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1.
Chemistry ; : e202401400, 2024 May 13.
Artículo en Inglés | MEDLINE | ID: mdl-38736421

RESUMEN

Coumestan represents a biologically relevant structural motif distributed in a number of natural products, and the rapid construction of related derivatives as well as the characterization of targets would accelerate lead compound discovery in medicinal chemistry. In this work, a general and scalable approach to 8,9-dihydroxycoumestans via two-electrode constant current electrolysis was developed. The application of a two-phase (aqueous/organic) system plays a crucial role for success, protecting the sensitive o-benzoquinone intermediates from over-oxidation. Based on the structurally diverse products, a primary SAR study on coumestan scaffold was completed, and compound 3 r exhibited potent antiproliferative activities and a robust topoisomerase I (Top1) inhibitory activity. Further mechanism studies demonstrates that compound 3 r was a novel Top1 poison, which might open an avenue for the development of Top1-targeted antitumor agent.

2.
Nucleic Acids Res ; 50(16): 9039-9050, 2022 09 09.
Artículo en Inglés | MEDLINE | ID: mdl-35993818

RESUMEN

Aptamers' vast conformation ensemble consisting of interconverting substates severely impairs their performance and applications in biomedicine. Therefore, developing new chemistries stabilizing aptamer conformation and exploring the conformation-performance relationship are highly desired. Herein, we developed an 8-methoxypsoralen-based photochemically covalent lock to stabilize aptamer conformation via crosslinking the inter-stranded thymine nucleotides at TpA sites. Systematical studies and molecular dynamics simulations were performed to explore the conformation-performance relationship of aptamers, revealing that conformation-stabilized aptamers displayed better ability to bind targets, adapt to physiological environment, resist macrophage uptake, prolong circulation half-life, accumulate in and penetrate into tumor than their counterparts. As expected, conformation-stabilized aptamers efficiently improved the therapeutic efficacy of aptamer-drug conjugation on tumor-bearing mice. Collectively, our study has developed a general, simple and economic strategy to stabilize aptamer conformation and shed light on the conformation-performance relationship of aptamers, laying a basis for promoting their basic researches and applications in biomedicine.


Asunto(s)
Aptámeros de Nucleótidos , Ratones , Animales , Aptámeros de Nucleótidos/química , Conformación Molecular , Simulación de Dinámica Molecular , Técnica SELEX de Producción de Aptámeros
3.
Bioorg Chem ; 138: 106586, 2023 09.
Artículo en Inglés | MEDLINE | ID: mdl-37178651

RESUMEN

Fusobacterium nucleatum (F. nucleatum) is closely associated with the occurrence and development of colorectal cancer (CRC). Discovery of specific antibacterial agents against F. nucleatum was urgent for the prevention and treatment of CRC. We screened a natural product library and successfully identified higenamine as an antibacterial hit against F. nucleatum. Further hit optimizations led to the discovery of new higenamine derivatives with improved anti-F. nucleatum activity. Among them, compound 7c showed potent antibacterial activity against F. nucleatum (MIC50 = 0.005 µM) with good selectivity toward intestinal bacteria and normal cells. It significantly inhibited the migration of CRC cells induced by F. nucleatum. Mechanism study revealed that compound 7c impaired the integrity of biofilm and cell wall, which represents a good starting point for the development of novel anti-F. nucleatum agents.


Asunto(s)
Neoplasias Colorrectales , Humanos , Fusobacterium nucleatum , Antibacterianos/farmacología
4.
Bioorg Chem ; 122: 105702, 2022 05.
Artículo en Inglés | MEDLINE | ID: mdl-35286923

RESUMEN

On the basis of synergistic effect between topoisomerase (Top) and histone deacetylase (HDAC) inhibitors, a series of novel evodiamine-based Top/HDAC dual inhibitors were designed and synthesized. Systematic structure-activity relationship (SAR) studies led to the discovery of compounds 29b and 45b, which simultaneously inhibited Top and HDAC and exhibited potent antitumor activities against the HCT116 cell line. Compounds 29b and 45b efficiently induced apoptosis with G2 cell cycle arrest and significantly inhibited cellular HDACs in HCT116 cells with good in vitro metabolic stabilities. Collectively, this work provides valuable SAR information and lead compounds for evodiamine-based Top/HDAC dual inhibitors.


