RESUMO
INTRODUCTION: The P2Y14 receptor (P2Y14R), a member of the G protein-coupled receptor family, is activated by extracellular nucleotides. Due to its involvement in inflammatory, immunological and other associated processes, P2Y14R has emerged as a promising therapeutic target. Despite lacking a determined three-dimensional crystal structure, the homology modeling technique based on closely related P2Y receptors' crystallography has been extensively utilized for developing active compounds targeting P2Y14R. Recent discoveries have unveiled numerous highly effective and subtype-specific P2Y14R inhibitors. This study presents an overview of the latest advancements in P2Y14R inhibitors. AREAS COVERED: This review presents an overview of the advancements in P2Y14R inhibitor research over the past five years, encompassing new patents, journal articles, and highlighting the therapeutic prospects inherent in these compounds. EXPERT OPINION: The recent revelation of the vast potential of P2Y14R inhibitors has led to the development of novel compounds that exhibit promising capabilities for the treatment of sterile inflammation of the kidney, potentially diabetes, and asthma. Despite being a relatively nascent class of compounds, certain members have already exhibited their capacity to surmount specific challenges posed by conventional P2Y14R inhibitors. Targeting P2Y14R through small molecules may present a promising therapeutic strategy for effectively managing diverse inflammatory diseases.
Assuntos
Desenvolvimento de Medicamentos , Inflamação , Patentes como Assunto , Animais , Humanos , Asma/tratamento farmacológico , Asma/fisiopatologia , Diabetes Mellitus/tratamento farmacológico , Desenho de Fármacos , Inflamação/tratamento farmacológico , Inflamação/fisiopatologia , Receptores Purinérgicos P2RESUMO
Dysregulation of IL17A drives numerous inflammatory and autoimmune disorders with inhibition of IL17A using antibodies proven as an effective treatment. Oral anti-IL17 therapies are an attractive alternative option, and several preclinical small molecule IL17 inhibitors have previously been described. Herein, we report the discovery of a novel class of small molecule IL17A inhibitors, identified via a DNA-encoded chemical library screen, and their subsequent optimization to provide in vivo efficacious inhibitors. These new protein-protein interaction (PPI) inhibitors bind in a previously undescribed mode in the IL17A protein with two copies binding symmetrically to the central cavities of the IL17A homodimer.
Assuntos
DNA , Descoberta de Drogas , Interleucina-17 , Bibliotecas de Moléculas Pequenas , Interleucina-17/metabolismo , Interleucina-17/antagonistas & inibidores , Bibliotecas de Moléculas Pequenas/química , Bibliotecas de Moléculas Pequenas/farmacologia , DNA/metabolismo , DNA/química , Humanos , Animais , Relação Estrutura-Atividade , Ligação Proteica , CamundongosRESUMO
INTRODUCTION: Lysine-specific demethylase 1 (LSD1), which belongs to the demethylase of non-histone proteins, is believed to promote cancer cell proliferation and metastasis by modifying histones. LSD1 dysfunction may play a key role in a variety of cancers, such as acute myeloid leukemia and non-small cell lung cancer, indicating that LSD1 is a promising epigenetic target for cancer therapy. Many different types of small molecule LSD1 inhibitors have been developed and shown to inhibit tumor cell proliferation, invasion, and migration, providing a new treatment strategy for solid tumors. AREAS COVERED: This review summarizes the progress of LSD1 inhibitor research in the last four years, including selected new patents and article publications, as well as the therapeutic potential of these compounds. EXPERT OPINION: Natural products offer a promising prospect for developing novel potent LSD1 inhibitors, as structural design and activity of irreversible and reversible inhibitors have been continuously optimized since the discovery of the LSD1 target in 2004. The use of 'microtubule-binding agents' and 'dual-agent combination' has recently become a new anticancer technique, reducing the resistance and adverse reactions of traditional drugs. Several microtubule-binding drugs have been used successfully in clinical practice, providing structural scaffolds and new ideas for the development of safer drugs.
Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Inibidores Enzimáticos/farmacologia , Histona Desmetilases , Histonas/química , Histonas/metabolismo , Humanos , Patentes como AssuntoRESUMO
AIM: It has been reported that necrostatin-1 (Nec-1) is a specific necroptosis inhibitor that could attenuate programmed cell death induced by myocardial ischemia/reperfusion (I/R) injury. This study aimed to observe the effect and mechanism of novel Nec-1 analog (Z)-5-(3,5-dimethoxybenzyl)-2-imine-1-methylimidazolin-4-1 (DIMO) on myocardial I/R injury. METHODS: Male SD rats underwent I/R injury with or without different doses of DIMO (1, 2, or 4 mg/kg) treatment. Isolated neonatal rat cardiomyocytes were subjected to oxygen-glucose deprivation/reoxygenation (OGD/R) treatment with or without DIMO (0.1, 1, 10, or 100 µM). Myocardial infarction was measured by TTC staining. Cardiomyocyte injury was assessed by lactate dehydrogenase assay (LDH) and flow cytometry. Receptor-interacting protein 1 kinase (RIP1K) and autophagic markers were detected by co-immunoprecipitation and Western blotting analysis. Molecular docking of DIMO into the ATP binding site of RIP1K was performed using GLIDE. RESULTS: DIMO at doses of 1 or 2 mg/kg improved myocardial infarct size. However, the DIMO 4 mg/kg dose was ineffective. DIMO at the dose of 0.1 µM decreased LDH leakage and the ratio of PI-positive cells followed by OGD/R treatment. I/R or OGD/R increased RIP1K expression and in its interaction with RIP3K, as well as impaired myocardial autophagic flux evidenced by an increase in LC3-II/I ratio, upregulated P62 and Beclin-1, and activated cathepsin B and L. In contrast, DIMO treatment reduced myocardial cell death and reversed the above mentioned changes in RIP1K and autophagic flux caused by I/R and OGD/R. DIMO binds to RIP1K and inhibits RIP1K expression in a homology modeling and ligand docking. CONCLUSION: DIMO exerts cardioprotection against I/R- or OGD/R-induced injury, and its mechanisms may be associated with the reduction in RIP1K activation and restoration impaired autophagic flux.
Assuntos
Autofagia/efeitos dos fármacos , Cardiotônicos/farmacologia , Cardiotônicos/uso terapêutico , Imidazóis/química , Indóis/química , Traumatismo por Reperfusão Miocárdica/prevenção & controle , Animais , Animais Recém-Nascidos , Proteína Beclina-1/metabolismo , Catepsina B/metabolismo , Catepsina L/metabolismo , Morte Celular/efeitos dos fármacos , Hemodinâmica/efeitos dos fármacos , Masculino , Proteínas Associadas aos Microtúbulos/metabolismo , Simulação de Acoplamento Molecular , Infarto do Miocárdio/metabolismo , Infarto do Miocárdio/prevenção & controle , Traumatismo por Reperfusão Miocárdica/metabolismo , Miócitos Cardíacos/efeitos dos fármacos , Necroptose/efeitos dos fármacos , Cultura Primária de Células , Proteínas Serina-Treonina Quinases/biossíntese , Proteínas Serina-Treonina Quinases/metabolismo , Ratos Sprague-Dawley , Proteína Serina-Treonina Quinases de Interação com Receptores/metabolismo , Homologia Estrutural de ProteínaRESUMO
Aberrant DNA methylation at the 5-position of cytosine, catalyzed by DNA methyltransferases (DNMTs), is associated with not only various cancers by silencing of tumor suppressor genes but also other diseases. The DNMTs, especially the DNMT1, DNMT3A and DNMT3B, are often overexpressed in various cancer tissues and cell lines. DNMTs are important epigenetic targets for drug development since the DNA methylation is reversible. This review summarizes an array of nucleoside and non-nucleoside inhibitors of DNMTs, as well as their biological activities. Among these inhibitors, the nucleoside analogue azacytidine and its deoxy derivative decitabine are both irreversible DNMT inhibitors and approved for the treatment of myelodysplastic syndrome.
