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1.
Bioorg Med Chem ; 92: 117417, 2023 09 07.
Artículo en Inglés | MEDLINE | ID: mdl-37531922

RESUMEN

Salirasib, or farnesylthiosalicylic acid (FTS), is a salicylic acid derivative with demonstrated antineoplastic activity. While designed as a competitor of the substrate S-farnesyl cysteine on Ras, it is a potent competitive inhibitor of isoprenylcysteine carboxymethyl transferase. In this study, the antiproliferative activity on six different solid tumor cell lines was evaluated with a series of lipophilic thioether modified salirasib analogues, including those with or without a 1,2,3-triazole linker. A combination of bioassay, cheminformatics, docking, and in silico ADME-Tox was also performed. SAR analysis that analogues with three or more isoprene units or a long aliphatic chain exhibited the most potent activity. Furthermore, three compounds display superior antiproliferative activity than salirasib and similar potency compared to control anticancer drugs across all tested solid tumor cell lines. In addition, the behavior of the collection on migration and invasion, a key process in tumor metastasis, was also studied. Three analogues with specific antimigratory activity were identified with differential structural features being interesting starting points on the development of new antimetastatic agents. The antiproliferative and antimigratory effects observed suggest that modifying the thiol aliphatic/prenyl substituents can modulate the activity.


Asunto(s)
Antineoplásicos , Antineoplásicos/farmacología , Salicilatos/farmacología , Farnesol/farmacología , Línea Celular Tumoral , Proliferación Celular
3.
Bioorg Med Chem Lett ; 30(14): 127247, 2020 07 15.
Artículo en Inglés | MEDLINE | ID: mdl-32527547

RESUMEN

A series of levoglucosenone-derived 1,2,3-triazoles and isoxazoles featuring a flexible spacer between the heteroaromatic and anhydropyranose cores have been designed and synthesized following an hetero Michael // 1,3-dipolar cycloaddition path. The use of a design of experiments approach allowed the optimization of the oxa-Michael reaction with propargyl alcohol as nucleophile, a key step for the synthesis of the target compounds. All of the compounds were tested for their anticancer activity on MDA-MB-231 cells, featuring mutant p53. The results highlighted the importance of the introduction of the flexible spacer as well as the higher activity of oxa-Michael isoxazole-derivatives. The most prominent compounds also showed anti-proliferative activities against lung and colon cancer cell lines. The compounds showed enhanced cytotoxic effects in the presence of mutant p53, determined both by endogenous mutant p53 knock down (R280K) and by reintroducing p53 R280K in cells lacking p53 expression.


Asunto(s)
Antineoplásicos/farmacología , Compuestos Bicíclicos Heterocíclicos con Puentes/farmacología , Diseño de Fármacos , Glucosa/análogos & derivados , Isoxazoles/farmacología , Triazoles/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/química , Compuestos Bicíclicos Heterocíclicos con Puentes/síntesis química , Compuestos Bicíclicos Heterocíclicos con Puentes/química , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Glucosa/síntesis química , Glucosa/química , Glucosa/farmacología , Humanos , Isoxazoles/química , Estructura Molecular , Relación Estructura-Actividad , Triazoles/química
4.
Gene Expr Patterns ; 36: 119114, 2020 06.
Artículo en Inglés | MEDLINE | ID: mdl-32330562

RESUMEN

CPSF6 is a component of the CFIm complex, involved in mRNA 3'end processing. Despite increasing interest on this protein as a consequence of proposed roles in cancer and HIV infection, several aspects of CPSF6 biological function are poorly understood. In this work we studied the expression of the zebrafish ortholog cpsf6 in early stages of embryo development. Quantitative RT-PCR studies showed that zebrafish cpsf6 mRNA is maternally inherited and that its concentration markedly decreases during early development. We found a generalized distribution of cpsf6 mRNA in early stages through whole mount hybridization experiments. By performing Western blot, we also found a decrease in zebrafish Cpsf6 levels during development. Our analysis of the subcellular localization of this protein using a heterologous system showed a distinct pattern characterized by the presence of nuclear foci. We also studied the relevance of different protein domains on subcellular localization, showing that the C-terminal domain is critical for nuclear localization. Collectively, our results showed that cpsf6 expression changes during early development and that the subcellular localization of the protein is similar to that of the human ortholog.


