RESUMO
(±)-Hypernumqulins A-H (1-8), eight pairs of enantiomeric quinoline alkaloids fused with an isopentenyl and a germacrane-type sesquiterpenoid, featuring an unprecedented skeleton with 6/6/6/4/10 ring system, were isolated from Hypericum monogynum L. under the guidance of molecular networking strategy. Their structures including absolute configuration were elucidated by NMR spectroscopy analysis, X-ray crystallography and quantum chemical calculation. The proposed [2+2] cycloaddition may play a key biogenic step in building the unexpected skeleton. Most of the isolates exhibited cytotoxicity with IC50 values ranging from 2.82 ± 0.03 to 45.25 ± 1.26 µM against MCF-7, A549 or SGC7901 cells. Furthermore, compounds (±)-1 and (-)-1 could induce apoptosis by upregulating the protein expression level of Bax and downregulating of Bcl-2 in MCF-7 cells. These findings provided the first example of germacrane sesquiterpene quinoline alkaloids, and supported the possibilities for the development of new anti-tumor agents.
Assuntos
Alcaloides , Antineoplásicos Fitogênicos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Hypericum , Sesquiterpenos , Humanos , Alcaloides/química , Alcaloides/farmacologia , Alcaloides/isolamento & purificação , Antineoplásicos Fitogênicos/farmacologia , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/isolamento & purificação , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Reação de Cicloadição , Hypericum/química , Estrutura Molecular , Sesquiterpenos/química , Sesquiterpenos/farmacologia , Sesquiterpenos/isolamento & purificação , Estereoisomerismo , Relação Estrutura-Atividade , Quinolinas/química , Quinolinas/isolamento & purificação , Quinolinas/farmacologiaRESUMO
Nine previously undescribed iridoids, ptehosides A-I (1-9), together with 12 known ones (10-21), were isolated from Pterocephalus hookeri (C.B. Clarke) Höeck. Their structures were elucidated using various spectroscopic methods including HR-ESI-MS, NMR, UV, IR and CD, etc. The cytotoxic activities of all isolates were evaluated using MTT method in three human cancer cell lines (Caco2, Huh-7, and SW982). As result, compound 9 exhibited substantial inhibitory activity on Caco2, Huh-7, and SW982 cells with IC50 values of 1.17 ± 0.05, 1.15 ± 0.05 and 1.14 ± 0.04 µM, respectively. A preliminary mechanism study showed that 9 arrested the cell cycle of SW982 cells in the G0/G1 phase and induced apoptosis by upregulating Bax expression and downregulating Bcl-2 expression.
Assuntos
Antineoplásicos Fitogênicos , Apoptose , Ensaios de Seleção de Medicamentos Antitumorais , Iridoides , Humanos , Antineoplásicos Fitogênicos/farmacologia , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/isolamento & purificação , Apoptose/efeitos dos fármacos , Iridoides/química , Iridoides/farmacologia , Iridoides/isolamento & purificação , Estrutura Molecular , Proliferação de Células/efeitos dos fármacos , Relação Estrutura-Atividade , Relação Dose-Resposta a Droga , Linhagem Celular Tumoral , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Proteína X Associada a bcl-2/metabolismoRESUMO
Telomere repeat binding factor 2 (TRF2), a critical element of the shelterin complex, plays a vital role in the maintenance of genome integrity. TRF2 overexpression is found in a wide range of malignant cancers, whereas its down-regulation could cause cell death. Despite its potential role, the selectively small-molecule inhibitors of TRF2 and its therapeutic effects on liver cancer remain largely unknown. Our clinical data combined with bioinformatic analysis demonstrated that TRF2 is overexpressed in liver cancer and that high expression is associated with poor prognosis. Flavokavain B derivative FKB04 potently inhibited TRF2 expression in liver cancer cells while having limited effects on the other five shelterin subunits. Moreover, FKB04 treatment induced telomere shortening and increased the amounts of telomere-free ends, leading to the destruction of T-loop structure. Consequently, FKB04 promoted liver cancer cell senescence without modulating apoptosis levels. In corroboration with these findings, FKB04 inhibited tumor cell growth by promoting telomeric TRF2 deficiency-induced telomere shortening in a mouse xenograft tumor model, with no obvious side effects. These results demonstrate that TRF2 is a potential therapeutic target for liver cancer and suggest that FKB04 may be a selective small-molecule inhibitor of TRF2, showing promise in the treatment of liver cancer.