Assuntos
Antineoplásicos/uso terapêutico , Metilases de Modificação do DNA/antagonistas & inibidores , Inibidores Enzimáticos/uso terapêutico , Neoplasias/tratamento farmacológico , Animais , Antineoplásicos/farmacologia , Metilação de DNA , Inibidores Enzimáticos/farmacologia , Epigênese Genética/efeitos dos fármacos , Humanos , Neoplasias/enzimologia , Neoplasias/genéticaRESUMO
Herein we disclose SAR studies of a series of dimethylamino pyrrolidines which we recently reported as novel inhibitors of the PRC2 complex through disruption of EED/H3K27me3 binding. Modification of the indole and benzyl moieties of screening hit 1 provided analogs with substantially improved binding and cellular activities. This work culminated in the identification of compound 2, our nanomolar proof-of-concept (PoC) inhibitor which provided on-target tumor growth inhibition in a mouse xenograft model. X-ray crystal structures of several inhibitors bound in the EED active-site are also discussed.
Assuntos
Complexo Repressor Polycomb 2/antagonistas & inibidores , Complexo Repressor Polycomb 2/metabolismo , Pirrolidinas/farmacologia , Sulfonamidas/farmacologia , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Humanos , Ligantes , Camundongos , Microssomos Hepáticos/efeitos dos fármacos , Microssomos Hepáticos/metabolismo , Complexo Repressor Polycomb 2/química , Ligação Proteica , Pirrolidinas/síntese química , Pirrolidinas/química , Estereoisomerismo , Relação Estrutura-Atividade , Sulfonamidas/síntese química , Sulfonamidas/química , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
A series of curcumin derivatives as potent dual inhibitors of xanthine oxidase (XOD) and urate transporter 1 (URAT1) was discovered as anti-hyperuricemic agents. These compounds proved efficient effects on anti-hyperuricemic activity and uricosuric activity in vivo. More importantly, some of them exhibited proved efficient effects on inhibiting XOD activity and suppressing uptake of uric acid via URAT1 in vitro. Especially, the treatment of 4d was demonstrated to improve uric acid over-production and under-excretion in oxonate-induced hyperuricemic mice through regulating XOD activity and URAT1 expression. Docking study was performed to elucidate the potent XOD inhibition of 4d. Compound 4d may serve as a tool compound for further design of anti-hyperuricemic drugs targeting both XOD and URAT1.
Assuntos
Curcumina/análogos & derivados , Curcumina/uso terapêutico , Inibidores Enzimáticos/química , Inibidores Enzimáticos/uso terapêutico , Hiperuricemia/tratamento farmacológico , Transportadores de Ânions Orgânicos/antagonistas & inibidores , Proteínas de Transporte de Cátions Orgânicos/antagonistas & inibidores , Xantina Oxidase/antagonistas & inibidores , Animais , Curcumina/farmacologia , Inibidores Enzimáticos/farmacologia , Células HEK293 , Humanos , Hiperuricemia/metabolismo , Masculino , Camundongos , Modelos Moleculares , Transportadores de Ânions Orgânicos/metabolismo , Proteínas de Transporte de Cátions Orgânicos/metabolismo , Ácido Úrico/metabolismo , Xantina Oxidase/metabolismoRESUMO
Polycomb repressive complex 2 (PRC2) is a regulator of epigenetic states required for development and homeostasis. PRC2 trimethylates histone H3 at lysine 27 (H3K27me3), which leads to gene silencing, and is dysregulated in many cancers. The embryonic ectoderm development (EED) protein is an essential subunit of PRC2 that has both a scaffolding function and an H3K27me3-binding function. Here we report the identification of A-395, a potent antagonist of the H3K27me3 binding functions of EED. Structural studies demonstrate that A-395 binds to EED in the H3K27me3-binding pocket, thereby preventing allosteric activation of the catalytic activity of PRC2. Phenotypic effects observed in vitro and in vivo are similar to those of known PRC2 enzymatic inhibitors; however, A-395 retains potent activity against cell lines resistant to the catalytic inhibitors. A-395 represents a first-in-class antagonist of PRC2 protein-protein interactions (PPI) for use as a chemical probe to investigate the roles of EED-containing protein complexes.