Asunto(s)
Dominios Proteicos , Pez Cebra/genética , Pez Cebra/metabolismo , Factores de Escisión y Poliadenilación de ARNm/genética , Factores de Escisión y Poliadenilación de ARNm/metabolismo , Secuencia de Aminoácidos , Animales , Desarrollo Embrionario , Regulación del Desarrollo de la Expresión Génica , Células HEK293 , Humanos , Hibridación in Situ , ARN Mensajero/metabolismo , Pez Cebra/embriología , Proteínas de Pez Cebra/genética , Proteínas de Pez Cebra/metabolismo
5.
J Org Chem ; 83(7): 3516-3528, 2018 04 06.
Artículo en Inglés | MEDLINE | ID: mdl-29481076

RESUMEN

The design and synthesis of biomass-derived triazoles and the in vitro evaluation as potential anticancer agents are described. The discovery of base-catalyzed retro-aza-Michael//aza-Michael isomerizations allowed the exploration of the chemical space by affording novel types of triazoles, difficult to obtain otherwise. Following this strategy, 2,4-disubstituted 1,2,3-triazoles could be efficiently obtained from the corresponding 1,4-disubstituted analogues.

6.
Subcell Biochem ; 85: 41-70, 2014.
Artículo en Inglés | MEDLINE | ID: mdl-25201188

RESUMEN

Following the initial findings suggesting a pro-oncogenic role for p53 point mutants, more than 30 years of research have unveiled the critical role exerted by these mutants in human cancer. A growing body of evidence, including mouse models and clinical data, has clearly demonstrated a connection between mutant p53 and the development of aggressive and metastatic tumors. Even if the molecular mechanisms underlying mutant p53 activities are still the object of intense scrutiny, it seems evident that full activation of its oncogenic role requires the functional interaction with other oncogenic alterations. p53 point mutants, with their pleiotropic effects, simultaneously activating several mechanisms of aggressiveness, are engaged in multiple cross-talk with a variety of other cancer-related processes, thus depicting a complex molecular landscape for the mutant p53 network. In this chapter revealing evidence illustrating different ways through which this cooperation may be achieved will be discussed. Considering the proposed role for mutant p53 as a driver of cancer aggressiveness, disarming mutant p53 function by uncoupling the cooperation with other oncogenic alterations, stands out as an exciting possibility for the development of novel anti-cancer therapies.


Asunto(s)
Genes p53 , Neoplasias/genética , Mutación Puntual , Humanos , Proteína Oncogénica p21(ras)/metabolismo , Transducción de Señal
7.
Pharmacol Res ; 79: 75-87, 2014 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-24246451

RESUMEN

In the last decade intensive research has confirmed the long standing hypothesis that some p53 point mutants acquire novel activities able to cooperate with oncogenic mechanisms. Particular attention has attracted the ability of several such mutants to actively promote the development of aggressive and metastatic tumors in vivo. This knowledge opens a new dimension on rational therapy design, suggesting novel strategies based on pharmacological manipulation of those neomorphic activities. P53 point mutants have several characteristics that make them attractive targets for anti-cancer therapies. Remarkably, mutant p53 has been found predominantly in tumor cells and may act pleiotropically by interfering with a variety of cellular processes. Therefore, drugs targeting mutant p53 may selectively affect tumor cells, inactivating simultaneously several mechanisms of tumor promotion. Moreover, the high frequency of missense mutations on the p53 gene suggests that interfering with mutant p53 function may provide a valuable approach for the development of efficient therapies able to target a wide range of tumor types.


