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Background: To date, the clinical management of advanced hepatocellular carcinoma (HCC) patients remains challenging and the mechanisms of E2F transcription factor 1 (E2F1) underlying HCC are obscure. Materials and Methods: Our study integrated datasets mined from several public databases to comprehensively understand the deregulated expression status of E2F1. Tissue microarrays and immunohistochemistry staining was used to validate E2F1 expression level. The prognostic value of E2F1 was assessed. In-depth subgroup analyses were implemented to compare the differentially expressed levels of E2F1 in HCC patients with various tumor stages. Functional enrichments were used to address the predominant targets of E2F1 and shedding light on their potential roles in HCC. Results: We confirmed the elevated expression of E2F1 in HCC. Subgroup analyses indicated that elevated E2F1 level was independent of various stages in HCC. E2F1 possessed moderate discriminatory capability in differentiating HCC patients from non-HCC controls. Elevated E2F1 correlated with Asian race, tumor classification, neoplasm histologic grade, eastern cancer oncology group, and plasma AFP levels. Furthermore, high E2F1 correlated with poor survival condition and pooled HR signified E2F1 as a risk factor for HCC. Enrichment analysis of differentially expressed genes, coexpressed genes, and putative targets of E2F1 emphasized the importance of cell cycle pathway, where CCNE1 and CCNA2 served as hub genes. Conclusions: We confirmed the upregulation of E2F1 and explored the prognostic value of E2F1 in HCC patients. Two putative targeted genes (CCNE1 and CCNA2) of E2F1 were identified for their potential roles in regulating cell cycle and promote antiapoptotic activity in HCC patients.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , Carcinoma Hepatocelular/patología , Ciclo Celular , Factor de Transcripción E2F1/genética , Regulación Neoplásica de la Expresión Génica , Neoplasias Hepáticas/patología , PronósticoRESUMEN
Background: Coronavirus disease 2019 (COVID-19) has been a public threat and healthcare concern caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. During the period of the pandemic of COVID-19, cancer patients should be paid more attention as more severe events are found in cancer patients infected with SARS-CoV-2. Basigin (BSG) is an essential factor for the infection and progression of COVID-19 and tumorigenesis of multiple tumors, which may serve as a novel target for the effective treatment against COVID-19 and multiple human cancers. Methods: A total of 19,020 samples from multiple centers were included in our research for the comprehensive investigation of the differences in BSG expression among human organs, cancer cells, cancer tissues, and normal tissues. Cox regression analysis and Kaplan-Meier curves were utilized to explore the prognosis factor of BSG in cancers. Correlation analyses were used to determine associations of BSG expression with tumor mutational burden, the immune microenvironment, etc. Gene set enrichment analysis was applied to explore the underlying mechanisms of BSG in cancers. Results: Compared with normal tissues, BSG expression was high in 13 types of cancers (cholangiocarcinoma, etc.) and low in colon adenocarcinoma and rectum adenocarcinoma. BSG expression was related to the prognosis of eight cancers (e.g., invasive breast carcinoma) (p < 0.05). The gene also demonstrated a pronounced effect in identifying 12 cancers (cholangiocarcinoma, etc.) from their control samples (AUC >0.7). The BSG expression was associated with DNA methyltransferases, mismatch repair genes, immune infiltration levels, tumor mutational burden, microsatellite instability, neoantigen, and immune checkpoints, suggesting the potential of BSG as an exciting target for cancer treatment. BSG may play its role in several cancers by affecting several signaling pathways such as drug cytochrome metabolism P450 and JAK-STAT. Conclusion: BSG may be a novel biomarker for treating and identifying multiple human cancers.
