RESUMEN
In our ongoing work to create potential antifungal agents, we synthesized and tested a group of C1-substituted acylhydrazone ß-carboline analogues 9a-o and 10a-o for their effectiveness against Valsa mali, Fusarium solani, Fusarium oxysporum, and Fusarium graminearum. Their compositions were analyzed using different spectral techniques, such as 1H/13C NMR and HRMS, with the structure of 9l being additionally confirmed through X-ray diffraction. The antifungal evaluation showed that, among all the target ß-carboline analogues, compounds 9n and 9o exhibited more promising and broad-spectrum antifungal activity than the commercial pesticide hymexazol. Several intriguing findings regarding structure-activity relationships (SARs) were examined. In addition, the cytotoxicity test showed that these acylhydrazone ß-carboline analogues with C1 substitutions exhibit a preference for fungi, with minimal harm to healthy cells (LO2). The reported findings provide insights into the development of ß-carboline analogues as new potential antifungal agents.
Asunto(s)
Antifúngicos , Carbolinas , Fusarium , Hidrazonas , Pruebas de Sensibilidad Microbiana , Carbolinas/química , Carbolinas/farmacología , Carbolinas/síntesis química , Antifúngicos/farmacología , Antifúngicos/síntesis química , Antifúngicos/química , Relación Estructura-Actividad , Fusarium/efectos de los fármacos , Hidrazonas/farmacología , Hidrazonas/química , Hidrazonas/síntesis química , Estructura Molecular , HumanosRESUMEN
In recent years, the 9H-pyrido[2,3-b]indole nuclei, also named α-carboline which is found in many organic compounds such as natural products, pharmaceuticals, and materials, have intensively stimulated the research of new synthetic pathways. After a brief report published in 2015 describing novel accesses and biological applications of α-carbolines, this update reports between 2015 and 2023 on the emergence of original syntheses to this heterocyclic nucleus. Examples representing these processes are described and the biological activities of α-carbolines are mentioned when they have been prepared for therapeutic purposes.
Asunto(s)
Carbolinas , Carbolinas/química , Carbolinas/síntesis química , Carbolinas/farmacología , Humanos , Estructura Molecular , Animales , Productos Biológicos/química , Productos Biológicos/farmacología , Productos Biológicos/síntesis químicaRESUMEN
Ir(III) and Ru(II) polypyridyl complexes are promising photosensitizers (PSs) for photodynamic therapy (PDT) due to their outstanding photophysical properties. Herein, one series of cyclometallated Ir(III) complexes and two series of Ru(II) polypyridyl derivatives bearing three different thiazolyl-ß-carboline N^N' ligands have been synthesized, aiming to evaluate the impact of the different metal fragments ([Ir(C^N)2]+ or [Ru(N^N)2]2+) and N^N' ligands on the photophysical and biological properties. All the compounds exhibit remarkable photostability under blue-light irradiation and are emissive (605 < λem < 720 nm), with the Ru(II) derivatives displaying higher photoluminescence quantum yields and longer excited state lifetimes. The Ir PSs display pKa values between 5.9 and 7.9, whereas their Ru counterparts are less acidic (pKa > 9.3). The presence of the deprotonated form in the Ir-PSs favours the generation of reactive oxygen species (ROS) since, according to theoretical calculations, it features a low-lying ligand-centered triplet excited state (T1 = 3LC) with a long lifetime. All compounds have demonstrated anticancer activity. Ir(III) complexes 1-3 exhibit the highest cytotoxicity in dark conditions, comparable to cisplatin. Their activity is notably enhanced by blue-light irradiation, resulting in nanomolar IC50 values and phototoxicity indexes (PIs) between 70 and 201 in different cancer cell lines. The Ir(III) PSs are also activated by green (with PI between 16 and 19.2) and red light in the case of complex 3 (PI = 8.5). Their antitumor efficacy is confirmed by clonogenic assays and using spheroid models. The Ir(III) complexes rapidly enter cells, accumulating in mitochondria and lysosomes. Upon photoactivation, they generate ROS, leading to mitochondrial dysfunction and lysosomal damage and ultimately cell apoptosis. Additionally, they inhibit cancer cell migration, a crucial step in metastasis. In contrast, Ru(II) complex 6 exhibits moderate mitochondrial activity. Overall, Ir(III) complexes 1-3 show potential for selective light-controlled cancer treatment, providing an alternative mechanism to chemotherapy and the ability to inhibit lethal cancer cell dissemination.
