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1.
Med Res Rev ; 44(4): 1727-1767, 2024 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-38314926

RESUMEN

Unprecedented therapeutic targeting of previously undruggable proteins has now been achieved by molecular-glue-mediated proximity-induced degradation. As a small GTPase, G1 to S phase transition 1 (GSPT1) interacts with eRF1, the translation termination factor, to facilitate the process of translation termination. Studied demonstrated that GSPT1 plays a vital role in the acute myeloid leukemia (AML) and MYC-driven lung cancer. Thus, molecular glue (MG) degraders targeting GSPT1 is a novel and promising approach for treating AML and MYC-driven cancers. In this Perspective, we briefly summarize the structural and functional aspects of GSPT1, highlighting the latest advances and challenges in MG degraders, as well as some representative patents. The structure-activity relationships, mechanism of action and pharmacokinetic features of MG degraders are emphasized to provide a comprehensive compendium on the rational design of GSPT1 MG degraders. We hope to provide an updated overview, and design guide for strategies targeting GSPT1 for the treatment of cancer.


Asunto(s)
Química Farmacéutica , Animales , Humanos , Antineoplásicos/química , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Proteolisis , Relación Estructura-Actividad
2.
Bioorg Chem ; 139: 106676, 2023 10.
Artículo en Inglés | MEDLINE | ID: mdl-37352720

RESUMEN

Neuronal PAS domain protein 3 (NPAS3), a basic helix-loop-helix PER-ARNT-SIM (bHLH-PAS) family member, is a pivotal transcription factor in neuronal regeneration, development, and related diseases, regulating the expression of downstream genes. Despite several modulators of certain bHLH-PAS family proteins being identified, the NPAS3-targeted compound has yet to be reported. Herein, we discovered a hit compound BI-78D3 that directly blocks the NPAS3-ARNT heterodimer formation by covalently binding to the aryl hydrocarbon receptor nuclear translocator (ARNT) subunit. Further optimization based on the hit scaffold yielded a highly potent Compound 6 with a biochemical EC50 value of 282 ± 61 nM and uncovered the 5-nitrothiazole-2-sulfydryl as a cysteine-targeting covalent warhead. Compound 6 effectively down-regulated NPAS3's transcriptional function by disrupting the interface of NPAS3-ARNT complexes at cellular level. In conclusion, our study identifies the 5-nitrothiazole-2-sulfydryl as a cysteine-modified warhead and provides a strategy that blocks the NPAS3-ARNT heterodimerization by covalently conjugating ARNT Cys336 residue. Compound 6 may serve as a promising chemical probe for exploring NPAS3-related physiological functions.


Asunto(s)
Translocador Nuclear del Receptor de Aril Hidrocarburo , Receptores de Hidrocarburo de Aril , Translocador Nuclear del Receptor de Aril Hidrocarburo/química , Translocador Nuclear del Receptor de Aril Hidrocarburo/metabolismo , Receptores de Hidrocarburo de Aril/metabolismo , Cisteína/metabolismo , Unión Proteica , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/metabolismo
3.
Bioorg Med Chem ; 70: 116921, 2022 09 15.
Artículo en Inglés | MEDLINE | ID: mdl-35863237

RESUMEN

>90% of genes in the human body undergo alternative splicing (AS) after transcription, which enriches protein species and regulates protein levels. However, there is growing evidence that various genetic isoforms resulting from dysregulated alternative splicing are prevalent in various types of cancers. Dysregulated alternative splicing leads to cancer generation and maintenance of cancer properties such as proliferation differentiation, apoptosis inhibition, invasion metastasis, and angiogenesis. Serine/arginine-rich proteins and SR protein-associated kinases mediate splice site recognition and splice complex assembly during variable splicing. Based on the impact of dysregulated alternative splicing on disease onset and progression, the search for small molecule inhibitors targeting alternative splicing is imminent. In this review, we discuss the structure and specific biological functions of SR proteins and describe the regulation of SR protein function by SR protein related kinases meticulously, which are closely related to the occurrence and development of various types of cancers. On this basis, we summarize the reported small molecule inhibitors targeting SR proteins and SR protein related kinases from the perspective of medicinal chemistry. We mainly categorize small molecule inhibitors from four aspects, including targeting SR proteins, targeting Serine/arginine-rich protein-specific kinases (SRPKs), targeting Cdc2-like kinases (CLKs) and targeting dual-specificity tyrosine-regulated kinases (DYRKs), in terms of structure, inhibition target, specific mechanism of action, biological activity, and applicable diseases. With this review, we are expected to provide a timely summary of recent advances in alternative splicing regulated by kinases and a preliminary introduction to relevant small molecule inhibitors.