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Background: Idiopathic pulmonary fibrosis (IPF) is the interstitial lung disease with the highest incidence and mortality. The lack of specific markers results in limited treatment methods for IPF patients. Numerous prognostic signatures represented effective indexes in predicting the survival of patients in various diseases; however, little is investigated on their application in IPF. Methods: This study attempted to explore the clinical markers suitable for IPF by constructing a prognostic signature from the perspective of 7-methylguanosine (m7G). An m7G-related prognostic signature (m7GPS) was established based on the discovery cohort with the LASSO algorithm and was verified by internal and external validation cohorts. The area under the curve (AUC) values were utilized to assess the accuracy of m7GPS in predicting the prognosis of IPF patients and the ability of m7GPS in screening IPF patients. Kaplan-Meier curves and Cox regression analyses were used to identify the relationship of m7GPS with the prognosis of IPF individuals. Enrichment analyses, CIBERSORT algorithm, and weighted gene co-expression network analysis were applied to explore the underlying mechanisms and correlation of m7GPS in IPF. Results: The two m7G regulatory genes can divide IPF into subtypes 1 and 2, and subtype 2 demonstrated a poor prognosis for IPF patients (p < 0.05). For the first time in this field, the m7GPS was constructed. m7GPS made it feasible to predict the 1-5 years survival status of IPF patients (AUC = 0.730-0.971), and it was an independent prognostic risk factor for IPF patients (hazard ratio > 1, p < 0.05). The conspicuous ability of m7GPS to screen IPF patients from the healthy was also revealed by an AUC value of 0.960. The roles of m7GPS in IPF may link to inflammation, immune response, and immune cell levels. Seven genes (CYR61, etc.) were identified as hub genes of m7GPS in IPF. Three drugs (ZM447439-1050, AZD1332-1463, and Ribociclib-1632) were considered sensitive to patients with high m7GPS risk scores. Conclusion: This study developed a novel m7GPS, which is a reliable indicator for predicting the survival status of IPF patients and is identified as an effective marker for prognosis and screening of IPF patients.
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BACKGROUND: Esophageal squamous cell carcinoma (ESCC) is one of the most common cancers in the world, the detection and prognosis of which are still unsatisfactory. Thus, it is essential to explore the factors that may identify ESCC and evaluate the prognosis of ESCC patients. RESULTS: Both protein and mRNA expression levels of BIRC5 are upregulated in ESCC group rather than non-ESCC group (standardized mean difference > 0). BIRC5 mRNA expression is related to the age, tumor location, lymph node stage and clinical stage of ESCC patients (p < 0.05). BIRC5 expression makes it feasible to distinguish ESCC from non-ESCC (area under the curve > 0.9), and its high expression is related to poor prognosis of ESCC patients (restrictive survival time difference = -0.036, p < 0.05). BIRC5 may play an important role in ESCC by influencing the cell cycle pathway, and CDK1, MAD2L and CDC20 may be the hub genes of this pathway. The transcription factors-MAZ and TFPD1 -are likely to regulate the transcription of BIRC5, which may be one of the factors for the high expression of BIRC5 in ESCC. CONCLUSIONS: The current study shows that upregulation of BIRC5 may have essential clinical value in ESCC, and contributes to the understanding of the pathogenesis of ESCC.
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Carcinoma de Células Escamosas , Neoplasias Esofágicas , Carcinoma de Células Escamosas de Esófago , Carcinoma de Células Escamosas/genética , Neoplasias Esofágicas/genética , Carcinoma de Células Escamosas de Esófago/genética , Regulación Neoplásica de la Expresión Génica , Humanos , Survivin/genética , Regulación hacia ArribaRESUMEN
During the pandemic of the coronavirus disease 2019, there exist quite a few studies on angiotensin-converting enzyme 2 (ACE2) and SARS-CoV-2 infection, while little is known about ACE2 in hepatocellular carcinoma (HCC). The detailed mechanism among ACE2 and HCC still remains unclear, which needs to be further investigated. In the current study with a total of 6,926 samples, ACE2 expression was downregulated in HCC compared with non-HCC samples (standardized mean difference = -0.41). With the area under the curve of summary receiver operating characteristic = 0.82, ACE2 expression showed a better ability to differentiate HCC from non-HCC. The mRNA expression of ACE2 was related to the age, alpha-fetoprotein levels and cirrhosis of HCC patients, and it was identified as a protected factor for HCC patients via Kaplan-Meier survival, Cox regression analyses. The potential molecular mechanism of ACE2 may be relevant to catabolic and cell division. In all, decreasing ACE2 expression can be seen in HCC, and its protective role for HCC patients and underlying mechanisms were explored in the study.