Assuntos
Senescência Celular , Neoplasias Hepáticas , Encurtamento do Telômero , Proteína 2 de Ligação a Repetições Teloméricas , Proteína 2 de Ligação a Repetições Teloméricas/metabolismo , Proteína 2 de Ligação a Repetições Teloméricas/antagonistas & inibidores , Proteína 2 de Ligação a Repetições Teloméricas/genética , Humanos , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Animais , Encurtamento do Telômero/efeitos dos fármacos , Senescência Celular/efeitos dos fármacos , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Linhagem Celular Tumoral , Camundongos , Camundongos Nus , Proliferação de Células/efeitos dos fármacos , Camundongos Endogâmicos BALB C , Masculino , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Leukemia, despite currently being one of the most lethal cancers worldwide, still lacks a focused treatment. The purpose of the present investigation was to evaluate the pharmacological effect of 1-methoxyerythrabyssin II, a pterocarpan identified in the roots of Lespedeza bicolor, on leukemic cells and to explore its underlying mechanism using a network pharmacology strategy. 1-Methoxyerythrabyssin II showed an antiproliferative effect in a concentration-dependent manner and exhibited a higher potency in human acute leukemia T cells (Jurkat). The G1 phase arrest induced by 1-methoxyerythrabyssin II was confirmed using a cell cycle assay, and the downregulation of CDK2 and cyclin D1 was observed using an immunoblot assay. Moreover, 1-methoxyerythrabyssin II-treated cells exhibited higher expression levels of LC3B, Atg-7, and Beclin 1 in addition to an enhanced fluorescence intensity in monodansylcadaverine staining, indicating autophagy induction by 1-methoxyerythrabyssin II. Furthermore, network pharmacology and molecular docking analyses revealed that the PI3K/Akt/mTOR pathway is a potential target of 1-methoxyerythrabyssin II in leukemic cells. In vitro assays further demonstrated that 1-methoxyerythrabyssin II promoted autophagy and suppressed cell proliferation by inhibiting the PI3K/Akt/mTOR pathway in leukemic cells. This discovery will contribute to the development of novel therapeutics and prophylactics against leukemia.
RESUMO
Osteosarcoma (OS) is a group of malignant tumors with high rates of malignancy and metastasis. OS most commonly affects adolescents and young individuals. However, owing to the lack of effective targeted treatments, the 5-year survival rate for OS is still around 20%. Thus, it is essential to develop effective drugs with low toxicity for OS treatment. In the present study, we investigated the antitumor effect and underlying mechanism of cyy260 in OS via suppressing PDGFR-ß and its downstream pathway. We demonstrated that cyy260 inhibits OS cell proliferation and promotes apoptosis via inducing DNA damage and causing cell cycle arrest. More importantly, cyy260 also significantly inhibits tumor migration. Further analysis of molecular mechanisms confirmed that PDGFR-ß and its downstream AKT, STAT3, and ERK were involved in the cyy260-mediated antitumor effect. Analysis of subcutaneously transplanted tumors in mice showed that cyy260 suppressed tumor cell growth and exhibited low toxicity in vivo. Collectively, these findings proved that cyy260 could serve as a promising PDGFR-ß inhibitor for the treatment of OS.
Assuntos
Neoplasias Ósseas , Osteossarcoma , Animais , Apoptose , Neoplasias Ósseas/metabolismo , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Camundongos , Osteossarcoma/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de SinaisRESUMO
Esophageal cancer (EC) is one of the malignant cancer with pool survival due to the limited therapeutic and drug-resistance. Narciclasine, a natural compound from Lycoris sanguinea possesses antitumor and anti-inflammatory properties. However, the mechanisms underlying the growth-inhibitory effect of narciclasine against EC have not yet been elucidated. Experimental evidences indicated that narciclasine treatment significantly affected the distribution of FAK and its phosphorylation, resulting in proliferation inhibition and migration inhibition of EC. Our study also showed that narciclasine treatment triggered DNA damage and inhibited DNA replication, leading to cell cycle arrest and apoptosis. Further mechanistic studies indicated that narciclasine inhibited EC cell proliferation and migration through FAK/JNK and p38 pathway. Altogether, these findings suggest that narciclasine could be a potential novel chemotherapeutic agent for esophageal cancer cell proliferation and migration.