Asunto(s)
Empalme Alternativo , Serina , Arginina/metabolismo , Humanos , Proteínas Nucleares/metabolismo , Fosforilación , Proteínas Serina-Treonina Quinasas , Proteínas Tirosina Quinasas , Serina/metabolismo , Factores de Empalme Serina-Arginina/genética , Factores de Empalme Serina-Arginina/metabolismo
4.
J Org Chem ; 86(18): 12537-12548, 2021 09 17.
Artículo en Inglés | MEDLINE | ID: mdl-34473515

RESUMEN

An efficient protocol for synthesizing furo[3,2-c]coumarin derivatives is described. The novel reaction could afford the desired furocoumarins with good to excellent yields in a mild and rapid manner. Large substrate scope screening and scale-up preparation have also been accomplished, and selected compounds were evaluated for their photophysical properties.


Asunto(s)
Cobre , Cumarinas , Catálisis
5.
Bioorg Med Chem ; 52: 116512, 2021 12 15.
Artículo en Inglés | MEDLINE | ID: mdl-34801827

RESUMEN

Histone acetylation is one of the most essential parts of epigenetic modification, mediating a variety of complex biological functions. In these procedure, p300/CBP could catalyze the acetylation of lysine 27 on histone 3 (H3K27ac), and had been reported to mediate tumorigenesis and development in a variety of tumors by enhancing chromatin transcription activity. Ovarian cancer, as an extremely malignant tumor, has also been observed to undergo abnormal acetylation of histones. However, whether the treatment of ovarian cancer could be achieved by inhibiting the acetylation activity of p300/CBP on H3K27 has not been well investigated. In this article, we modified the structure of p300/CBP HAT domain inhibitor A-485 and obtained a highly active small molecule known as 13f, which has an IC50 value of 0.49 nM for inhibiting the in vitro enzyme activity of p300, as well as the anti-proliferation IC50 value on ovarian cancer cell line OVCAR-3 was 153 nM. In addition, 13f had strong acetylase family selectivity, good metabolic stability and promising in vivo anti-tumor activity in OVCAR-3 xenograft model. The discovery of 13f revealed a more active chemical entity of the HATs domain of p300/CBP and provided a novel idea for the application of epigenetic inhibitors in the treatment of ovarian cancer.


Asunto(s)
Antineoplásicos/farmacología , Diseño de Fármacos , Inhibidores Enzimáticos/farmacología , Neoplasias Ováricas/tratamiento farmacológico , Oxazoles/farmacología , Compuestos de Espiro/farmacología , Factores de Transcripción p300-CBP/antagonistas & inhibidores , Antineoplásicos/síntesis química , Antineoplásicos/química , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Femenino , Humanos , Estructura Molecular , Neoplasias Ováricas/metabolismo , Neoplasias Ováricas/patología , Oxazoles/síntesis química , Oxazoles/química , Compuestos de Espiro/síntesis química , Compuestos de Espiro/química , Relación Estructura-Actividad , Factores de Transcripción p300-CBP/metabolismo
6.
Pharm Res ; 37(9): 169, 2020 Aug 13.
Artículo en Inglés | MEDLINE | ID: mdl-32794010