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Enzima Convertidora de Angiotensina 2/genética , Carcinoma Hepatocelular/genética , Cirrosis Hepática/genética , Neoplasias Hepáticas/genética , Proteínas de Neoplasias/genética , Receptores Virales/genética , alfa-Fetoproteínas/genética , Factores de Edad , Anciano , Enzima Convertidora de Angiotensina 2/metabolismo , Área Bajo la Curva , COVID-19/virología , Carcinoma Hepatocelular/diagnóstico , Carcinoma Hepatocelular/mortalidad , Carcinoma Hepatocelular/patología , Bases de Datos Genéticas , Conjuntos de Datos como Asunto , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Cirrosis Hepática/diagnóstico , Cirrosis Hepática/mortalidad , Cirrosis Hepática/patología , Neoplasias Hepáticas/diagnóstico , Neoplasias Hepáticas/mortalidad , Neoplasias Hepáticas/patología , Masculino , Persona de Mediana Edad , Proteínas de Neoplasias/clasificación , Proteínas de Neoplasias/metabolismo , Factores Protectores , Mapeo de Interacción de Proteínas , Curva ROC , Receptores Virales/metabolismo , SARS-CoV-2/patogenicidad , Análisis de Supervivencia , alfa-Fetoproteínas/metabolismoRESUMEN
Synaptojanin 2 (SYNJ2) regulates cell proliferation and apoptosis via dephosphorylating plasma membrane phosphoinositides. Aim of this study is to first seek the full-scale expression levels and potential emerging roles of SYNJ2 in hepatocellular carcinoma (HCC). We systematically analyzed SYNJ2 mRNA expression and protein levels in HCC tissues based on large-scale data and in-house immunohistochemistry (IHC). The clinical significance and risk factors for SYNJ2-related HCC cases were identified. A nomogram of prognosis was created and its performance was validated by concordance index (C-index) and shown in calibration plots. Based on the identified differentially coexpressed genes (DCGs) of SYNJ2, enriched annotations and potential pathways were predicted, and the protein interacting networks were mapped. Upregulated SYNJ2 in 3,728 HCC and 3,203 non-HCC tissues were verified and in-house IHC showed higher protein levels of SYNJ2 in HCC tissues. Pathologic T stage was identified as a risk factor. Upregulated mRNA levels and mutated SYNJ2 might cause a poorer outcome. The C-index of the nomogram model constructed by SYNJ2 level, age, gender, TNM classification, grade, and stage was evaluated as 0.643 (95%CI = 0.619-0.668) with well-calibrated plots. A total of 2,533 DCGs were extracted and mainly functioned together with SYNJ2 in metabolic pathways. Possible transcriptional axis of CTCF/POLR2A-SYNJ2/INPP5B (transcription factor-target) in metabolic pathways was discovered based on ChIP-seq datasets. In summary, transcriptional regulatory axis CTCF/POLR2A-SYNJ2 might influence SYNJ2 expression levels. Increased SYNJ2 expression level could be utilized for predicting HCC prognosis and potentially accelerates the occurrence and development of HCC via metabolic perturbations pathways.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Monoéster Fosfórico Hidrolasas , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/mortalidad , Carcinoma Hepatocelular/patología , Femenino , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/mortalidad , Neoplasias Hepáticas/patología , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Monoéster Fosfórico Hidrolasas/genética , Monoéster Fosfórico Hidrolasas/metabolismo , Factores de Riesgo , Regulación hacia ArribaRESUMEN
The screening and treatment of laryngeal squamous cell carcinoma (LSCC) still perplexes clinicians, making it necessary to explore new markers. To this end, this research examined the underlying molecular mechanism of LSCC based on high-throughput datasets (n = 249) from multiple databases. It also identified transcription factors (TFs) independently associated with LSCC prognosis. Through Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses, differential expression genes of LSCC were deemed relevant to the extracellular matrix and its related structures or pathways, suggesting that the extracellular matrix plays an important role in LSCC. At the same time, several hub genes that may also have important roles in LSCC were identified via protein-protein interaction analysis, including CDC45, TPX2, AURKA, KIF2C, NUF, MUC1, MUC7, MUC4, MUC15, and MUC21. Eight unreported LSCC prognostic TFs - BCAT1, CHD4, FOXA2, GATA6, HNF1A, HOXB13, MAFF, and TCF4 - were screened via Kaplan-Meier curves. Cox analysis determined for the first time that HOXB13 expression and gender were independently associated with LSCC prognosis. Compared to control tissues, elevated expression of HOXB13 was found in LSCC tissues (standardized mean difference = 0.44, 95% confidence interval [0.13-0.76]). HOXB13 expression also makes it feasible to screen LSCC from non-LSCC (area under the curve = 0.77), and HOXB13 may play an essential role in LSCC by regulating HOXB7. In conclusion, HOXB13 may be a novel marker for LSCC clinical screening and treatment.