Assuntos
Antineoplásicos/farmacologia , Indanos/farmacologia , Complexo Repressor Polycomb 2/antagonistas & inibidores , Sulfonamidas/farmacologia , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Indanos/química , Modelos Moleculares , Estrutura Molecular , Complexo Repressor Polycomb 2/química , Complexo Repressor Polycomb 2/metabolismo , Ligação Proteica/efeitos dos fármacos , Relação Estrutura-Atividade , Sulfonamidas/química , Células Tumorais CultivadasRESUMO
INTRODUCTION: Since the first pan-HDAC inhibitor SAHA was approved by U.S. FDA 10 years ago, HDACs including SIRT1-7 have received significant attention due to the fact that aberrant histone deacetylase activtiy has been implicated in a variety of human diseases, such as cancers, virus infection, and neurodegenerative diseases. During the past years, a considerable achievement of development of isoform- or class-selective HDAC inhibitors has been made, yielding many drug candidates for further clinical studies, which represents a state-of-the-art technology in the drug discovery arena. Areas covered: This review covers new patents and articles about isoform- or class-selective HDAC inhibitors during the last four years, as well as the therapeutic potential of these compounds. Expert opinion: HDACs represent one of the most promising therapeutic targets, particularly for tumor therapy though their roles in cancer are still blurry. From 2012 to present, along with the advances of structural biology and homology models, lots of isoform- or class-selective HDAC inhibitors, such as hydroxamic acids and benzamides with various capping groups were found, providing a promising way to circumvent drug toxicity and side-effect issues, as well as providing chemical probes for further better understanding of the biological process related to specific isoform.
Assuntos
Antineoplásicos/farmacologia , Inibidores de Histona Desacetilases/farmacologia , Neoplasias/tratamento farmacológico , Animais , Antineoplásicos/efeitos adversos , Antineoplásicos/uso terapêutico , Desenho de Fármacos , Inibidores de Histona Desacetilases/efeitos adversos , Inibidores de Histona Desacetilases/uso terapêutico , Histona Desacetilases/efeitos dos fármacos , Histona Desacetilases/metabolismo , Humanos , Neoplasias/enzimologia , Doenças Neurodegenerativas/tratamento farmacológico , Doenças Neurodegenerativas/enzimologia , Patentes como Assunto , Viroses/tratamento farmacológico , Viroses/enzimologiaRESUMO
A type of novel rhodanine-based 4-anilinoquinazoline, which designed the combination between quinazoline as the backbone and various substituted biological rhodanine groups as the side chain, have been synthesized, and their antiproliferative activities were also evaluated firstly. These compounds displayed good antiproliferative activity and EGFR-TK inhibitory activity. Among them, compound 8d showed good inhibitory activity (IC50=2.7µM for Hep G2, IC50=3.1µM for A549) and molecular docking of 8d into EGFR TK active site was also performed, this inhibitor well fitting the active site might well explain its excellent inhibitory activity.
