manifestations, and clinical features and avoid misdiagnosis of CTX for timely intervention.
RESUMO
Background: PRMT5 is an epigenetics-related enzyme, which plays a critical role in cancer development. Hence PRMT5 inhibition has been validated as a promising therapeutic strategy. Methods & Results: We synthesized a series of methylpiperazinyl derivatives as novel PRMT5 inhibitors that were achieved by scaffold-hopping from EPZ015666 by virtual screening followed by rational drug design. Among all compounds 43g, bearing a thiourea linker, showed antitumor activity across multiple cancer cell lines and reduced the level of symmetric arginine dimethylation of SmD3 dose-dependently. Moreover, 43g selectively inhibited PRMT5 among protein arginine methyltransferase isoforms. Further proteomics analysis revealed that 43g remarkably reduced the global arginine dimethylation level in a cellular context. Conclusion: This work provides new chemical templates for future structural optimization of PRMT5-related cancer treatments.
Assuntos
Inibidores Enzimáticos , Proteína-Arginina N-Metiltransferases , Arginina , Linhagem Celular Tumoral , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Relação Estrutura-AtividadeRESUMO
Ferroptosis is a non-apoptotic cell death characterized by iron-mediated ROS accumulation and increasing lipid peroxidation. The activation of ferroptosis results in the destruction of cancer cells and overcoming the drug resistance associated with existing chemotherapeutic agents. It is essential to develop new ferroptosis inducers to provide new opportunities for cancer therapy. In this study, we found a small molecule Compound 8 which we had demonstrated to inhibit tumor growth in vivo initiated ferroptosis. Compound 8 treatment elevated the ferroptosis-related genes PTGS2 and CHAC1 mRNA levels in tumor cells. Ferroptosis inhibitors but not the necroptosis inhibitor or the apoptosis inhibitor can suppress the cell death induced by Compound 8. Compound 8 causes overall greater quantity of lipid peroxidation than the classic ferroptosis inducer Erastin through Flow cytometry analysis. The non-targeted lipidomic analysis also showed Compound 8 treatment resulted in oxidized lipid metabolites, similar to Erastin. The mechanism research showed that Compound 8 initiated ferroptosis by inhibiting the system Xc- to deplete GSH. Based on our previous study that Compound 8 blocked the interaction of PKM2 and VDAC3 (a regulator of ferroptosis) to inhibit tumor growth in vivo, Compound 8 may also trigger ferroptosis by regulating VADC3. Thus, Compound 8 not only will offer a potential tumor therapeutic alternative, but also provide an entrance to explore the new mechanism of ferroptosis.
Assuntos
Ferroptose , Neoplasias , Espécies Reativas de Oxigênio/metabolismo , Linhagem Celular Tumoral , Ciclo-Oxigenase 2/metabolismo , Peroxidação de Lipídeos , Ferro/metabolismo , RNA Mensageiro/metabolismo , Neoplasias/tratamento farmacológicoRESUMO
The ovarian-tumor-domain-containing deubiquitinases (OTUDs) block ubiquitin-dependent protein degradation and are involved in diverse signaling pathways. We discovered a rare OTUD3 c.863G>A mutation in a family with an early age of onset of diabetes. This mutation reduces the stability and catalytic activity of OTUD3. We next constructed an experiment with Otud3-/- mice and found that they developed worse obesity, dyslipidemia, and insulin resistance than wild-type mice when challenged with a high-fat diet (HFD). We further found that glucose and fatty acids stimulate CREB-binding-protein-dependent OTUD3 acetylation, promoting its nuclear translocation, where OTUD3 regulates various genes involved in glucose and lipid metabolism and oxidative phosphorylation by stabilizing peroxisome-proliferator-activated receptor delta (PPARδ). Moreover, targeting PPARδ using a specific agonist can partially rescue the phenotype of HFD-fed Otud3-/- mice. We propose that OTUD3 is an important regulator of energy metabolism and that the OTUD3 c.863G>A is associated with obesity and a higher risk of diabetes.
