RESUMEN
The Janus kinase-signal transducer and activator of transcription (JAK-STAT) pathway serves as a paradigm for signal transduction from the extracellular environment to the nucleus. It plays a pivotal role in physiological functions, such as hematopoiesis, immune balance, tissue homeostasis, and surveillance against tumors. Dysregulation of this pathway may lead to various disease conditions such as immune deficiencies, autoimmune diseases, hematologic disorders, and cancer. Due to its critical role in maintaining human health and involvement in disease, extensive studies have been conducted on this pathway, ranging from basic research to medical applications. Advances in the structural biology of this pathway have enabled us to gain insights into how the signaling cascade operates at the molecular level, laying the groundwork for therapeutic development targeting this pathway. Various strategies have been developed to restore its normal function, with promising therapeutic potential. Enhanced comprehension of these molecular mechanisms, combined with advances in protein engineering methodologies, has allowed us to engineer cytokines with tailored properties for targeted therapeutic applications, thereby enhancing their efficiency and safety. In this review, we outline the structural basis that governs key nodes in this pathway, offering a comprehensive overview of the signal transduction process. Furthermore, we explore recent advances in cytokine engineering for therapeutic development in this pathway.
Asunto(s)
Citocinas , Quinasas Janus , Factores de Transcripción STAT , Transducción de Señal , Humanos , Quinasas Janus/genética , Quinasas Janus/metabolismo , Quinasas Janus/química , Factores de Transcripción STAT/genética , Factores de Transcripción STAT/metabolismo , Factores de Transcripción STAT/química , Transducción de Señal/genética , Citocinas/genética , Citocinas/metabolismo , Ingeniería de ProteínasRESUMEN
The Janus kinase-signal transducer and activator of transcription (JAK-STAT) pathway functions as a central hub for transmitting signals from more than 50 cytokines, playing a pivotal role in maintaining hematopoiesis, immune balance, and tissue homeostasis. Dysregulation of this pathway has been implicated in various diseases, including immunodeficiency, autoimmune conditions, hematological disorders, and certain cancers. Proteins within this pathway have emerged as effective therapeutic targets for managing these conditions, with various approaches developed to modulate key nodes in the signaling process, spanning from receptor engagement to transcription factor activation. Following the success of JAK inhibitors such as tofacitinib for RA treatment and ruxolitinib for managing primary myelofibrosis, the pharmaceutical industry has obtained approvals for over 10 small molecule drugs targeting the JAK-STAT pathway and many more are at various stages of clinical trials. In this review, we consolidate key strategies employed in drug discovery efforts targeting this pathway, with the aim of contributing to the collective understanding of small molecule interventions in the context of JAK-STAT signaling. We aspire that our endeavors will contribute to advancing the development of innovative and efficacious treatments for a range of diseases linked to this pathway dysregulation.
Asunto(s)
Descubrimiento de Drogas , Quinasas Janus , Factores de Transcripción STAT , Transducción de Señal , Humanos , Quinasas Janus/metabolismo , Quinasas Janus/antagonistas & inhibidores , Factores de Transcripción STAT/metabolismo , Factores de Transcripción STAT/antagonistas & inhibidores , Descubrimiento de Drogas/métodos , Animales , Transducción de Señal/efectos de los fármacos , Inhibidores de las Cinasas Janus/uso terapéutico , Inhibidores de las Cinasas Janus/farmacología , Terapia Molecular DirigidaRESUMEN
The development of highly selective Janus Kinase 1 (JAK1) inhibitors is crucial for improving efficacy and minimizing adverse effects in the clinical treatment of autoimmune diseases. In a prior study, we designed a series of C-5 4-pyrazol substituted pyrrolopyridine derivatives that demonstrated significant potency against JAK1, with a 10 â¼ 20-fold selectivity over Janus Kinase 2 (JAK2). Building on this foundation, we adopted orthogonal strategy by modifying the C-5 position with 3-pyrazol/4-pyrazol/3-pyrrol groups and tail with substituted benzyl groups on the pyrrolopyridine head to enhance both potency and selectivity. In this endeavor, we have identified several compounds that exhibit excellent potency and selectivity for JAK1. Notably, compounds 12b and 12e, which combined 4-pyrazol group at C-5 site and meta-substituted benzyl tails, displayed IC50 value with 2.4/2.2 nM and high 352-/253-fold selectivity for JAK1 over JAK2 in enzyme assays. Additionally, both compounds showed good JAK1-selective in Ba/F3-TEL-JAK1/2 cell-based assays. These findings mark a substantial improvement, as these compounds are 10-fold more potent and over 10-fold more selective than the best compound identified in our previous study. The noteworthy potency and selectivity properties of compounds 12b and 12e suggest their potential utility in furthering the development of drugs for autoimmune diseases.