RESUMEN

PURPOSE: Penetration enhancers (PEs) enhancing efficacy depends on two processes: PEs release from patches and action on skin. Compared with their action on skin, PEs release process was poorly understood. Therefore, the purpose of this study was to make a mechanistic understanding of PEs release from acrylic pressure-sensitive adhesive of patches and propose an unconventional enhancement of PEs efficacy. METHODS: PEs efficacy was evaluated both in drug permeation study and drug pharmacokinetic study. Confocal Raman spectroscopy was employed to observe PEs release behavior by mapping PEs dynamic distribution in skin. The mechanism of PEs release behavior was provided from molecular interaction and rheology using FT-IR, molecular docking, molecular dynamic simulation and rheometer, separately. RESULTS: The release behavior of PEs themselves greatly restricted their efficacy. By using PEG 400, an improvement of oleic acid (OA) release behavior was achieved, and the efficacy of OA was significantly enhanced with enhancing ratio (ER) from 2.69 to 4.10 and AUClast from 1574 ± 87 to 2664 ± 249 ng·h/mL, separately. The improvement of OA release behavior was primarily resulted from reduction of the interaction between OA and adhesive, which was caused by other small molecules with a strong ability in forming hydrogen bonds with adhesive. Also, the rigidity of adhesive was a factor in affecting PEs release behavior. CONCLUSIONS: An unconventional passive enhancement of transdermal drug delivery was achieved via improving PEs themselves releasing from acrylic pressure-sensitive adhesive. Graphical abstract Influence of PEs release behavior on drug permeation through skin and molecular mechanism.


Asunto(s)
Liberación de Fármacos/fisiología , Absorción Cutánea/fisiología , Adhesivos/química , Administración Cutánea , Animales , Química Farmacéutica , Sistemas de Liberación de Medicamentos , Ácidos Grasos/química , Felodipino/administración & dosificación , Felodipino/farmacocinética , Masculino , Modelos Moleculares , Simulación del Acoplamiento Molecular , Preparaciones Farmacéuticas/metabolismo , Ratas , Piel/metabolismo , Espectroscopía Infrarroja por Transformada de Fourier , Parche Transdérmico
7.
Bioorg Med Chem ; 28(13): 115554, 2020 07 01.
Artículo en Inglés | MEDLINE | ID: mdl-32546299

RESUMEN

Prostate cancer is the most common carcinoma of the male urinary system in developed countries. Androgen deprivation therapy has been commonly used in the treatment of prostate cancer for decades, but most patients will inevitably develop into more aggressive castration-resistant prostate cancer. Therefore, novel strategies are urgent to address this resistance mechanism. In this review, we discussed some new strategies for targeting androgen receptors through degradation pathways as potential treatments for prostate cancer.


Asunto(s)
Antagonistas de Receptores Androgénicos/química , Antineoplásicos/química , Neoplasias de la Próstata/tratamiento farmacológico , Receptores Androgénicos/metabolismo , Antagonistas de Receptores Androgénicos/farmacología , Animales , Antineoplásicos/farmacología , Resistencia a Antineoplásicos , Ensayos de Selección de Medicamentos Antitumorales , Proteínas de Choque Térmico/metabolismo , Humanos , Masculino , Proteolisis , Transducción de Señal , Tiohidantoínas/química , Ubiquitinación
8.
Bioorg Chem ; 101: 103962, 2020 08.
Artículo en Inglés | MEDLINE | ID: mdl-32480171

RESUMEN

USP8, one member of deubiquitinating enzymes (DUBs) families, maintains the ubiquitination level of EGFR and regulates the downstream signaling pathways. The deregulation of USP8 has been implicated in many human diseases, especially in cancer. Therefore, USP8 has been identified as a promising target for drug design. Herein, via high throughput screening based on Ubiquitin-rhodamine-110 (Ubiquitin-Rho-110) fluorometric activity assay, we discovered a novel inhibitor DC-U43. By structure optimization, DC-U43-10 reached a half-maximal inhibitory concentration (IC50) value of 2.6 ± 1.1 µM and exhibited 10-fold selectivity against USP7. The binding between DC-U43-10 and USP8 was validated by surface plasmon resonance (SPR) assay with a KD value of 10.5 ± 3.7 µM. It also inhibited the colony formation of H1975 cells. Hence, DC-U43-10 represents a kind of USP8 inhibitors with novel scaffold and has broad prospects for being a probe for USP8-related academic and clinical research.