Assuntos
Compostos de Anilina/síntese química , Antineoplásicos/síntese química , Receptores ErbB/antagonistas & inibidores , Inibidores de Proteínas Quinases/síntese química , Quinazolinas/síntese química , Rodanina/química , Compostos de Anilina/farmacologia , Antineoplásicos/farmacologia , Domínio Catalítico , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Receptores ErbB/química , Receptores ErbB/metabolismo , Humanos , Simulação de Acoplamento Molecular , Ligação Proteica , Inibidores de Proteínas Quinases/farmacologia , Quinazolinas/farmacologia , Relação Estrutura-AtividadeRESUMO
INTRODUCTION: The signaling pathways downstream of epidermal growth factor receptor (EGFR) are central to the biology of colorectal cancer. EGFR kinase represents an attractive target for the development of novel therapies for the treatment of cancers. A considerable achievement during the past 2 years was the development of targeted therapies against EGFR using small-molecule inhibitors such as quinazoline derivatives, pyrimidine derivatives, thiazole derivatives, acrylamide derivatives and urea derivatives. Some new methods and technologies were also used to discover novel reversible and irreversible EGFR inhibitors. In this review, recent advances in the research of EGFR inhibitors are reviewed. AREAS COVERED: This review summarized new patents and articles published on EGFR inhibitors within 2010 to present. EXPERT OPINION: From 2010 to present, some novel scaffolds have been discovered as first-generation EGFR inhibitors, which are more potent against both EGFR-activating (EGFR WT) and resistance mutations (EGFRDM, T790M/L858R). 'Fast-Forwarding Hit to Lead' and 'Combi-Molecule' postulate to represent a novel approach to cancer therapy. The focus on irreversible inhibitors is also of significance for the design of kinase inhibitors. Searching nature for novel scaffolds is a promising way to find new chemical tools with which we can better understand the development of drug resistance to current targeted therapy and study ways to bypass and overcome such drug resistance.
Assuntos
Antineoplásicos/uso terapêutico , Receptores ErbB/antagonistas & inibidores , Neoplasias/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Animais , Antineoplásicos/química , Desenho de Fármacos , Resistencia a Medicamentos Antineoplásicos , Receptores ErbB/genética , Receptores ErbB/metabolismo , Humanos , Legislação de Medicamentos , Estrutura Molecular , Terapia de Alvo Molecular , Neoplasias/enzimologia , Neoplasias/genética , Neoplasias/patologia , Patentes como Assunto , Inibidores de Proteínas Quinases/química , Transdução de Sinais/efeitos dos fármacos , Relação Estrutura-AtividadeRESUMO
INTRODUCTION: Fatty acid biosynthesis is essential for the bacterial viability and growth. In recent years, ß-ketoacyl-acyl carrier protein synthase III (FabH) become an attractive new target, which catalyzes the first step of fatty acid biosynthesis, and FabH inhibitors could be potential candidates for antibacterial agents. In this review, recent advances in the research of FabH inhibitors are reviewed. AREAS COVERED: This updated review summarized new patents and articles publications on FabH inhibitors within July 2012 to June 2013. EXPERT OPINION: The review gives the latest development in the area of FabH inhibitors which aim to solve the bacterial resistance. The potent antibacterial activities of the selected compounds are probably correlated to their FabH inhibitory. Molecular docking of the most potent compound in every kind of compounds against FabH was also reviewed to explore the binding mode of the compound at the active site.
Assuntos
3-Oxoacil-(Proteína de Transporte de Acila) Sintase/antagonistas & inibidores , Antibacterianos/farmacologia , Bactérias/efeitos dos fármacos , Proteínas de Bactérias/antagonistas & inibidores , Desenho de Fármacos , Inibidores Enzimáticos/farmacologia , Terapia de Alvo Molecular , 3-Oxoacil-(Proteína de Transporte de Acila) Sintase/metabolismo , Animais , Antibacterianos/química , Bactérias/enzimologia , Bactérias/crescimento & desenvolvimento , Proteínas de Bactérias/metabolismo , Resistencia a Medicamentos Antineoplásicos , Inibidores Enzimáticos/química , Humanos , Legislação de Medicamentos , Simulação de Acoplamento Molecular , Estrutura Molecular , Patentes como Assunto , Relação Estrutura-AtividadeRESUMO
Cyclopamine is a naturally occurring steroidal alkaloid that attenuates the Hedgehog signaling pathway by inhibiting the Smoothened receptor. The Hedgehog pathway plays an important role in many human cancers. Cyclopamine has served as a pivotal tool compound in elucidating the pharmacological effect of the Hedgehog signaling pathway, however, due to its poor solubility, stability, and moderate activity, its clinical development has been impeded. Significant efforts were made to overcome the shortcomings of cyclopamine, giving which results cultivated in the identification of IPI- 926, a derivative of cyclopamine, which proceeded to clinical trials.