Asunto(s)
Enfermedades Autoinmunes , Compuestos Heterocíclicos , Humanos , Relación Estructura-Actividad , Janus Quinasa 1/metabolismo , Inhibidores de Proteínas Quinasas/farmacología , Janus Quinasa 2/metabolismoRESUMEN
Chemotherapy is the mainstay in the treatment of breast cancer. However, many drugs that are commonly used in clinical practice have a high incidence of side effects and multidrug resistance (MDR), which is mainly caused by overexpression of drug transporters and related enzymes in breast cancer cells. In recent years, researchers have been working hard to find newer and safer drugs to overcome MDR in breast cancer. In this review, we provide the molecule mechanism of MDR in breast cancer, categorize potential lead compounds that inhibit single or multiple drug transporter proteins, as well as related enzymes. Additionally, we have summarized the structure-activity relationship (SAR) based on potential breast cancer MDR modulators with lower side effects. The development of novel approaches to suppress MDR is also addressed. These lead compounds hold great promise for exploring effective chemotherapy agents to overcome MDR, providing opportunities for curing breast cancer in the future.
Asunto(s)
Antineoplásicos , Neoplasias de la Mama , Humanos , Femenino , Neoplasias de la Mama/tratamiento farmacológico , Resistencia a Antineoplásicos , Resistencia a Múltiples Medicamentos , Antineoplásicos/farmacología , Antineoplásicos/uso terapéuticoRESUMEN
Ursolic acid (UA) is a pentacyclic triterpenoid, which exhibits many biological activities, particularly in anti-cardiovascular and anti-diabetes. The further application of UA is greatly limited due to its low bioavailability and poor water solubility. Up to date, various UA derivatives have been designed to overcome these shortcomings. In this paper, the authors reviewed the development of UA derivatives as the anti-diabetes anti-cardiovascular reagents.
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Triterpenos , Solubilidad , Triterpenos/farmacología , Triterpenos/uso terapéutico , Ácido UrsólicoRESUMEN
Resveratrol is one of the most interesting naturally-occurring nonflavonoid phenolic compounds with various biological activities, such as anticancer, neuroprotection, antibacterial, and anti-inflammatory. However, there is no clinical usage of resveratrol due to either its poor activity or poor pharmacokinetic properties. Heteroarenes-modified resveratrol is one pathway to improve its biological activities and bioavailability, and form more modification sites. In this review, we present the progress of heteroaryl analogues of resveratrol with promising biological activities in the latest five years, ranging from the synthesis to the structure-activity relationship and mechanism of actions. Finally, introducing heteroarenes into resveratrol is an effective strategy, which focuses on the selectivity of structure-activity relationship in vivo.
RESUMEN
Developing selective inhibitors for Janus kinase 1 (JAK1) is a significant focus for improving the efficacy and alleviating the adverse effects in treating immune-inflammatory diseases. Herein, we report the discovery of a series of C-5 pyrazole-modified pyrrolopyrimidine derivatives as JAK1-selective inhibitors. The potential hydrogen bond between the pyrazole group and E966 in JAK1 is the key point that enhances JAK1 selectivity. These compounds exhibit 10- to 20-fold JAK1 selectivity over JAK2 in enzyme assays. Compound 12b also exhibits excellent JAK1 selectivity in Ba/F3-TEL-JAK cellular assays. Metabolism studies and the results of the hair growth model in mice indicate that compound 12b may be a viable lead compound for the development of highly JAK1-selective inhibitors for immune and inflammatory diseases.
Asunto(s)
Inhibidores de las Cinasas Janus , Pirazoles , Ratones , Animales , Relación Estructura-Actividad , Janus Quinasa 1 , Pirazoles/farmacología , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/química , Inhibidores de las Cinasas Janus/farmacología , Janus Quinasa 2 , Janus Quinasa 3RESUMEN
Curcumin is a potential plant-derived drug for the treatment of breast cancer. Poor solubility and bioavailability are the main factors that limit its clinical application. Various structural modification strategies have been developed to improve the anti-breast cancer activity of curcumin. This review focuses on the difference of modification sites and heterocyclic/non-heterocyclic modifications to systematically summarize curcumin derivatives with better anti-breast cancer activity.
Asunto(s)
Antineoplásicos , Neoplasias de la Mama , Curcumina , Humanos , Femenino , Curcumina/farmacología , Curcumina/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Disponibilidad Biológica , Solubilidad , Antineoplásicos/farmacología , Antineoplásicos/uso terapéuticoRESUMEN
BACKGROUND: Genistein has been limited in clinical application due to its low bioavailability, extremely poor liposolubility, and fast glycosylation rate, though it possesses anti-breast cancer activity. Therefore, the discovery of novel genistein derivatives is an urgency. OBJECTIVE: To enhance the anti-breast cancer activity of genistein, a series of novel fluorinated genistein derivatives were synthesized. METHODS: Their in vitro antitumor activity was investigated by the MTT assay against three cancer cell lines, via, MDA-MB-231, MCF-7, and MDA-MB-435, respectively. RESULTS: Analogs 1d, 2b, and 3b showed remarkable anticancer activities compared to tamoxifen, a clinical anti-breast cancer drug on the market. CONCLUSION: The activities against breast cancer of genistein were enhanced by introducing the 7- alkoxyl group and fluorine atom into the B-ring. Therefore, these compounds may be potential candidates for treating breast cancer.