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Biomarcadores de Tumor , Neoplasias de Cabeza y Cuello , Carcinoma de Células Escamosas de Cabeza y Cuello , Factores de Transcripción , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Bases de Datos Genéticas , Femenino , Neoplasias de Cabeza y Cuello/diagnóstico , Neoplasias de Cabeza y Cuello/genética , Neoplasias de Cabeza y Cuello/metabolismo , Neoplasias de Cabeza y Cuello/mortalidad , Proteínas de Homeodominio/genética , Proteínas de Homeodominio/metabolismo , Humanos , Masculino , Pronóstico , Mapas de Interacción de Proteínas/genética , Carcinoma de Células Escamosas de Cabeza y Cuello/diagnóstico , Carcinoma de Células Escamosas de Cabeza y Cuello/genética , Carcinoma de Células Escamosas de Cabeza y Cuello/metabolismo , Carcinoma de Células Escamosas de Cabeza y Cuello/mortalidad , Factores de Transcripción/genética , Factores de Transcripción/metabolismoRESUMEN
A series of substituted aryl glycoside analogues of gastrodin have been identified as potential anti-influenza agents. The most potent inhibitor 1a exhibited moderate inhibitory activity against the A/Hanfang/359/95(H3N2) and A/FM/1/47(H1N1) strains of the influenza A virus (IC(50) values of 44.40 and 34.45 µM, respectively) and the oseltamivir-null B/Jifang/13/97 strain of influenza B (IC(50) value of 33.01 µM). In this article, multiple doses of compound 1a (80 mg/kg/day, oral administration) were used for the treatment of mice infected with influenza A/FM/1/47-MA (H1N1), and surprisingly we found that compound 1a significantly increased the number of survivors and prolonged the mean survival time. The preliminary studies on the mechanism of antiviral activity showed no interaction between compound 1a and the neuraminidase or the M2 protein. The novel target to overcome drug resistance combined with its good in vivo profile support compound 1a to be a new lead for further development of antiviral agents.
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Antivirales/síntesis química , Alcoholes Bencílicos/síntesis química , Glucósidos/síntesis química , Subtipo H1N1 del Virus de la Influenza A/efectos de los fármacos , Animales , Antivirales/farmacología , Alcoholes Bencílicos/farmacología , Femenino , Glucósidos/farmacología , Hemaglutinación/efectos de los fármacos , Subtipo H1N1 del Virus de la Influenza A/crecimiento & desarrollo , Concentración 50 Inhibidora , Ratones , Neuraminidasa/antagonistas & inhibidores , Neuraminidasa/metabolismo , Oseltamivir/farmacología , Relación Estructura-Actividad , Proteínas de la Matriz Viral/antagonistas & inhibidores , Proteínas de la Matriz Viral/metabolismoRESUMEN
A series of novel N-phenylbenzamide derivatives were synthesized and their anti-EV 71 activities were assayed in vitro. Among the compounds tested, 3-amino-N-(4-bromophenyl)-4-methoxybenzamide (1e) was active against the EV 71 strains tested at low micromolar concentrations, with IC50 values ranging from 5.7 ± 0.8-12 ± 1.2 µM, and its cytotoxicity to Vero cells (TC50 = 620 ± 0.0 µM) was far lower than that of pirodavir (TC50 = 31 ± 2.2 µM). Based on these results, compound 1e is a promising lead compound for the development of anti-EV 71 drugs.
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Antivirales/síntesis química , Benzamidas/síntesis química , Animales , Antivirales/farmacología , Antivirales/toxicidad , Benzamidas/farmacología , Benzamidas/toxicidad , Chlorocebus aethiops , Evaluación Preclínica de Medicamentos , Enterovirus/efectos de los fármacos , Concentración 50 Inhibidora , Piperidinas/farmacología , Piperidinas/toxicidad , Piridazinas/farmacología , Piridazinas/toxicidad , Relación Estructura-Actividad , Células VeroRESUMEN
The influenza virus is a persistent cause of mortality and morbidity on an annual basis and thus presents itself as an important target for pharmaceutical investigation. In this work, substituted bisaryl amide compounds were found to be a new class of potential anti-influenza agents, and a series of substituted bisaryl amide compounds were synthesised and evaluated for their anti-influenza virus activities. The analysis of the results produced a preliminary structure-activity relationship study (SAR). Compounds 1a, 1g, 1h, 1j, 1l and 1n exhibited clear antiviral activities against the influenza A (A/Guangdong Luohu/219/2006, H1N1) virus with 50% inhibitory concentrations (IC(50)) for virus growth ranging from 12.5 to 59.0 µM. Specifically, compound 1j also possessed antiviral activity against both oseltamivir-resistant influenza (A/Jinnan/15/2009) virus and influenza B (B/Jifang/13/97) virus with IC(50) values of 9.2 µM and 21.4 µM, respectively. Compound 1j is thus worth further investigation as an anti-influenza virus candidate.