Asunto(s)
Antineoplásicos , Inhibidores de Histona Desacetilasas , Antineoplásicos/farmacología , Línea Celular Tumoral , Proliferación Celular , Diseño de Fármacos , Ensayos de Selección de Medicamentos Antitumorales , Inhibidores de Histona Desacetilasas/farmacología , Histona Desacetilasas/metabolismo , Humanos , Quinazolinas , Relación Estructura-Actividad
5.
Bioorg Med Chem Lett ; 30(1): 126662, 2020 01 01.
Artículo en Inglés | MEDLINE | ID: mdl-31784322

RESUMEN

Starting from easy accessible pyrazoletetrahydropyran acetals, a series of new pyrazolone spirocyclohexadienone derivatives were synthesized and assayed for antitumor activity. Compound 10s was identified to possess good antitumor activity. It could induce MDA-MB-231 cancer cell apoptosis in a concentration dependent manner and arrest the cell cycle progression mainly at the G1 phase.


Asunto(s)
Antineoplásicos/uso terapéutico , Neoplasias/tratamiento farmacológico , Pirazolonas/uso terapéutico , Antineoplásicos/farmacología , Humanos , Estructura Molecular , Pirazolonas/farmacología , Relación Estructura-Actividad
6.
Angew Chem Int Ed Engl ; 59(8): 3028-3032, 2020 02 17.
Artículo en Inglés | MEDLINE | ID: mdl-31943585

RESUMEN

As one of the most aggressive and lethal human malignancies with extremely poor prognosis, there is an urgent demand of more effective therapy for the treatment of pancreatic cancer. Reported here is a new, effective therapeutic strategy and the design of small-molecule inhibitors that simultaneously target bromodomain and extra-terminal (BET) and histone deacetylase (HDAC), potentially serving as promising therapeutic agents for pancreatic cancer. A highly potent dual inhibitor (13 a) is identified to possess excellent and balanced activities against BRD4 BD1 (IC50 =11 nm) and HDAC1 (IC50 =21 nm). Notably, this compound shows higher in vitro and in vivo antitumor potency than the BET inhibitor (+)-JQ1 and the HDAC inhibitor vorinostat, either alone or and in combination, highlighting the advantages of BET/HDAC dual inhibitors for more effective treatment of pancreatic cancer.


Asunto(s)
Inhibidores de Histona Desacetilasas/uso terapéutico , Neoplasias Pancreáticas/tratamiento farmacológico , Inhibidores de Histona Desacetilasas/farmacología , Humanos , Neoplasias Pancreáticas/patología , Relación Estructura-Actividad
7.
Bioorg Med Chem Lett ; 27(9): 1929-1933, 2017 05 01.
Artículo en Inglés | MEDLINE | ID: mdl-28351590

RESUMEN

Previously, 4-tosylanthra[1,2-c][1,2,5]thiadiazole-6,11-dione (1) was identified as a novel non-camptothecin topoisomerase I (Top1) inhibitor by structure-based virtual screening. Herein, a series of 4-substituted derivatives were designed and synthesized. Most of them showed potent Top1 inhibitory activity. Their in vitro antiproliferative activity was also evaluated in A549, HCT-116 and ZR-75-30 human cancer cell lines. Compound 8s showed good antiproliferative activity with IC50 of 0.52µM and 0.42µM against HCT-116 and ZR-75-30 cell line, respectively. Top1 unwinding assay and molecular modeling studies rationalized the mode of action of this new class of inhibitors.