Assuntos
Alcaloides/farmacologia , Antineoplásicos/farmacologia , Neoplasias/tratamento farmacológico , Alcaloides de Veratrum/farmacologia , Animais , Humanos , Estrutura MolecularRESUMO
Two new series of new compounds containing a 6-amino-substituted group or 6-acrylamide-substituted group linked to a 4-anilinoquinazoline nucleus have been discovered as potential EGFR inhibitors. These compounds proved efficient effects on antiproliferative activity and EGFR-TK inhibitory activity. Especially, N(6)-((5-bromothiophen-2-yl)methyl)-N(4)-(3-chlorophenyl)quinazoline-4,6-diamine (5e), showed the most potent inhibitory activity (IC50=3.11µM for Hep G2, IC50=0.82µM for A549). The EGFR molecular docking model suggested that the new compound is nicely bound to the region of EGFR, and cell morphology by Hoechst stain experiment suggested that these compounds efficiently induced apoptosis of A549 cells.
Assuntos
Compostos de Anilina/síntese química , Antineoplásicos/síntese química , Descoberta de Drogas , Receptores ErbB/antagonistas & inibidores , Quinazolinas/síntese química , Compostos de Anilina/química , Compostos de Anilina/farmacologia , Antineoplásicos/química , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Células Hep G2 , Humanos , Concentração Inibidora 50 , Estrutura Molecular , Ligação Proteica/efeitos dos fármacos , Quinazolinas/química , Quinazolinas/farmacologia , Relação Estrutura-AtividadeRESUMO
A type of novel α,ß-unsaturated cyclohexanone analogous, which designed based on the curcumin core structure, have been discovered as potential EGFR inhibitors. These compounds exhibit potent antiproliferative activity in two human tumor cell lines (Hep G2 and B16-F10). Among them, compounds I(3) and I(12) displayed the most potent EGFR inhibitory activity (IC(50) = 0.43 µM and 1.54 µM, respectively). Molecular docking of I(12) into EGFR TK active site was also performed. This inhibitor nicely fitting the active site might well explain its excellent inhibitory activity.
Assuntos
Antineoplásicos/síntese química , Curcumina/análogos & derivados , Cicloexanonas/química , Desenho de Fármacos , Receptores ErbB/antagonistas & inibidores , Inibidores de Proteínas Quinases/síntese química , Antineoplásicos/química , Antineoplásicos/toxicidade , Sítios de Ligação , Domínio Catalítico , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Curcumina/síntese química , Curcumina/toxicidade , Receptores ErbB/metabolismo , Células Hep G2 , Humanos , Simulação de Acoplamento Molecular , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/toxicidade , Relação Estrutura-AtividadeRESUMO
11ß-Hydroxysteroid dehydrogenase type 1 (11ß-HSD1) catalyzes the conversion of inactive glucocorticoid cortisone to its active form, cortisol. The glucocorticoid receptor (GR) signaling pathway has been linked to the pathophysiology of diabetes and metabolic syndrome. Herein, the structure-activity relationship of a series of piperazine sulfonamide-based 11ß-HSD1 inhibitors is described. (R)-3,3,3-Trifluoro-2-(5-(((R)-4-(4-fluoro-2-(trifluoromethyl)phenyl)-2-methylpiperazin-1-yl)sulfonyl)thiophen-2-yl)-2-hydroxypropanamide 18a (HSD-621) was identified as a potent and selective 11ß-HSD1 inhibitor and was ultimately selected as a clinical development candidate. HSD-621 has an attractive overall pharmaceutical profile and demonstrates good oral bioavailability in mouse, rat, and dog. When orally dosed in C57/BL6 diet-induced obesity (DIO) mice, HSD-621 was efficacious and showed a significant reduction in both fed and fasting glucose and insulin levels. Furthermore, HSD-621 was well tolerated in drug safety assessment studies.