Asunto(s)
Complejos de Clasificación Endosomal Requeridos para el Transporte/antagonistas & inhibidores , Ensayos Analíticos de Alto Rendimiento/métodos , Ubiquitina Tiolesterasa/antagonistas & inhibidores , Endopeptidasas , Humanos , Simulación del Acoplamiento Molecular , Transducción de Señal , Espectrometría de Fluorescencia/métodos , Resonancia por Plasmón de Superficie , Ubiquitinación
9.
Bioorg Med Chem ; 27(5): 677-685, 2019 03 01.
Artículo en Inglés | MEDLINE | ID: mdl-30733087

RESUMEN

Protein kinases have been important targets for antitumor targets due to their key roles in regulating multiple cell signaling pathways. Numerous compounds containing flavonoid scaffold as an indispensable anchor have been found to be potent inhibitors of protein kinases. Some of these flavonoids have been in clinical research as protein kinases inhibitors. Thus, the present review mainly focuses on the structural requirement for anticancer potential of flavone derivatives targeting several key serine/threonine protein kinases. This information may provide an opportunity to scientists of medicinal chemistry to design multi-functional flavone derivatives for the treatment of cancer.


Asunto(s)
Antineoplásicos/uso terapéutico , Flavonas/uso terapéutico , Neoplasias/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/uso terapéutico , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Animales , Antineoplásicos/química , Antineoplásicos/metabolismo , Flavonas/química , Flavonas/metabolismo , Humanos , Unión Proteica , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/metabolismo , Proteínas Serina-Treonina Quinasas/química , Proteínas Serina-Treonina Quinasas/metabolismo
10.
Bioorg Chem ; 91: 103181, 2019 10.
Artículo en Inglés | MEDLINE | ID: mdl-31404795

RESUMEN

Two new series of compounds were designed and synthesized as potent PARP-1 inhibitors. These compounds were evaluated for PARP-1 enzyme and cellular inhibitory activities. All efforts lead to the identification of 9k (named as LG-12) with efficient potency both for PARP-1 and BRCA1 deficient MDA-MB-436 cells. Additionally, the novel PARP-1 inhibitor LG-12 is an efficient chemosensitizer, which could potentiate the anti-cancer effect of TMZ. Our data presented herein provide a comprehensive preclinical in vitro evaluation of the potential therapeutic efficacy and potency of chemotherapeutic agent-PARP-1 inhibitor combinations for LG-12. The combined results indicated that LG-12 could be a promising candidate for further study.


Asunto(s)
Neoplasias de la Mama/tratamiento farmacológico , Diseño de Fármacos , Imidazoles/síntesis química , Imidazoles/farmacología , Ftalazinas/química , Poli(ADP-Ribosa) Polimerasa-1/antagonistas & inhibidores , Inhibidores de Poli(ADP-Ribosa) Polimerasas/síntesis química , Inhibidores de Poli(ADP-Ribosa) Polimerasas/farmacología , Tiohidantoínas/química , Antineoplásicos/química , Antineoplásicos/farmacología , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Ciclo Celular , Proliferación Celular , Femenino , Humanos , Estructura Molecular , Relación Estructura-Actividad , Células Tumorales Cultivadas
11.
J Enzyme Inhib Med Chem ; 34(1): 250-263, 2019 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-30734612

RESUMEN

With the aim of discovering novel IDO1 inhibitors, a combined similarity search and molecular docking approach was employed to the discovery of 32 hit compounds. Testing the screened hit compounds has led to several novel submicromolar inhibitors. Especially for compounds LVS-019 with cyanopyridine scaffold, showed good IDO1 inhibitory activity. To discover more compounds with similar structures to LVS-019, a shape-based model was then generated on the basis of it and the second-round virtual screening was carried out leading to 23 derivatives. Molecular docking studies suggested a possible binding mode of LVS-019, which provides a good starting point for the development of cyanopyridine scaffold compounds as potent IDO1 inhibitor. To improve potency of these hits, we further designed and synthesised another 14 derivatives of LVS-019. Among these compounds, LBJ-10 showed improved potency compared to the hits and displayed comparable potency to the control GDC-0919 analogue. LBJ-10 can serve as ideal leads for further modifications as IDO1 inhibitors for cancer treatment.