Asunto(s)
Antraquinonas/química , Antraquinonas/farmacología , Antineoplásicos/química , Antineoplásicos/farmacología , Tiadiazoles/química , Tiadiazoles/farmacología , Inhibidores de Topoisomerasa I/química , Inhibidores de Topoisomerasa I/farmacología , Antraquinonas/síntesis química , Antineoplásicos/síntesis química , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , ADN-Topoisomerasas de Tipo I/metabolismo , Diseño de Fármacos , Humanos , Simulación del Acoplamiento Molecular , Neoplasias/tratamiento farmacológico , Neoplasias/enzimología , Tiadiazoles/síntesis química , Inhibidores de Topoisomerasa I/síntesis química
8.
Org Biomol Chem ; 15(47): 9992-9995, 2017 Dec 06.
Artículo en Inglés | MEDLINE | ID: mdl-29177308

RESUMEN

The development of small molecules for cancer immunotherapy is highly challenging and indoleamine 2,3-dioxygenase 1 (IDO1) represents a promising target. Inspired by the synergistic effects between IDO1 inhibitors and traditional antitumor chemotherapeutics, the first orally active dual IDO1 and DNA targeting agents were designed by the pharmacophore fusion strategy. The bifunctional hybrids exhibited enhanced IDO1 enzyme inhibitory activity and in vitro cytotoxicity as compared to IDO1 inhibitor 1-methyl-tryptophan and DNA alkylating agent melphalan. In a murine LLC tumor model, the dual targeting agents demonstrated excellent antitumor efficacy, highlighting the advantages of this novel design strategy to improve the efficacy of small molecule cancer immunotherapy.


Asunto(s)
Antineoplásicos/farmacología , ADN de Neoplasias/efectos de los fármacos , Inhibidores Enzimáticos/farmacología , Indolamina-Pirrol 2,3,-Dioxigenasa/antagonistas & inhibidores , Melfalán/farmacología , Triptófano/análogos & derivados , Animales , Antineoplásicos/síntesis química , Antineoplásicos/química , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Descubrimiento de Drogas , Ensayos de Selección de Medicamentos Antitumorales , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Humanos , Inmunoterapia , Indolamina-Pirrol 2,3,-Dioxigenasa/metabolismo , Melfalán/síntesis química , Melfalán/química , Ratones , Estructura Molecular , Neoplasias Experimentales/tratamiento farmacológico , Relación Estructura-Actividad , Triptófano/síntesis química , Triptófano/química , Triptófano/farmacología
9.
Org Biomol Chem ; 14(16): 3926-33, 2016 Apr 28.
Artículo en Inglés | MEDLINE | ID: mdl-27044054

RESUMEN

The Michael reaction of substituted isorhodanines with α,ß-unsaturated aldehydes in the presence of a catalytic amount of a chiral secondary amine is presented. This transformation proceeds in good to high yields furnishing the corresponding 4,5-disubstituted isorhodanine adducts in good to excellent enantioselectivities.

10.
Bioorg Med Chem Lett ; 24(12): 2648-50, 2014 Jun 15.
Artículo en Inglés | MEDLINE | ID: mdl-24813735

RESUMEN

Introducing an aryl moiety to our previous pyrrolidone scaffold by molecule fusing strategy afforded two sets of isopropylether-pyrrolidone and α-phenylethylamine-pyrrolidone derivatives. Two novel compounds 8b and 8g of the latter serial showed potent p53-MDM2 inhibitory activities with Ki values of 90nM which were three-time higher than that of the parent compound. We also confirmed compound 8b can activate p53 proteins in lung cancer A549 cells. The results offered us valuable information for further lead optimization.


Asunto(s)
Diseño de Fármacos , Proteínas Proto-Oncogénicas c-mdm2/antagonistas & inhibidores , Proteínas Proto-Oncogénicas c-mdm2/metabolismo , Pirrolidinonas/química , Pirrolidinonas/farmacología , Proteína p53 Supresora de Tumor/antagonistas & inhibidores , Antineoplásicos/síntesis química , Antineoplásicos/química , Antineoplásicos/farmacología , Línea Celular Tumoral , Humanos , Imidazolinas/química , Imidazolinas/farmacología , Neoplasias Pulmonares/tratamiento farmacológico , Proteínas Proto-Oncogénicas c-mdm2/química , Pirrolidinonas/síntesis química , Proteína p53 Supresora de Tumor/química , Proteína p53 Supresora de Tumor/metabolismo
11.
ACS Nano ; 17(14): 13430-13440, 2023 07 25.
Artículo en Inglés | MEDLINE | ID: mdl-37410377