Assuntos
Alcaloides de Amaryllidaceae , Neoplasias Esofágicas , Alcaloides de Amaryllidaceae/farmacologia , Alcaloides de Amaryllidaceae/uso terapêutico , Apoptose , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Neoplasias Esofágicas/tratamento farmacológico , Humanos , Fenantridinas , Transdução de SinaisRESUMO
Platelet-derived growth factor receptors (PDGFRs) are now considered promising targets for the treatment of osteosarcoma. Herein, the design, synthesis, and structure-activity relationships (SAR) of novel pyrimidine-2,4-diamine derivatives that selectively inhibit PDGFRα/ß kinases have been studied. The screening cascades revealed that 7m was the preferred compound among these derivatives, with IC50 values of 2.4 and 0.9 nM for PDGFRα and PDGFRß, respectively. Moreover, the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) experiment revealed that 7m has a substantial cytotoxic effect against all osteosarcoma cancer cell lines; 7m also displayed robust antitumor effects and low toxicity in a xenograft model. Additionally, 7m showed excellent bioavailability (F = 62.9%), suitable half-life (T1/2 = 2.12 h), satisfactory metabolic stability, and weak CYP isoform inhibitory activity, suggesting that 7m is a potential drug candidate for PDGFR-driven osteosarcoma.
Assuntos
Antineoplásicos , Neoplasias Ósseas , Osteossarcoma , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Neoplasias Ósseas/tratamento farmacológico , Humanos , Osteossarcoma/tratamento farmacológico , Osteossarcoma/metabolismo , Receptores Proteína Tirosina Quinases/metabolismo , Receptor alfa de Fator de Crescimento Derivado de Plaquetas , Receptor beta de Fator de Crescimento Derivado de Plaquetas , Receptores do Fator de Crescimento Derivado de Plaquetas , Relação Estrutura-AtividadeRESUMO
BACKGROUND: Carnosic acid (CA) is a polyphenolic diterpene extracted from rosemary. Reports have shown that CA possesses anticancer activity. However, whether CA inhibits esophageal squamous cell carcinoma, an aggressive type of esophageal cancer, remains untested. METHODS: The effects of CA on cell survival, migration, and apoptosis were evaluated by a combination of MTT, colony formation assay, flow cytometry, and Transwell assay. The potential signaling pathways involved were investigated via Western blot assay. RESULTS: CA dose-dependently inhibited cell proliferation, apoptosis, migration, and colony formation. Mechanistically, CA arrested the cell cycle at G2/M phase, promoted cell apoptosis, induced DNA damage, and inhibited the MAPK signaling pathways. CONCLUSION: Our results suggest that CA is a potential anticancer drug for esophageal squamous cell carcinoma.
RESUMO
Breast cancer is now the most common type of cancer worldwide, surpassing lung cancer. This issue is further worsened by the lack of effective therapies for the disease. Recent reports indicate that the inhibition of ubiquitin-like modifier-activating enzyme 5 (UBA5) can impede tumor development. However, there have been few reports regarding UBA5-inhibiting compounds. This work studied usenamine A, a natural product from the lichen Usnea longissimi that exhibits UBA5-inhibitory effects. Bioinformatics analysis was performed using public databases, and the anti-proliferative ability of usenamine A in breast cancer cells was examined through MTS and colony formation assays. Flow cytometry and western blot analysis were also conducted to examine and analyze cell cycle arrest and apoptosis. In addition, LC3B-RFP and UBA5 expression plasmids were used for the analysis of usenamine A-induced autophagy. According to the bioinformatics analysis results, UBA5 was upregulated in breast cancer. According to in vitro studies, usenamine A displayed prominent anti-proliferative activity and resulted in G2/M phase arrest in MDA-MB-231 cells. Moreover, usenamine A induced autophagy and endoplasmic reticulum stress in MDA-MB-231 cells. In conclusion, the findings support the potential of usenamine A as an agent that can attenuate the development and progression of breast cancer.