Asunto(s)
Neoplasias/genética , Proteína p53 Supresora de Tumor/genética , Animales , Humanos , Mutación , Neoplasias/metabolismo , Proteína p53 Supresora de Tumor/metabolismo
10.
Cancer Cell ; 20(1): 79-91, 2011 Jul 12.
Artículo en Inglés | MEDLINE | ID: mdl-21741598

RESUMEN

TP53 missense mutations dramatically influence tumor progression, however, their mechanism of action is still poorly understood. Here we demonstrate the fundamental role of the prolyl isomerase Pin1 in mutant p53 oncogenic functions. Pin1 enhances tumorigenesis in a Li-Fraumeni mouse model and cooperates with mutant p53 in Ras-dependent transformation. In breast cancer cells, Pin1 promotes mutant p53 dependent inhibition of the antimetastatic factor p63 and induction of a mutant p53 transcriptional program to increase aggressiveness. Furthermore, we identified a transcriptional signature associated with poor prognosis in breast cancer and, in a cohort of patients, Pin1 overexpression influenced the prognostic value of p53 mutation. These results define a Pin1/mutant p53 axis that conveys oncogenic signals to promote aggressiveness in human cancers.


Asunto(s)
Neoplasias de la Mama/enzimología , Neoplasias de la Mama/patología , Proteínas Mutantes/metabolismo , Isomerasa de Peptidilprolil/metabolismo , Proteína p53 Supresora de Tumor/metabolismo , Animales , Neoplasias de la Mama/genética , Línea Celular Tumoral , Movimiento Celular/genética , Modelos Animales de Enfermedad , Femenino , Regulación Neoplásica de la Expresión Génica , Técnicas de Sustitución del Gen , Humanos , Ratones , Modelos Biológicos , Proteínas Mutantes/genética , Peptidilprolil Isomerasa de Interacción con NIMA , Invasividad Neoplásica , Transcripción Genética , Resultado del Tratamiento , Proteína p53 Supresora de Tumor/genética
12.
Cancer Res ; 68(16): 6550-8, 2008 Aug 15.
Artículo en Inglés | MEDLINE | ID: mdl-18701478

RESUMEN

Mutations in the p53 tumor suppressor gene frequently result in expression of p53 point mutants that accumulate in cancer cells and actively collaborate with tumor progression through the acquisition of novel properties. Interfering with mutant p53 functions may represent a valid alternative for blocking tumor growth and development of aggressive phenotypes. The interactions and activities of selected proteins can be specifically modulated by the binding of peptide aptamers (PA). In the present work, we isolated PAs able to interact more efficiently with p53 conformational mutants compared with wild-type p53. The interaction between mutant p53 and PAs was further characterized using molecular modeling. Transient expression of PAs was able to reduce the transactivation activity of mutant p53 and to induce apoptosis specifically in cells expressing mutant p53. These PAs could provide a potential strategy to inhibit the oncogenic functions of mutant p53 and improve mutant p53-targeted cancer therapies.


Asunto(s)
Apoptosis/efectos de los fármacos , Aptámeros de Péptidos/farmacología , Neoplasias/patología , Proteína p53 Supresora de Tumor/genética , Western Blotting , Técnicas Químicas Combinatorias , Humanos , Inmunoprecipitación , Luciferasas/metabolismo , Modelos Moleculares , Mutación , Neoplasias/metabolismo , Biblioteca de Péptidos , Transcripción Genética , Activación Transcripcional , Transfección , Células Tumorales Cultivadas , Proteína p53 Supresora de Tumor/química , Proteína p53 Supresora de Tumor/metabolismo
13.
Exp Parasitol ; 110(2): 157-61, 2005 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-15888298

RESUMEN

Mitochondrial-type ferredoxin-NADP(H) oxidoreductases (FNR) catalyze the electron transport between NADPH and substrates such as ferredoxins. Even though enzymes belonging to this family are present in several organisms, including prokaryotes, their biological function is not clearly understood. In a previous work, we reported the existence of a mitochondrial-type FNR in the trematode Schistosoma mansoni (SmFNR). This enzyme conferred tolerance to oxidative stress conditions when tested in an heterologous system. In this work, we demonstrate that the SmFNR can be imported to mitochondria in mammal cells and show that its expression is induced in parasite cultures by reactive oxygen species (ROS). The results reported herein give further support to the involvement of SmFNR in ROS metabolism.