RESUMEN

Although many smart probes for precise tumor recognition have been reported, the challenge of "on-target, off-tumor" remains. Therefore, we herein report the fabrication of a series of allosterically tunable DNA nanosensing-circles (NSCs). The recognition affinity of NSCs is programmed through sensitivity to tumor microenvironment (TME) hallmarks such as small molecules, acidity, or oncoproteins. Because of their special programming conditions and active targeting capabilities, NSCs can overcome the obstacles noted above, thus achieving precise tumor recognition. Results from in vitro analysis demonstrated that NSCs obtain their recognition ability through allosteric regulation after sensing TME hallmarks. Furthermore, in vivo imaging indicated that NSCs enable precise tumor imaging. These results demonstrate that our NSCs will be promising tools for precise tumor imaging and therapy.


Asunto(s)
Neoplasias , Humanos , Microambiente Tumoral
12.
J Med Chem ; 65(6): 4818-4831, 2022 03 24.
Artículo en Inglés | MEDLINE | ID: mdl-35238576

RESUMEN

On the basis of the synergism of topoisomerase (Top) and histone deacetylase (HDAC) inhibitors in antitumor therapy, a series of novel Top/HDAC dual inhibitors were designed and synthesized by the pharmacophore fusion strategy. After systematic structure-activity relationship studies, lead compound 16j was identified to simultaneously inhibit both Top and HDAC with good potency, which showed potent antiproliferative activities with a broad spectrum. Mechanistic studies indicated that compound 16j efficiently induced apoptosis with S cell-cycle arrest in HEL cancer cells. It was orally active in HEL xenograft models and exhibited excellent in vivo antitumor efficacy (TGI = 68.5%; 10 mg/kg). Altogether, this work highlights the therapeutic potential of evodiamine-inspired Top/HDAC dual inhibitors and provides a valuable lead compound for the development of novel antitumor agents for leukemia therapy.


Asunto(s)
Antineoplásicos , Leucemia , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Apoptosis , Línea Celular Tumoral , Proliferación Celular , Diseño de Fármacos , Ensayos de Selección de Medicamentos Antitumorales , Inhibidores de Histona Desacetilasas/farmacología , Inhibidores de Histona Desacetilasas/uso terapéutico , Histona Desacetilasas/metabolismo , Humanos , Leucemia/tratamiento farmacológico , Relación Estructura-Actividad
13.
J Med Chem ; 65(11): 7619-7628, 2022 06 09.
Artículo en Inglés | MEDLINE | ID: mdl-35588495

RESUMEN

Autophagosome-tethering compounds (ATTECs) are an emerging new technology in targeted protein degradation. However, effective tools and successful examples for autophagosome-tethering chimeras are still rather limited. Herein, ATTEC ispinesib was identified for the first time to be an effective warhead to design autophagosome-tethering chimeras. As a conceptual validation study, the first generation of autophagic degraders of nicotinamide phosphoribosyltransferase (NAMPT) were developed by connecting the NAMPT inhibitor and LC3-binding ispinesib through a flexible linker. In particular, compound A3 significantly induced the degradation of NAMPT through the autophagy-lysosomal pathway, leading to excellent cellular antitumor potency. Ispinesib may have broad applications in the design of potent autophagosome-tethering chimeras.


Asunto(s)
Autofagosomas , Nicotinamida Fosforribosiltransferasa , Autofagosomas/metabolismo , Benzamidas , Quimera/metabolismo , Citocinas/metabolismo , Inhibidores Enzimáticos/farmacología , Quinazolinas
14.
Eur J Med Chem ; 220: 113544, 2021 Aug 05.
Artículo en Inglés | MEDLINE | ID: mdl-34052678

RESUMEN

10-Hydroxyevodiamine is a multitargeting antitumor lead compound with excellent in vitro activity. However, its in vivo antitumor potency is rather limited, which has hampered its further clinical development. To overcome this obstacle, a series of novel water-soluble derivatives of 10-hydroxyevodiamine were designed and synthesized. Most of them exhibited good to excellent antitumor activities against several cancer cell lines. In particular, phosphate derivative 9 was orally active and showed improved in vivo antitumor efficacy in HCT116 xenograft models. Further antitumor mechanism studies indicated that compound 9 acted by triple Top1/Top2/tubulin inhibition and induced apoptosis with G2/M cell cycle arrest. Taken together, this study extended the structure-activity relationship of evodiamine and identified phosphate derivative 9 as a promising antitumor lead compound.