Asunto(s)
Antineoplásicos , Carbolinas , Complejos de Coordinación , Ensayos de Selección de Medicamentos Antitumorales , Iridio , Fotoquimioterapia , Fármacos Fotosensibilizantes , Rutenio , Humanos , Iridio/química , Iridio/farmacología , Rutenio/química , Rutenio/farmacología , Antineoplásicos/farmacología , Antineoplásicos/química , Antineoplásicos/síntesis química , Ligandos , Fármacos Fotosensibilizantes/farmacología , Fármacos Fotosensibilizantes/química , Fármacos Fotosensibilizantes/síntesis química , Complejos de Coordinación/farmacología , Complejos de Coordinación/química , Complejos de Coordinación/síntesis química , Carbolinas/química , Carbolinas/farmacología , Carbolinas/síntesis química , Estructura Molecular , Relación Estructura-Actividad , Proliferación Celular/efectos de los fármacos , Piridinas/química , Piridinas/farmacología , Piridinas/síntesis química , Especies Reactivas de Oxígeno/metabolismo , Relación Dosis-Respuesta a Droga , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Apoptosis/efectos de los fármacosRESUMEN
Our previously reported HDAC6 inhibitor (HDAC6i) Marbostat-100 (4) has provided many arguments for further clinical evaluation. By the substitution of the acidic hydrogen of 4 for different carbon residues, we were able to generate an all-carbon stereocenter, which significantly improves the hydrolytic stability of the inhibitor. Further asymmetric synthesis has shown that the (S)-configured inhibitors preferentially bind to HDAC6. This led to the highly selective and potent methyl-substituted derivative S-29b, which elicited a long-lasting tubulin hyperacetylation in MV4-11 cells. Finally, a crystal structure of the HDAC6/S-29b complex provided mechanistic explanation for the high potency and stereoselectivity of synthesized compound series.
Asunto(s)
Carbolinas , Histona Desacetilasa 6 , Inhibidores de Histona Desacetilasas , Humanos , Carbolinas/química , Carbolinas/farmacología , Carbolinas/síntesis química , Línea Celular Tumoral , Cristalografía por Rayos X , Relación Dosis-Respuesta a Droga , Histona Desacetilasa 6/antagonistas & inhibidores , Histona Desacetilasa 6/metabolismo , Inhibidores de Histona Desacetilasas/química , Inhibidores de Histona Desacetilasas/farmacología , Inhibidores de Histona Desacetilasas/síntesis química , Modelos Moleculares , Estructura Molecular , Relación Estructura-Actividad , Morfolinas/síntesis química , Morfolinas/química , Morfolinas/farmacologíaRESUMEN
In the quest for potent α-glucosidase inhibitors to combat diabetes, a series of novel thiosemicarbazide-based ß-carboline derivatives (CTL1â¼36) were synthesized and evaluated. CTL1â¼36 exhibited remarkable inhibitory effects against α-glucosidase, with IC50 values ranging from 2.81 to 12.40 µM, significantly surpassing the positive control acarbose (IC50 = 564.28 µM). Notably, CTL26 demonstrated the most potent inhibition (IC50 = 2.81 µM) and was characterized as a non-competitive inhibitor. Through a combination assay with fluorescence quenching, 3D fluorescence spectra, CD spectra, and molecular docking, we elucidated that CTL26 formed a complex with α-glucosidase via hydrogen bondings and hydrophobic interactions, leading to α-glucosidase conformation changes that impaired enzymatic activity. In vivo studies revealed that oral administration of CTL26 (25 and 50 mg/kg/d) reduced fasting blood glucose levels, enhanced glucose tolerance, and ameliorated lipid abnormalities in diabetic mice. These findings positioned CTL26 as a promising candidate for the development of α-glucosidase inhibitors with anti-diabetic potential.