Assuntos
Autofagia , Neoplasias da Mama/patologia , Enzimas Ativadoras de Ubiquitina/antagonistas & inibidores , Apoptose/efeitos dos fármacos , Apoptose/genética , Autofagia/efeitos dos fármacos , Autofagia/genética , Neoplasias da Mama/genética , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/genética , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Estresse do Retículo Endoplasmático/genética , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Ontologia Genética , Humanos , Simulação de Acoplamento Molecular , Invasividade Neoplásica , Prognóstico , Mapas de Interação de Proteínas/efeitos dos fármacos , Mapas de Interação de Proteínas/genética , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Reprodutibilidade dos Testes , Análise de Sobrevida , Enzimas Ativadoras de Ubiquitina/metabolismoRESUMO
BACKGROUND: Metastatic castration-resistant prostate cancer (CRPC) is the leading cause of death among men diagnosed with prostate cancer. Piperlongumine (PL) is a novel potential anticancer agent that has been demonstrated to exhibit anticancer efficacy against prostate cancer cells. However, the effects of PL on DNA damage and repair against CRPC have remained unclear. The aim of this study was to further explore the anticancer activity and mechanisms of action of PL against CRPC in terms of DNA damage and repair processes. METHODS: The effect of PL on CRPC was evaluated by MTT assay, long-term cell proliferation, reactive oxygen species assay, western blot assay, flow cytometry assay (annexin V/PI staining), ß-gal staining assay and DAPI staining assay. The capacity of PL to inhibit the invasion and migration of CRPC cells was assessed by scratch-wound assay, cell adhesion assay, transwell assay and immunofluorescence (IF) assay. The effect of PL on DNA damage and repair was determined via IF assay and comet assay. RESULTS: The results showed that PL exhibited stronger anticancer activity against CRPC compared to that of taxol, cisplatin (DDP), doxorubicin (Dox), or 5-Fluorouracil (5-FU), with fewer side effects in normal cells. Importantly, PL treatment significantly decreased cell adhesion to the extracellular matrix and inhibited the migration of CRPC cells through affecting the expression and distribution of focal adhesion kinase (FAK), leading to concentration-dependent inhibition of CRPC cell proliferation and concomitantly increased cell death. Moreover, PL treatment triggered persistent DNA damage and provoked strong DNA damage responses in CRPC cells. CONCLUSION: Collectively, our findings demonstrate that PL potently inhibited proliferation, migration, and invasion of CRPC cells and that these potent anticancer effects were potentially achieved via triggering persistent DNA damage in CRPC cells.
Assuntos
Antineoplásicos/farmacologia , Proliferação de Células/efeitos dos fármacos , Dano ao DNA/efeitos dos fármacos , Dioxolanos , Humanos , Masculino , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológicoRESUMO
Rumex japonicus Houtt (RJH) is a valuable plant used in traditional medicine to treat several diseases, such as scabies and jaundice. In this study, Jurkat cell growth inhibitory extracts of R. japonicus roots were subjected to bioassay-guided fractionation, resulting in the isolation of three naphthalene derivatives (3-5) along with one anthraquinone (6) and two phenolic compounds (1 and 2). Among these compounds, 2-methoxystypandrone (5) exhibited potent anti-proliferative effects on Jurkat cells. Analysis by flow cytometry confirmed that 2-methoxystypandrone (5) could significantly reduce mitochondrial membrane potential and promote increased levels of mitochondrial reactive oxygen species (ROS), suggesting a strong mitochondrial depolarization effect. Real-time quantitative polymerase chain reaction (qPCR) analysis was also performed, and the results revealed that the accumulation of ROS was caused by reduced mRNA expression levels of heme oxygenase (HO-1), catalase (CAT), glutathione peroxidase (GPx), and superoxide dismutase (SOD). In addition, 2-methoxystypandrone (5) triggered strong apoptosis that was mediated by the arrest of the G0/G1 phase of the cell cycle. Furthermore, 2-methoxystypandrone (5) downregulated p-IκB-α, p-NF-κB p65, Bcl2, and Bcl-xl and upregulated BAX proteins. Taken together, these findings revealed that 2-methoxystypandrone (5) isolated from RJH could potentially serve as an early lead compound for leukemia treatment involving intracellular signaling by increasing mitochondrial ROS and exerting anti-proliferative effects.