Asunto(s)
Antineoplásicos/farmacología , Descubrimiento de Drogas , Fosfatos/farmacología , Quinazolinas/farmacología , Administración Oral , Animales , Antineoplásicos/administración & dosificación , Antineoplásicos/química , Apoptosis/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , ADN-Topoisomerasas de Tipo I/metabolismo , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Femenino , Células HCT116 , Humanos , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Estructura Molecular , Neoplasias Experimentales/tratamiento farmacológico , Neoplasias Experimentales/metabolismo , Neoplasias Experimentales/patología , Fosfatos/administración & dosificación , Fosfatos/química , Quinazolinas/administración & dosificación , Quinazolinas/química , Solubilidad , Relación Estructura-Actividad , Agua/química
15.
Acta Pharm Sin B ; 11(6): 1617-1628, 2021 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-34221872

RESUMEN

The dose-related adverse effects of MDM2‒P53 inhibitors have caused significant concern in the development of clinical safe anticancer agents. Herein we report an unprecedented homo-PROTAC strategy for more effective disruption of MDM2‒P53 interaction. The design concept is inspired by the capacity of sub-stoichiometric catalytic PROTACs enabling to degrade an unwanted protein and the dual functions of MDM2 as an E3 ubiquitin ligase and a binding protein with tumor suppressor P53. The new homo-PROTACs are designed to induce self-degradation of MDM2. The results of the investigation have shown that PROTAC 11a efficiently dimerizes MDM2 with highly competitive binding activity and induces proteasome-dependent self-degradation of MDM2 in A549 non-small cell lung cancer cells. Furthermore, markedly, enantiomer 11a-1 exhibits potent in vivo antitumor activity in A549 xenograft nude mouse model, which is the first example of homo-PROTAC with in vivo therapeutic potency. This study demonstrates the potential of the homo-PROTAC as an alternative chemical tool for tumorigenic MDM2 knockdown, which could be developed into a safe therapy for cancer treatment.

16.
Acta Pharm Sin B ; 10(7): 1294-1308, 2020 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-32874829

RESUMEN

A great challenge in multi-targeting drug discovery is to identify drug-like lead compounds with therapeutic advantages over single target inhibitors and drug combinations. Inspired by our previous efforts in designing antitumor evodiamine derivatives, herein selective histone deacetylase 1 (HDAC1) and topoisomerase 2 (TOP2) dual inhibitors were successfully identified, which showed potent in vitro and in vivo antitumor potency. Particularly, compound 30a was orally active and possessed excellent in vivo antitumor activity in the HCT116 xenograft model (TGI = 75.2%, 150 mg/kg, p.o.) without significant toxicity, which was more potent than HDAC inhibitor vorinostat, TOP inhibitor evodiamine and their combination. Taken together, this study highlights the therapeutic advantages of evodiamine-based HDAC1/TOP2 dual inhibitors and provides valuable leads for the development of novel multi-targeting antitumor agents.

17.
ACS Med Chem Lett ; 11(4): 439-444, 2020 Apr 09.
Artículo en Inglés | MEDLINE | ID: mdl-32292547

RESUMEN

In order to improve the antitumor potency of the natural product evodiamine, novel boron-containing evodiamine derivatives were designed by incorporating boronic acid and boronate as trigger units. Boronate derivative 13a could be triggered by reactive oxygen species (ROS) in the HCT116 colon cancer cell line and showed excellent antitumor activity in vitro and in vivo. It induced apoptosis in HCT116 cancer cells in a dose-dependent manner and cell growth arrest at the G2 phase.

18.
ACS Med Chem Lett ; 11(1): 40-44, 2020 Jan 09.
Artículo en Inglés | MEDLINE | ID: mdl-31938461

RESUMEN

Chidamide is a histone deacetylase (HDAC) inhibitor that is currently used to treat cutaneous T-cell lymphoma in clinic. Herein nicotinamide phosphoribosyltransferase (NAMPT) was identified to be a new target of chidamide on the basis of the pharmacophore analysis, molecular docking, biological assays, inhibitor design, and structure-activity relationship study. The polypharmacology of chidamide will provide important information for better understanding its antitumor mechanism. Also, design of dual NAMPT/HDAC inhibitors may serve as an effective strategy to develop novel antitumor agents.