Asunto(s)
Descubrimiento de Drogas , Inhibidores Enzimáticos/farmacología , Indolamina-Pirrol 2,3,-Dioxigenasa/antagonistas & inhibidores , Piridinas/farmacología , Relación Dosis-Respuesta a Droga , Evaluación Preclínica de Medicamentos , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Humanos , Indolamina-Pirrol 2,3,-Dioxigenasa/metabolismo , Simulación del Acoplamiento Molecular , Estructura Molecular , Piridinas/síntesis química , Piridinas/química , Relación Estructura-Actividad
12.
J Org Chem ; 83(15): 8003-8010, 2018 08 03.
Artículo en Inglés | MEDLINE | ID: mdl-29882670

RESUMEN

An efficient reaction utilizing propargyl carbonates through Claisen rearrangement to synthesize furanonaphthoquinones is described. The remarkable transformation exhibits excellent functional group tolerance, affording the target furanonaphthoquinones in moderate to good yields (41-85%) under mild reaction conditions. Scaled-up preparation of the model product can make this reaction a method of choice for synthesis of furanonaphthoquinone derivatives. The resulting furanonaphthoquinones were evaluated as potential indoleamine 2,3-dioxygenase inhibitors in vitro.


Asunto(s)
Carbonatos/química , Indolamina-Pirrol 2,3,-Dioxigenasa/antagonistas & inhibidores , Naftoquinonas/química , Paladio/química , Quinonas/química , Quinonas/farmacología , Catálisis , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Células HeLa , Humanos , Estereoisomerismo
13.
Bioorg Med Chem ; 26(2): 366-375, 2018 01 15.
Artículo en Inglés | MEDLINE | ID: mdl-29254895

RESUMEN

P2Y receptors are G-protein-coupled receptors (GPCRs) for extracellular nucleotides. There are eight mammalian P2Y receptor subtypes (P2Y1, P2Y2, P2Y4, P2Y6, P2Y11, P2Y12, P2Y13, and P2Y14). P2Y2 receptors are widely expressed and play important roles in multiple functionalities. Diquafosol tetrasodium, known as INS365, which was the first P2Y2 receptor agonists that had been approved in April 2010 and launched in Japan by Santen Pharmaceuticals. Besides, a series of similar agonists for the P2Y2 receptor are undergoing development to cure different diseases related to the P2Y2 receptor. This article illustrated the structure and functions of the P2Y2 receptor and focused on several kinds of agonists about their molecular structures, research progress and chemical synthesis methods. Last but not the least, we summarized the structures-activity relationship (SAR) of agonists for the P2Y2 receptor and expected more efficient agonists for the P2Y2 receptor.


Asunto(s)
Nucleótidos/farmacología , Receptores Purinérgicos P2Y2/metabolismo , Relación Dosis-Respuesta a Droga , Humanos , Estructura Molecular , Nucleótidos/química , Relación Estructura-Actividad
14.
Bioorg Chem ; 81: 373-381, 2018 12.
Artículo en Inglés | MEDLINE | ID: mdl-30196207

RESUMEN

Wogonin is a natural product isolated from the Scutellaria baicalensis and has been proved to be a potent and selective inhibitor of CDK9. Using this scaffold, we designed and synthesized a series of proteolysis targeting chimeras (PROTACs) targeting CDK9 by recruiting ubiquitin E3 ligase cereblon (CRBN). For constructing diverse Wogonin-based PROTACs, a "click chemistry" approach was employed for the synthesis of CDK9-targeting PROTACs. The results of western blotting assays showed that compounds containing triazole group in the linker could selectively downregulate the intracellular CDK9 level. Among these compounds, 11c could selectively degrade CDK9 in a concentration-dependent manner. In addition, the application of the proteasome inhibitor MG132 and CRBN siRNA silencing confirmed that 11c could promote the proteasome-dependent and CRBN-dependent degradation. Consistent with the degradation of the CDK9 protein, 11c selectively inhibits proliferation of CDK9-overexpressed cancer cells. Thus, our Wogonin-based PROTAC would be an efficient probe that induces the degradation of CDK9.