RESUMO
A series of novel rhodanine-based acylsulfonamide derivatives were designed, synthesized, and evaluated as small-molecule inhibitors of anti-apoptotic Bcl-2 protein. These compounds exhibit potent antiproliferative activity in three human tumor cell lines (Hep G2, PC-3 and B16-F10). Among them, the most potent compounds 10 and 11 bind to Bcl-2 with a K(i) of 20 and 25 nM, respectively. Docking studies demonstrated that these two compounds orient similarly at the binding site of Bcl-2, and the calculated binding affinities (Glide XP score) of compound 10 is more negative than that of compound 11. The binding interactions of compounds with high binding affinity to Bcl-2 protein were analyzed.
Assuntos
Desenho de Fármacos , Proteínas Proto-Oncogênicas c-bcl-2/antagonistas & inibidores , Rodanina/química , Sulfonamidas/química , Antineoplásicos/farmacologia , Sítios de Ligação , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Simulação por Computador , Células Hep G2 , Humanos , Ligação Proteica/efeitos dos fármacos , Estrutura Terciária de Proteína , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Relação Estrutura-Atividade , Sulfonamidas/síntese química , Sulfonamidas/farmacologiaRESUMO
Two series of urea and thiourea derivatives (1a-11a, 1b-11b) have been synthesized; all the 22 compounds were reported for the first time. Their anti-proliferative activities against the melanoma cell line B16-F10 were evaluated. Among the compounds tested, compound 6b exhibited the most potent activity in melanoma cells growth inhibition (IC(50) = 0.33 µM). The bioassay tests showed that anti-proliferative activities of these novel compounds were possibly caused by inhibition of ERK1/2 phosphorylation level. Therefore, compound 6b can be a potential anti-melanoma agent and an inhibitor of ERK1/2 phosphorylation deserving further research.
Assuntos
Melanoma Experimental/tratamento farmacológico , Ureia/síntese química , Ureia/farmacologia , Animais , Bioensaio , Linhagem Celular Tumoral , Ensaios de Seleção de Medicamentos Antitumorais , Ensaio de Imunoadsorção Enzimática , Imunofluorescência , Concentração Inibidora 50 , Sistema de Sinalização das MAP Quinases , Espectroscopia de Ressonância Magnética , Melanoma Experimental/patologia , Camundongos , Fosforilação , Espectrometria de Massas por Ionização por Electrospray , Tioureia/síntese química , Tioureia/farmacologia , Tioureia/uso terapêutico , Ureia/uso terapêuticoRESUMO
A type of novel 4,6-substituted-(diaphenylamino)quinazolines, which designed based on the 4-(phenylamino)quinazoline moiety, have been discovered as potential EGFR inhibitors. These compounds displayed good antiproliferative activity and EGFR-TK inhibitory activity. Especially, 4-((4-(3-bromophenylamino)quinazolin-6-ylamino)methyl)phenol (5b), showed the most potent inhibitory activity (IC(50)=0.28µM for Hep G2, IC(50)=0.59µM for A16-F10 and IC(50)=0.87µM for EGFR) and effectively induces apoptosis in a dose-dependent manner in the Hep G2 cell line. Molecular docking of 5b into EGFR TK active site was also performed. This inhibitor nicely fitting the active site might well explain its excellent inhibitory activity.