RESUMEN
Topoisomerase (Top) inhibitors used in clinical cancer treatments are limited because of their toxicity and severe side effects. Noteworthily, Top1/2 dual inhibitors overcome the compensatory effect between Top1 and 2 inhibitors to exhibit stronger antitumor efficacies. In this study, a series of indolo[3,2-c]isoquinoline derivatives were designed as Top1/2 dual inhibitors possessing apparent antiproliferative activities. Mechanistic studies indicated that the optimal compounds 23 and 31 with increasing reactive oxygen species levels damage DNA, inducing both cancer cell apoptosis and cycle arrest. Importantly, the results of the toxicity studies showed that compounds 23 and 31 possessed good oral safety profiles. In xenograft models, compound 23 exhibited remarkable antitumor potency, which was superior to the clinical Top inhibitors irinotecan and etoposide. Overall, this work highlights the therapeutic potential and safety profile of compound 23 as a Top1/2 dual inhibitor in tumor therapy and provides valuable lead compounds for further development of Top inhibitors.
Asunto(s)
Antineoplásicos , ADN-Topoisomerasas de Tipo II , Isoquinolinas , Inhibidores de Topoisomerasa I , Inhibidores de Topoisomerasa II , Humanos , Animales , Isoquinolinas/farmacología , Isoquinolinas/química , Isoquinolinas/uso terapéutico , Isoquinolinas/síntesis química , Isoquinolinas/farmacocinética , Antineoplásicos/farmacología , Antineoplásicos/química , Antineoplásicos/uso terapéutico , Antineoplásicos/síntesis química , Inhibidores de Topoisomerasa II/farmacología , Inhibidores de Topoisomerasa II/uso terapéutico , Inhibidores de Topoisomerasa II/química , Inhibidores de Topoisomerasa II/síntesis química , Inhibidores de Topoisomerasa I/farmacología , Inhibidores de Topoisomerasa I/uso terapéutico , Inhibidores de Topoisomerasa I/química , Inhibidores de Topoisomerasa I/síntesis química , Administración Oral , ADN-Topoisomerasas de Tipo II/metabolismo , Línea Celular Tumoral , Relación Estructura-Actividad , Ratones , Apoptosis/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , ADN-Topoisomerasas de Tipo I/metabolismo , Ensayos de Selección de Medicamentos Antitumorales , Ensayos Antitumor por Modelo de Xenoinjerto , Indoles/farmacología , Indoles/química , Indoles/uso terapéutico , Ratones Desnudos , Descubrimiento de Drogas , Especies Reactivas de Oxígeno/metabolismoRESUMEN
Aberrant phosphorylation of receptor tyrosine kinases (RTKs) is usually involved in tumor initiation, progression, and metastasis. However, developing specific and efficient molecular tools to regulate RTK phosphorylation remains a considerable challenge. In this study, we reported novel aptamer-based chimeras to inhibit the phosphorylation of RTKs, such as c-Met and EGFR, by enforced recruitment of a protein tyrosine phosphatase receptor type F (PTPRF). Our studies revealed that aptamer-based chimeras displayed a generic and potent inhibitory effect on RTK phosphorylation induced by growth factor or auto-dimerization in different cell lines and modulated cell biological behaviors by recruiting PTPRF. Furthermore, based on angstrom accuracy of the DNA duplex, the maximum catalytic radius of PTPRF was determined as â¼25.84 nm, providing a basis for the development of phosphatase-recruiting strategies. Taken together, our study provides a generic methodology not only for selectively mediating RTK phosphorylation and cellular biological processes but also for developing novel therapeutic drugs.
Asunto(s)
Aptámeros de Nucleótidos , Transducción de Señal , Aptámeros de Nucleótidos/química , Aptámeros de Nucleótidos/metabolismo , Humanos , Transducción de Señal/efectos de los fármacos , Fosforilación , Proteínas Tirosina Quinasas Receptoras/metabolismo , Proteínas Tirosina Quinasas Receptoras/antagonistas & inhibidores , Línea Celular Tumoral , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/químicaRESUMEN
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.
Asunto(s)
Antineoplásicos , Cumarinas , ADN-Topoisomerasas de Tipo I , Inhibidores de Topoisomerasa I , Inhibidores de Topoisomerasa I/química , Inhibidores de Topoisomerasa I/farmacología , Inhibidores de Topoisomerasa I/síntesis química , ADN-Topoisomerasas de Tipo I/metabolismo , ADN-Topoisomerasas de Tipo I/química , Humanos , Relación Estructura-Actividad , Antineoplásicos/química , Antineoplásicos/farmacología , Antineoplásicos/síntesis química , Cumarinas/química , Cumarinas/farmacología , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Oxidación-Reducción , Umbeliferonas/química , Umbeliferonas/farmacología , Ensayos de Selección de Medicamentos AntitumoralesRESUMEN
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 TumoralRESUMEN
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/farmacologíaRESUMEN
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 AptámerosRESUMEN
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 , QuinazolinasRESUMEN
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-ActividadRESUMEN
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-ActividadRESUMEN
The dose-related adverse effects of MDM2âP53 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 MDM2âP53 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.
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/químicaRESUMEN
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.
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/metabolismoRESUMEN
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.
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.
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 =11â nm) and HDAC1 (IC50 =21â 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-ActividadRESUMEN
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-ActividadRESUMEN
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 XenoinjertoRESUMEN
Natural product evodiamine and its derivatives represent a promising class of multi-target antitumor agents. However, the clinical development of these compounds has been hampered by a poor understanding of their antitumor mechanisms. To tackle this obstacle, herein, novel fluorescent probes were designed to elucidate the antitumor mode of action of 10-hydroxyevodiamine. This compound was proven to be distributed in the mitochondria and lysosomes and to act by autophagy and apoptosis mechanisms.
RESUMEN
An iridium-catalyzed asymmetric allylation of dioxindoles, 3-hydroxyoxindoles, regulated by prosthetic groups has been accomplished under mild conditions. The methodology is applicable to a diverse array of 3-hydroxyoxindole and cinnamyl acetate substrates. A range of 3-allyl-3-hydroxyoxindoles containing vicinal tetrasubstituted and trisubstituted stereocenters can be efficiently synthesized in one-step with excellent enantioselectivity (up to >99% enaniomeric excess (ee)) and good diastereoselectivity (up to 11:1 diastereomeric ratio (dr)).