Asunto(s)
Antineoplásicos/química , Antineoplásicos/farmacología , Quinasa 9 Dependiente de la Ciclina/antagonistas & inhibidores , Flavanonas/química , Flavanonas/farmacología , Proteolisis/efectos de los fármacos , Proteínas Adaptadoras Transductoras de Señales , Antineoplásicos/síntesis química , Química Clic , Quinasa 9 Dependiente de la Ciclina/metabolismo , Descubrimiento de Drogas , Flavanonas/síntesis química , Humanos , Células MCF-7 , Simulación del Acoplamiento Molecular , Neoplasias/tratamiento farmacológico , Neoplasias/metabolismo , Péptido Hidrolasas/metabolismo , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/farmacología , Ubiquitina-Proteína Ligasas
16.
Bioorg Med Chem Lett ; 27(4): 1012-1016, 2017 02 15.
Artículo en Inglés | MEDLINE | ID: mdl-28117202

RESUMEN

A novel series of 49 wogonin derivatives were synthesized by introducing group at 7-, 8- or B ring of wogonin. The cytotoxic activities against HepG2, A549 and BCG-823 cancer cell lines were also investigated in vitro. Several of them showed obvious cytotoxic activities and compound 3h possessed the highest potency against HepG2, A549, and BCG-823 with IC50 values of 1.07µM, 1.74µM and 0.98µM, respectively. A quantitative structure-activity relationship (QSAR) study of these synthetic derivatives as well as wogonin indicated that high solubility and low octanol/water partition coefficient are favorable, and excessive electrostatic properties and refractivity are unfavorable for the cytotoxic activities of these wogonin derivatives. These findings and results provide a base for further investigations.


Asunto(s)
Antineoplásicos/farmacología , Flavanonas/farmacología , Antineoplásicos/química , Línea Celular Tumoral , Ensayos de Selección de Medicamentos Antitumorales , Flavanonas/química , Humanos , Relación Estructura-Actividad Cuantitativa
17.
Bioorg Med Chem ; 24(5): 1006-13, 2016 Mar 01.
Artículo en Inglés | MEDLINE | ID: mdl-26803578

RESUMEN

A new series of ortho-naphthoquinone analogs of ß-lapachone were designed, synthesized and evaluated. The biological results indicated that most of our compounds were efficient substrates for NQO1. The new scaffold with water-soluble side chain resulted in greater solubility under acidic condition compared to ß-lapachone. Thus avoiding the use of hydroxylpropyl ß-cyclodextrin which would finally cause the rapid drug clearance from the blood and dose-limiting toxicity in the form of hemolytic anemia. The most soluble and promising compound in this series was 2-((4-benzylpiperazin-1-yl)methyl)naphtho[2,1-d]oxazole-4,5-dione (3k), which inhibited cancer cell (NQO1-rich A549 cell line) growth at IC50 values of 4.6±1.0µmol·L(-1). Furthermore, compound 3k had in vivo antitumor activity in an A549 tumor xenografts mouse model comparable to the activity obtained with ß-lapachone. The results indicated that these ortho-naphthoquinones could serve as promising leads for further optimization as novel substrates for NQO1.


Asunto(s)
Antineoplásicos/química , Antineoplásicos/uso terapéutico , Neoplasias Pulmonares/tratamiento farmacológico , NAD(P)H Deshidrogenasa (Quinona)/metabolismo , Naftoquinonas/química , Naftoquinonas/uso terapéutico , Animales , Antineoplásicos/síntesis química , Línea Celular Tumoral , Humanos , Pulmón/efectos de los fármacos , Pulmón/metabolismo , Pulmón/patología , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patología , Ratones , Ratones Desnudos , Simulación del Acoplamiento Molecular , Naftoquinonas/síntesis química , Naftoquinonas/metabolismo , Solubilidad , Agua/química
18.
Bioorg Med Chem Lett ; 25(12): 2584-8, 2015 Jun 15.
Artículo en Inglés | MEDLINE | ID: mdl-25958244