Assuntos
Diabetes Mellitus , Resistência à Insulina , Estresse Fisiológico , Proteases Específicas de Ubiquitina , Animais , Enzimas Desubiquitinantes/metabolismo , Diabetes Mellitus/metabolismo , Glucose/metabolismo , Homeostase , Resistência à Insulina/fisiologia , Camundongos , Estado Nutricional , Obesidade/metabolismo , PPAR delta/metabolismo , Proteases Específicas de Ubiquitina/metabolismoRESUMO
On the basis of combination strategy, a novel series of EGFR inhibitors were designed and synthesized by combination of dithiocarbamic acid esters and 4-anilinoquinazolines. The effect of the synthesized compounds on cell proliferation was evaluated by MTT assay in three human cancer cell lines: MDA-MB-468, SK-BR-3 and HCT-116. Two compounds (11d and 11f) were found more potent against all three cell lines and five compounds (11a, 11d-11g) were found more potent against both MDA-MB-468 and SK-BR-3 than Lapatinib. SAR studies revealed that the substituents on C6 and C7 positions of quinazoline, the amine component of dithiocarbamate moiety and the linker greatly affected the activity. This work provides a promising new strategy for the preparation of potent tyrosine kinase inhibitors.
Assuntos
Compostos de Anilina/síntese química , Antineoplásicos/síntese química , Receptores ErbB/antagonistas & inibidores , Ésteres/síntese química , Quinazolinas/síntese química , Tiocarbamatos/síntese química , Compostos de Anilina/química , Compostos de Anilina/farmacologia , Antineoplásicos/química , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Ésteres/química , Ésteres/farmacologia , Humanos , Estrutura Molecular , Quinazolinas/química , Quinazolinas/farmacologia , Relação Estrutura-Atividade , Tiocarbamatos/química , Tiocarbamatos/farmacologiaRESUMO
Recent decades have witnessed several nanocrystal-based hydrophobic drug formulations because of their excellent performance in improving drug loading and controlling drug release as mediate drug forms in tablets or capsules. However, the intravenous administration of drug nanocrystals was usually hampered by their hydrophobic surface properties, causing short half-life time in circulation and low drug distribution in tumor. Here, we proposed to enclose nanocrystals (NC) of hydrophobic drug, such as paclitaxel (PTX) into erythrocyte membrane (EM). By a series of formulation optimizations, spherical PTX nanoparticles (PN) with the particle size of around 280 nm were successfully cloaked in erythrocyte membrane, resulting in a PTX-NP-EM (PNM) system. The PNM could achieve high drug loading of PTX (>60%) and stabilize the particle size significantly compared to PN alone. Besides, the fluorescence-labeling PNM presented better tumor cell uptake, stronger cytotoxicity, and higher drug accumulation in tumor compared to PN. Finally, the PNM was found to be the most effective against tumor growth among all PTX formulations in tumor-bearing mice models, with much lower system toxicity than control formulation. In general, the PNM system with high drug-loading as well as superior bio-distributions in vivo could be served as a promising formulation.
Assuntos
Membrana Eritrocítica/metabolismo , Nanopartículas , Neoplasias/tratamento farmacológico , Paclitaxel/administração & dosagem , Animais , Antineoplásicos Fitogênicos/administração & dosagem , Linhagem Celular Tumoral , Portadores de Fármacos/química , Liberação Controlada de Fármacos , Feminino , Humanos , Interações Hidrofóbicas e Hidrofílicas , Camundongos , Camundongos Endogâmicos BALB C , Neoplasias/patologia , Paclitaxel/farmacocinética , Paclitaxel/farmacologia , Tamanho da Partícula , Distribuição Tecidual , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
A method for the enantioselective synthesis of cis-3-quinuclidinols by Ru-catalyzed asymmetric transfer hydrogenation via dynamic kinetic resolution is described. The reaction proceeded under mild conditions using ammonium formate as the hydrogen donor, affording the products in high yields (up to 99%) with excellent diastereoselectivity (up to 99:1 dr) and enantioselectivity (95-99% ee). This protocol was applicable to gram-scale preparation with perfect enantioselectivity through simple recrystallization.
RESUMO
Anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase responsible for development of various tumor types. In this study, we synthesized a series of novel 2,4-diarylaminopyrimidine derivatives possessing a unique N-(3-pyridinylmethyl)urea moiety as ALK inhibitors. The most promising analog 5m bearing a 3-methoxy-4-morpholinophenyl substituent significantly inhibited proliferation of ALK positive H3122 and Karpas-299â¯cells with IC50 values about 10â¯nM, which were comparable with positive control LDK378. Compound 5m suppressed phosphorylation of ALK and its downstream proteins, and showed low cytotoxicity on normal human primary fibroblast cells (BJ cells). The binding mode of 5m was proposed by docking simulation, which explains the important role of N-(3-pyridinylmethyl)urea moiety. Furthermore, compound 5m exhibited favorable liver microsomal stability and significant efficacy in H3122 xenograft mice model. Interestingly, compound 5m also showed broader anti-proliferative activity on other human tumor cell lines, which was different from other ALK inhibitors.