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Amidas/síntesis química , Amidas/farmacología , Antivirales/síntesis química , Antivirales/farmacología , Subtipo H1N1 del Virus de la Influenza A/efectos de los fármacos , Virus de la Influenza B/efectos de los fármacos , Amidas/química , Antivirales/química , Técnicas de Química Sintética , Relación Estructura-ActividadRESUMEN
A series of novel glutarimide compounds were synthesized and their antiviral activities were evaluated. The compounds displaying the strongest antiviral activities included 5, 6f, 7e and 9 against coxsackievirus B3 (Cox B3), 10 and 6f against influenza virus A (influenza A) and 7a against herpes simplex virus 2 (HSV-2). However, most of the synthetic glutarimides showed comparatively much weaker activity against influenza A, Cox B3 and HSV-2 than the natural glutarimide compounds tested. Based on the results, it seemed likely that a conjugated system at the ß-substituted moiety provides stronger antiviral activity.
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Antivirales/farmacología , Infecciones por Coxsackievirus/tratamiento farmacológico , Enterovirus Humano B/efectos de los fármacos , Herpes Simple/tratamiento farmacológico , Herpesvirus Humano 2/efectos de los fármacos , Virus de la Influenza A/efectos de los fármacos , Infecciones por Orthomyxoviridae/tratamiento farmacológico , Piperidonas/farmacología , Animales , Antivirales/síntesis química , Antivirales/química , Línea Celular , Supervivencia Celular/efectos de los fármacos , Chlorocebus aethiops , Humanos , Estructura Molecular , Piperidonas/síntesis química , Piperidonas/química , Relación Estructura-Actividad , Células VeroRESUMEN
Cycloheximide (CHX) inhibits protein synthesis in most eukaryotic cells and it is a well-known tool commonly used in biochemical research. In this paper, the antiviral spectrum of CHX against several DNA and RNA viruses have been evaluated. CHX showed strong inhibitory activities against several RNA viruses such as HIV-1, influenza viruses, coxsackie B virus, enterovirus (EV71) and several DNA viruses such as HSV and HCMV. Especially the strong inhibitory activities of CHX against coxsackie B virus and enterovirus caught our attention, since effective drugs available in clinic are limited. The SAR of CHX derivatives also has been discussed in the paper. The hydroxyl group at C-2' and carbonyl group at C-2" of CHX are essential for its antiviral activity. And modification to these groups results its derivatives' antiviral activities reduced or lost.
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Antivirales , Cicloheximida , Virus ADN/efectos de los fármacos , Virus ARN/efectos de los fármacos , Antivirales/síntesis química , Antivirales/química , Antivirales/farmacología , Línea Celular , Cicloheximida/análogos & derivados , Cicloheximida/síntesis química , Cicloheximida/química , Cicloheximida/farmacología , Enterovirus/efectos de los fármacos , Enterovirus Humano B/efectos de los fármacos , HumanosRESUMEN
Influenza virus is a virus causing upper respiratory tract infection disease with high morbidity and mortality. China is considered as an area with high rate of influenza morbidity. Prevention and treatment of influenza currently rely on vaccines and antiviral agents in the world. In addition, traditional Chinese medicines also have been used in clinical for influenza therapy. In vitro anti-influenza virus activities of 10 traditional Chinese medicines were studied by cytopathic effect (CPE). Qingre Jiedu oral liquid (factory H) had strong antiviral activity against influenza virus A/Guangdong Luohu/219/2006 (H1N1); Yinhuang oral liquid had strong antiviral activity against influenza virus A/Hanfang/359/95 and A/Yuefang/243/72 (H3N2). Qingkailing oral liquid (factory G) had strong antiviral activity against influenza virus A/Jifang/15/90 (H3N2). Qingre Jiedu oral liquid (factory H) had strong antiviral activity against influenza virus A/Jifang/15/90, A/Yuefang/243/72 (H3N2) and virus B.