Assuntos
Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Células Jurkat/efeitos dos fármacos , Mitocôndrias/metabolismo , Extratos Vegetais/farmacologia , Rumex/química , Antraquinonas , Proteínas Reguladoras de Apoptose/metabolismo , Ciclo Celular/efeitos dos fármacos , Humanos , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Naftoquinonas , Raízes de Plantas/química , Espécies Reativas de Oxigênio/metabolismo , República da Coreia , Transdução de Sinais/efeitos dos fármacos , Proteína X Associada a bcl-2/metabolismoRESUMO
Myeloid differentiation protein 2 (MD2) is a co-receptor of toll-like receptor 4 (TLR4) responsible for the recognition of lipopolysaccharide (LPS) and mediates a series of TLR4-dependent inflammatory responses in inflammatory lung diseases including acute lung injury (ALI). Targeting MD2 thus may provide a therapeutic strategy against these lung diseases. In this study, we identified a novel compound 4k with the potent anti-inflammatory activity among 39 methyl gallate derivatives (MGDs). MGD 4k exhibited a high binding affinity to MD2, which in turn prevented the formation of the LPS/MD2/TLR4 complex. In addition, MGD 4k significantly reversed the upregulation of LPS-induced inflammatory mediators such as tumor necrosis factor-α, interleukin-6, intracellular adhesion molecule-1, vascular cell adhesion molecule-1, and monocyte chemoattractant protein-1 in vitro and in vivo. Mechanistically, MGD 4k performed anti-inflammatory function by inactivating JNK, ERK and p38 signaling pathways. Taken together, our study identified MGD 4k as a novel potential therapeutic agent for ALI through inhibiting MD2, inflammatory responses, and major inflammation-associated signaling pathways.
Assuntos
Lesão Pulmonar Aguda/tratamento farmacológico , Anti-Inflamatórios não Esteroides/farmacologia , Ácido Gálico/análogos & derivados , Antígeno 96 de Linfócito/antagonistas & inibidores , Lesão Pulmonar Aguda/induzido quimicamente , Lesão Pulmonar Aguda/metabolismo , Animais , Anti-Inflamatórios não Esteroides/síntese química , Anti-Inflamatórios não Esteroides/química , Líquido da Lavagem Broncoalveolar/química , Células Cultivadas , Relação Dose-Resposta a Droga , Ácido Gálico/síntese química , Ácido Gálico/química , Ácido Gálico/farmacologia , Lipopolissacarídeos/antagonistas & inibidores , Lipopolissacarídeos/farmacologia , Antígeno 96 de Linfócito/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Estrutura Molecular , Relação Estrutura-AtividadeRESUMO
PURPOSE: Ovarian cancer is the most lethal cancer among all gynaecological malignancies. The combination theraputics of cisplatin and taxol is widely used in clinicals for ovarian cancer treatment. However, long-term use of cisplatin and taxol induces strong tolerance and hepatotoxicity. Since silibinin is a commonly used anti-hepatotoxic drug in Europe and Asia, the aim of this study was to determine whether silibinin could restore the sensitivity of combination use of cisplatin and taxol in drug-resistant human ovarian cancer cells and reduce drug-induced hepatotoxicity. PATIENTS AND METHODS: Normal hepatocyte LO2 cells and A2780/DDP cells were treated with silibinin, cisplatin, taxol, cisplatin and taxol plus silibinin for 48 h. Cell viability was determined by MTT and long-term proliferation assay, while apoptosis and cell cycle progression were assessed by flow cytometric analysis. DNA damage was evluated by immunofluorescence assays. The metastatic activity of A2780/DDP was determined by cell adhesion assay. RESULTS: The addition of silibinin on cisplatin and/or toxal could sensitize the antitumor activity of cisplatin and toxal on A2780/DDP cells, supress cell-matrix adhesion of A2780/DDP, inhibit the cell proliferation, result in A2780/DDP cells apoptosis. In addition, silibinin could effectively reduce cisplatin and/or toxal-induced hepatotoxicity by protecting DNA from damage and restoring the potential of cell proliferation in cisplatin and/or toxal-treated LO2 cells. CONCLUSION: Our results suggest that silibinin could restore the sensitivity of cisplatin and taxol in drug-resistant human ovarian cancer cells and reduce durg-induced hepatotoxicity in cell level.