RESUMEN

DDO-6101, a natural-product-like caged xanthone discovered previously in our laboratory based on the pharmacophoric scaffold of Garcinia natural product gambogic acid (GA), shows potent cytotoxicity in vitro but poor efficacy in vivo due to its poor druglike properties. In order to improve the druglike properties and in vivo cytotoxic potency, a novel series of 19 prenyl group-modified derivatives of DDO-6101 was synthesized and evaluated for their in vitro antitumor activity and druglike properties. The SAR and SPR information of these compounds was also obtained. In the light of the in vitro antitumor activity and druglike properties such as aqueous solubility and permeability, compound 6f (named as DDO-6306) was advanced into in vivo efficacy experiment. The results showed that DDO-6306 is more potent than DDO-6101 in vivo and is a promising antitumor candidate for further evaluation.


Asunto(s)
Antineoplásicos/química , Antineoplásicos/farmacología , Productos Biológicos/química , Xantonas/química , Xantonas/farmacología , Animales , Antineoplásicos/síntesis química , Apoptosis/efectos de los fármacos , Peso Corporal/efectos de los fármacos , Línea Celular Tumoral , Permeabilidad de la Membrana Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Ensayos de Selección de Medicamentos Antitumorales , Garcinia/química , Garcinia/metabolismo , Humanos , Ratones , Relación Estructura-Actividad , Trasplante Heterólogo , Xantonas/síntesis química
19.
Bioorg Med Chem Lett ; 25(6): 1244-8, 2015 Mar 15.
Artículo en Inglés | MEDLINE | ID: mdl-25677663

RESUMEN

Natural product (±)-dunnione (2) and its ortho-quinone analogues (3-8) were synthesized and found to be substrates for NQO1. The structure-activity relationship study revealed that the biological activity was favored by the presence of methyl group at the C ring and methoxy group at the A ring. The docking studies supported the rationalization of the metabolic studies. Deeper location in the active site of NQO1, interactions with hydrophobic pocket and C-H…π interactions with the adjacent Phe178 residue contributed to the better catalytic efficiency and specificity to NQO1. Cytotoxicity studies and determination of superoxide (O2(-)) production in the presence and absence of the NOQ1 inhibitor dicoumarol confirmed that the ortho-quinones exerted their antitumor activity through NQO1-mediated ROS production by redox cycling.


Asunto(s)
Inhibidores Enzimáticos/síntesis química , NAD(P)H Deshidrogenasa (Quinona)/metabolismo , Naftoquinonas/química , Sitios de Unión , Dominio Catalítico , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Humanos , Cinética , Simulación del Acoplamiento Molecular , NAD(P)H Deshidrogenasa (Quinona)/antagonistas & inhibidores , Naftoquinonas/síntesis química , Naftoquinonas/farmacología , Quinonas/química , Especies Reactivas de Oxígeno/metabolismo , Estereoisomerismo , Relación Estructura-Actividad , Especificidad por Sustrato , Superóxidos/metabolismo
20.
Drug Discov Today ; 29(2): 103880, 2024 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-38216118

RESUMEN

Glutamine transporters are integral to the metabolism of glutamine in both healthy tissues and cancerous cells, playing a pivotal role in maintaining amino acid balance, synthesizing biomolecules, and regulating redox equilibrium. Their critical functions in cellular metabolism make them promising targets for oncological therapies. Recent years have witnessed substantial progress in the field of glutamine transporters, marked by breakthroughs in understanding of their protein structures and the discovery of novel inhibitors, prodrugs, and radiotracers. This review provides a comprehensive update on the latest advancements in modulators targeting the glutamine transporter, with special attention given to LAT1 and ASCT2. It also discusses innovative approaches in drug design aimed at these transporters.


Asunto(s)
Aminoácidos , Glutamina , Glutamina/metabolismo , Proteínas de Transporte de Membrana
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