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Antivirales/farmacología , Efecto Citopatogénico Viral/efectos de los fármacos , Medicamentos Herbarios Chinos/farmacología , Subtipo H1N1 del Virus de la Influenza A/efectos de los fármacos , Subtipo H3N2 del Virus de la Influenza A/efectos de los fármacos , Administración Oral , Animales , Antivirales/administración & dosificación , Compuestos Bicíclicos Heterocíclicos con Puentes/administración & dosificación , Compuestos Bicíclicos Heterocíclicos con Puentes/farmacología , Línea Celular , Ácido Clorogénico/administración & dosificación , Ácido Clorogénico/farmacología , Perros , Medicamentos Herbarios Chinos/administración & dosificación , Flavonoides/administración & dosificación , Flavonoides/farmacología , Indoles/administración & dosificación , Indoles/farmacología , Virus de la Influenza B/efectos de los fármacos , Iridoides/administración & dosificación , Iridoides/farmacologíaRESUMEN
Ribavirin is a broad-spectrum inhibitor against several unrelated DNA or RNA viruses in vitro and in vivo. In this paper the in vitro and in vivo study of anti-influenza virus activity of ribavirin (RBV) injection had been reported. The in vitro antiviral activity of ribavirin injection against influenza virus A and B was studied by CPE. The in vivo protective action of ribavirin injection against influenza A/FM/1/47(H1N1) mouse adapted strain infected mouse was studied with mouse model. The results showed ribavirin injection has strong inhibitory activity against 7 virus strains tested in vitro. Ribavirin injection could significantly increase virus infected mouse survival rate and survival days and improve lung pathogen and lung index.
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Antivirales , Subtipo H1N1 del Virus de la Influenza A/efectos de los fármacos , Infecciones por Orthomyxoviridae/tratamiento farmacológico , Ribavirina , Animales , Antivirales/administración & dosificación , Antivirales/farmacología , Antivirales/uso terapéutico , Línea Celular , Efecto Citopatogénico Viral/efectos de los fármacos , Perros , Femenino , Subtipo H3N2 del Virus de la Influenza A/efectos de los fármacos , Virus de la Influenza B/efectos de los fármacos , Inyecciones , Pulmón/patología , Ratones , Infecciones por Orthomyxoviridae/patología , Ribavirina/administración & dosificación , Ribavirina/farmacología , Ribavirina/uso terapéuticoRESUMEN
We have discovered several tubulin-active compounds in our previous studies. In the establishment of a compound library of small molecule weight tubulin ligands, 14 new N-3-haloacylaminophenyl-N'-(alkyl/aryl) urea analogs were designed and synthesized. The structure-activity relationship (SAR) analysis revealed that (i) the order of anticancer potency for the 3-haloacylamino chain was following -CH(2)Br>-CHBrCH(3); (ii) the N'-substituent moiety was not essential for the anticancer activity, and a proper alkyl substitution might enhance the anticancer activity. Among these analogs, the compounds 16j bearing bromoacetyl at the N'-end exhibited a potent activity against eight human tumor cell lines, including CEM (leukemia), Daudi (lymphoma), MCF-7 (breast cancer), Bel-7402 (hepatoma), DU-145 (prostate cancer), DND-1A (melanoma), LOVO (colon cancer) and MIA Paca (pancreatic cancer), with the IC(50) values between 0.38 and 4.07 microM. Interestingly, compound 16j killed cancer cells with a mechanism independent of the tubulin-based mechanism, indicating a significant change of the action mode after the structure modification.
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Antineoplásicos/química , Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Compuestos de Fenilurea/química , Compuestos de Fenilurea/farmacología , Antineoplásicos/síntesis química , Línea Celular Tumoral , Relación Dosis-Respuesta a Droga , Femenino , Citometría de Flujo , Humanos , Concentración 50 Inhibidora , Masculino , Estructura Molecular , Compuestos de Fenilurea/síntesis químicaRESUMEN
3-Haloacylamino benzoylureas (3-HBUs) consist of a new family of tubulin ligands that kill cancer cells through mitotic arrest. In exploring the structure-activity relationship (SAR), 17 analogues defined through variations of formylurea at the 1-position of the aromatic ring were synthesized. SAR analysis revealed that (i) the p-pi conjugation between the aromatic ring and formylurea was essential; (ii) suitable aryl substitutions at the N'-end increased anticancer activity with a mechanism different from that of parent compounds; and (iii) introduction of pyridyl at the N'-end provided an opportunity of making soluble salts to improve bioavailability. Among the analogues, 16c bearing 3,4,5-trimethoxyphenyl and 16g bearing 2-pyridyl at the N'-end showed an enhanced activity and were active in hepatoma cells that were resistant to tubulin ligands including the parent compounds. Furthermore, 16c and 16g killed cancer cells with a mechanism independent of mitotic arrest, indicating a change of action mode.