RESUMO
The known chalcone (±)-sanjuanolide (1) can be isolated from Dalea frutescens. This study presents a convergent strategy for the first total synthesis of ( R)-, ( S)-, and (±)-sanjuanolide (1). The key step for synthesizing ( R)- and ( S)-1 was a Corey-Bakshi-Shibata enantioselective carbonyl reduction to construct the C-2â³ configuration. ( R)-1 efficiently inhibited the lipopolysaccharides (LPS)-induced expression of tumor necrosis factor alpha (TNF-α) and interleukin-6 (IL-6), while ( S)-1 produced no significant anti-inflammatory effect. ( R)-1 also effectively inhibited the mRNA expression of several inflammatory cytokines after the LPS challenge in vitro. The synthesis and biological properties of these compounds have confirmed ( R)-sanjuanolide and (±)-sanjuanolide as promising new leads for developing anti-inflammatory agents.
Assuntos
Anti-Inflamatórios/síntese química , Anti-Inflamatórios/farmacologia , Fabaceae/química , Animais , Anti-Inflamatórios/química , Humanos , Interleucina-6/antagonistas & inibidores , Lipopolissacarídeos/antagonistas & inibidores , Estrutura Molecular , Estereoisomerismo , Fator de Necrose Tumoral alfa/antagonistas & inibidoresRESUMO
PURPOSE: The purpose of this study was to design and synthesize novel 2-benzylidene-1-indanone derivatives for treatment of acute lung injury. METHODS: A series of 39 novel 2-benzylidene-indanone structural derivatives were synthesized and evaluated for anti-inflammatory activity in lipopolysaccharide (LPS)-stimulated murine primary macrophages. RESULTS: Most of the obtained compounds effectively inhibited the LPS-induced expression of IL-6 and TNF-α. The most active compound, 8f, was found to significantly reduce LPS-induced pulmonary inflammation, as reflected by reductions in the concentration of total protein, inflammatory cell count, as well as the lung wet/dry ratio in bronchoalveolar lavage (BAL) fluid. Furthermore, 8f effectively inhibited mRNA expression of several inflammatory cytokines after LPS challenge in vitro and in vivo. Administration of 8f also blocked LPS-induced activation of the proinflammatory NF-κB/MAPK signaling pathway. CONCLUSION: The simple synthetic preparation and biological properties of these derivatives make these 2-benzylidene-indanone scaffolds promising new entities for the development of anti-inflammatory therapeutics for the treatment of acute lung injury.
Assuntos
Lesão Pulmonar Aguda/tratamento farmacológico , Anti-Inflamatórios não Esteroides/farmacologia , Desenho de Fármacos , Indanos/farmacologia , Lesão Pulmonar Aguda/patologia , Animais , Anti-Inflamatórios não Esteroides/síntese química , Anti-Inflamatórios não Esteroides/química , Relação Dose-Resposta a Droga , Indanos/síntese química , Indanos/química , Macrófagos/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Estrutura Molecular , Relação Estrutura-AtividadeRESUMO
Mutated epidermal growth factor receptor (EGFR) is a major driver of non-small cell lung cancer (NSCLC). The EGFRT790M secondary mutation has become a leading cause of clinically-acquired resistance to gefitinib and erlotinib. Herein, we present a structure-based design approach to increase the potency and selectivity of the previously reported reversible EGFR inhibitor 7, at the kinase and cellular levels. Three-step structure-activity relationship exploration led to promising compounds 19e and 19h with unique chemical structure and binding mode from the other third-generation tyrosine kinase inhibitors. In a human NSCLC xenograft model, 19e and 19h exhibited dose-dependent tumor growth suppression without toxicity. These selective inhibitors are promising drug candidates for EGFRT790M-driven NSCLC.