Asunto(s)
Antineoplásicos , Neoplasias de la Mama , Humanos , Femenino , Genisteína/farmacología , Genisteína/uso terapéutico , Neoplasias de la Mama/patología , Tamoxifeno/farmacología , Tamoxifeno/uso terapéutico , Línea Celular , Proliferación Celular , Línea Celular Tumoral , Ensayos de Selección de Medicamentos Antitumorales , Estructura MolecularRESUMEN
Sub-10 nm monodisperse alkaline-earth sulfide nanodots (ASNDs) with bright near-infrared (NIR)-excitation fluorescence and adjustable emission wavelength were prepared by a thermal decomposition method for the first time. The ASNDs exhibited high NIR-to-vis conversion efficiency and served as multicolor fluorescent labels in the proposed miR-224 assay. Targeted detection of the miR-224 level and single-nucleotide variation in miR-224 was carried out on a smartphone-based platform using a hybridization chain reaction (HCR) amplification strategy. In the presence of miR-224, the ASND-labeled HCR probes self-assembled on the surface of the diagnosis kits, generating strong fluorescent signals linearly proportional to miR-224 contents in the range of 10-2000 fM. Significantly, mutations in miR-224 led to the variation in the fluorescence intensity ratio in RGB channels. Simultaneously, evident changes of fluorescent brightness and color were easily visualized by the naked eye, which enabled on-site discrimination of miR-224 with different mutant loci. This work provides a novel preparation approach for ultrasmall NIR excitation sulfide nanodots and reveals the potential of the as-synthesized ASNDs in point-of-care (POC) nucleic acid testing. Further, it may provide a handheld platform for miRNA single-nucleotide polymorphism analysis.
Asunto(s)
MicroARNs , Colorantes Fluorescentes , Límite de Detección , MicroARNs/análisis , MicroARNs/genética , Mutación , Hibridación de Ácido Nucleico , SulfurosRESUMEN
Retraction of 'Molybdenum-silver co-catalyzed cycloaddition of alkynes with N-isocyanoiminotriphenylphosphorane (NIITP): an efficient strategy for the synthesis of monosubstituted pyrazoles' by Pengbing Mi et al., Chem. Commun., 2019, 55, 7986-7989.
RESUMEN
Nickel-catalyzed cycloaddition of alkynes and 2-sulfobenzoic anhydrides gives highly functionalized thiochromenones. The reaction undergoes a deoxygenative rather than decarbonylative pathway and shows advantages of an excellent isolated yield (up to 95%), high reaction efficiency, and high regioselectivity. As one of the resulted products, 2,3-di(triphenylamine)-thiolchromenone possesses a typical aggregation-induced emission property and emits efficient near-infrared fluorescence.
RESUMEN
A new molybdenum-silver co-catalyzed [3+2] cycloaddition of alkynes with N-isocyanoiminotriphenylphosphorane (NIITP) has been described. The NIITP serves as a non-toxic, facile "CNN" source. Over 30 substrates were successfully converted to the desired compounds in good to excellent yields.
RESUMEN
A direct cyanation of terminal alkynes for the synthesis of propionitrile derivatives, with the aid of silver salt using water additive, has been achieved. The cyano source used is N-isocyanoiminotriphenylphosphorane, which is nontoxic, safe, and easy to handle. This protocol is characterized by its operational simplicity, high efficiency with excellent yields, broad substrate scope, and greater functional group tolerance.
RESUMEN
A new silver-promoted [3+2] cycloaddition of azomethine ylides with isocyanides has been described. The methodology provides an efficient and modular approach to 1,2,4-trisubstituted imidazoles of vital bioactive molecules and atypical antipsychotics analogues.
RESUMEN
Alcohols are among the most abundant and commonly used organic feedstock in industrial processes and academic research. The first tandem O-H insertion/[1,3]-alkyl shift reaction reported is between benzylic alcohols and rhodium azavinyl carbenoids derived from N-sulfonyl-1,2,3-triazoles, which provides a strategically novel way of cleaving C-OH bonds and forming C-C bonds. The substrate scope is broad, capable of covering 1°-, 2°-, and 3°-benzylic alcohols. Moreover, it constitutes a new and powerful synthetic method for constructing α-aminoketones. Mechanistic studies suggest that a [1,3]-alkyl shift of oxonium ylides is responsible for cleavage of the C-OH bonds.
RESUMEN
Decarbonylation of saccharins by nickel catalysis enables two kinds of CC bond-forming reactions; homocoupling of saccharins to form biaryls and cycloaddition with alkynes to form benzosultams. The former represents the first reported nickel-catalyzed decarbonylative CC homocoupling reaction, whereas the latter constitutes a powerful method to pharmaceutically relevant benzosultams. The reactions proceed with good functional-group tolerance and excellent regioselectivity.
RESUMEN
A copper(I)-catalyzed, regioselective C-H α-trifluoromethylation of α,ß-unsaturated carbonyl compounds using Togni's reagent was developed. Diverse substrates, including enones as well as α,ß-unsaturated esters, thioesters, and amides, stereospecifically afforded the corresponding (E)-α-trifluoromethylated products in moderate to high yields. Further, this method was applied to the C-H trifluoromethylation of drugs.