Asunto(s)
Ferredoxina-NADP Reductasa/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Schistosoma mansoni/enzimología , Secuencia de Aminoácidos , Animales , Secuencia de Bases , Biomphalaria , Chlorocebus aethiops , Cricetinae , Femenino , Ferredoxina-NADP Reductasa/química , Ferredoxina-NADP Reductasa/genética , Regulación Enzimológica de la Expresión Génica , Masculino , Mesocricetus , Mitocondrias/enzimología , Mitocondrias/metabolismo , Datos de Secuencia Molecular , NADPH Deshidrogenasa/metabolismo , ARN de Helminto/genética , ARN de Helminto/aislamiento & purificación , ARN Mensajero/análisis , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Schistosoma mansoni/genética , Schistosoma mansoni/metabolismo , Células Vero
14.
J Clin Microbiol ; 41(4): 1753-5, 2003 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-12682178

RESUMEN

We developed a seminested PCR for the diagnosis of histoplasmosis that amplifies a portion of the Histoplasma capsulatum H antigen gene. This assay is highly sensitive and specific, being able to detect genomic material corresponding to less than 10 yeast cells without cross-reaction against other bacterial or fungal pathogens.


Asunto(s)
Histoplasma/aislamiento & purificación , Histoplasmosis/diagnóstico , Reacción en Cadena de la Polimerasa/métodos , Antígenos Fúngicos/genética , Medios de Cultivo , ADN de Hongos/análisis , Histoplasma/genética , Histoplasmosis/microbiología , Humanos , Sensibilidad y Especificidad , Coloración y Etiquetado/métodos
15.
Mol Biochem Parasitol ; 124(1-2): 37-45, 2002.
Artículo en Inglés | MEDLINE | ID: mdl-12387848

RESUMEN

Ferredoxin NADP(H) oxidoreductases (FNR) are flavoenzymes that catalyze the electron transfer between NADP(H) and a wide range of compounds including ferredoxins and bacterial flavodoxins. FNRs are classified into two major groups: plant- and vertebrate-type. Plant-type FNRs are implicated in photosynthesis and nitrogen fixation in plastids and photosynthetic bacteria, and were recently implicated in cell protection against reactive oxygen species (ROS). Vertebrate-type FNRs are mitochondrial enzymes implicated in steroid hormone biosynthesis in mammals and in Fe(+) uptake and metabolism in yeasts. We have cloned and sequenced a cDNA coding for the vertebrate-type Schistosoma mansoni FNR. Gel diaphorase activity and western blot assays demonstrated that SmFNR represented the major diaphorase activity of adult worms. An active recombinant SmFNR was expressed in Escherichia coli that made the bacteria tolerant to oxygen peroxide, cumene hydroperoxide and the superoxide-generating herbicide, methyl viologen (MV).


Asunto(s)
Ferredoxina-NADP Reductasa/metabolismo , Estrés Oxidativo , Schistosoma mansoni/enzimología , Secuencia de Aminoácidos , Animales , Clonación Molecular , Dihidrolipoamida Deshidrogenasa/metabolismo , Escherichia coli/efectos de los fármacos , Escherichia coli/enzimología , Escherichia coli/genética , Femenino , Ferredoxina-NADP Reductasa/química , Ferredoxina-NADP Reductasa/genética , Masculino , Datos de Secuencia Molecular , Paraquat/farmacología , Peróxidos/farmacología , Schistosoma mansoni/crecimiento & desarrollo , Análisis de Secuencia de ADN
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