19.
Eur J Med Chem ; 201: 112515, 2020 Sep 01.
Artículo en Inglés | MEDLINE | ID: mdl-32623209

RESUMEN

Secreted aspartic protease 2 (SAP2), a kind of virulence factor, is an emerging new antifungal target. Using docking-based virtual screening and structure-based inhibitor design, a series of novel SAP2 inhibitors were successfully identified. Among them, indolone derivative 24a showed potent SAP2 inhibitory activity (IC50 = 0.92 µM). It blocked fungi biofilm and hypha formation by down-regulating the expression of genes SAP2, ECE1, ALS3 and EFG1. As a virulence factor inhibitor, compound 24a was inactive in vitro and showed potent in vivo efficacy in a murine model of invasive candidiasis. It represents a promising lead compound for the discovery of novel antifungal agents.


Asunto(s)
Antifúngicos/farmacología , Ácido Aspártico Endopeptidasas/antagonistas & inhibidores , Oxindoles/farmacología , Inhibidores de Proteasas/farmacología , Pirazolonas/farmacología , Factores de Virulencia/antagonistas & inhibidores , Antifúngicos/síntesis química , Antifúngicos/metabolismo , Ácido Aspártico Endopeptidasas/química , Ácido Aspártico Endopeptidasas/metabolismo , Biopelículas/efectos de los fármacos , Candida albicans/efectos de los fármacos , Candida albicans/fisiología , Candida tropicalis/efectos de los fármacos , Candida tropicalis/fisiología , Dominio Catalítico , Proteínas Fúngicas/antagonistas & inhibidores , Proteínas Fúngicas/química , Proteínas Fúngicas/metabolismo , Pruebas de Sensibilidad Microbiana , Simulación del Acoplamiento Molecular , Estructura Molecular , Oxindoles/síntesis química , Oxindoles/metabolismo , Inhibidores de Proteasas/síntesis química , Inhibidores de Proteasas/metabolismo , Unión Proteica , Pirazolonas/síntesis química , Pirazolonas/metabolismo , Relación Estructura-Actividad , Factores de Virulencia/química , Factores de Virulencia/metabolismo
20.
J Med Chem ; 63(2): 696-713, 2020 01 23.
Artículo en Inglés | MEDLINE | ID: mdl-31880942

RESUMEN

Inspired by the natural product evodiamine, a novel antitumor indolopyrazinoquinazolinone scaffold was designed by scaffold hopping. Structure-activity relationship studies led to the discovery of compound 15j, which shows low nanomolar inhibitory activity against the HCT116 cell line. Further antitumor mechanism studies indicated that compound 15j acted by the dual inhibition of topoisomerase 1 and tubulin and induced apoptosis with G2 cell-cycle arrest. The quaternary ammonium salt of compound 15j (compound 15js) exhibited excellent in vivo antitumor activity (TGI = 66.6%) in the HCT116 xenograft model with low toxicity. Indolopyrazinoquinazolinone derivatives represent promising multitargeting antitumor leads for the development of novel antitumor agents.


Asunto(s)
Antineoplásicos/química , Antineoplásicos/farmacología , Neoplasias del Colon/tratamiento farmacológico , Quinazolinas/química , Quinazolinas/farmacología , Animales , Apoptosis/efectos de los fármacos , Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Diseño de Fármacos , Fase G2/efectos de los fármacos , Células HCT116 , Humanos , Ratones , Relación Estructura-Actividad , Inhibidores de Topoisomerasa I/síntesis química , Inhibidores de Topoisomerasa I/farmacología , Inhibidores de Topoisomerasa II/síntesis química , Inhibidores de Topoisomerasa II/farmacología , Moduladores de Tubulina/síntesis química , Moduladores de Tubulina/farmacología , Ensayos Antitumor por Modelo de Xenoinjerto
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