Asunto(s)
Carbolinas , Diabetes Mellitus Experimental , Inhibidores de Glicósido Hidrolasas , Semicarbacidas , alfa-Glucosidasas , Inhibidores de Glicósido Hidrolasas/farmacología , Inhibidores de Glicósido Hidrolasas/síntesis química , Inhibidores de Glicósido Hidrolasas/química , Animales , alfa-Glucosidasas/metabolismo , Carbolinas/farmacología , Carbolinas/química , Carbolinas/síntesis química , Semicarbacidas/farmacología , Semicarbacidas/química , Semicarbacidas/síntesis química , Ratones , Relación Estructura-Actividad , Diabetes Mellitus Experimental/tratamiento farmacológico , Hipoglucemiantes/farmacología , Hipoglucemiantes/síntesis química , Hipoglucemiantes/química , Estructura Molecular , Simulación del Acoplamiento Molecular , Relación Dosis-Respuesta a Droga , Masculino , Glucemia/efectos de los fármacos , Glucemia/metabolismo , Glucemia/análisis , HumanosRESUMEN
With the intensive research on the pathogenesis of Alzheimer's disease (AD), inhibition of HDAC6 appears to be a potential therapeutic approach for AD. In this paper, a series of tetrahydro-ß-carboline derivatives with hydroxamic acid group were fast synthesized. Among all, the most potent 15 selectively inhibited HDAC6 with IC50 of 15.2 nM and markedly increased acetylated alpha-tubulin levels. In cellular assay, 15 showed excellent neurotrophic effect by increasing the expression of GAP43 and Beta-3 tubulin markers. Besides, 15 showed neuroprotective effects in PC12 or SH-SY5Y cells against H2O2 and 6-OHDA injury through activation of Nrf2, catalase and Prx II, and significantly reduced H2O2-induced reactive oxygen species (ROS) production. In vivo, 15 significantly attenuated zebrafish anxiety-like behaviour and memory deficits in a SCOP-induced zebrafish model of AD. To sum up, multifunctional 15 might be a good lead to develop novel tetrahydrocarboline-based agents for the treatment of AD.
Asunto(s)
Enfermedad de Alzheimer , Carbolinas , Histona Desacetilasa 6 , Inhibidores de Histona Desacetilasas , Fármacos Neuroprotectores , Pez Cebra , Carbolinas/farmacología , Carbolinas/química , Carbolinas/síntesis química , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/metabolismo , Humanos , Animales , Histona Desacetilasa 6/antagonistas & inhibidores , Histona Desacetilasa 6/metabolismo , Ratas , Inhibidores de Histona Desacetilasas/farmacología , Inhibidores de Histona Desacetilasas/síntesis química , Inhibidores de Histona Desacetilasas/química , Relación Estructura-Actividad , Fármacos Neuroprotectores/farmacología , Fármacos Neuroprotectores/síntesis química , Fármacos Neuroprotectores/química , Estructura Molecular , Relación Dosis-Respuesta a Droga , Células PC12 , Especies Reactivas de Oxígeno/metabolismoRESUMEN
The quest for novel antibacterial agents is imperative in the face of escalating antibiotic resistance. Naturally occurring tetrahydro-ß-carboline (THßC) alkaloids have been highlighted due to their significant biological derivatives. However, these structures have been little explored for antibacterial drugs development. In this study, a series of 1,2,3,4-THßC derivatives were synthesized and assessed for their antibacterial prowess against both gram-positive and gram-negative bacteria. The compounds exhibited moderate to good antibacterial activity, with some compounds showing superior efficacy against gram-positive bacteria, especially methicillin-resistant Staphylococcus aureus (MRSA), to that of Gentamicin. Among these analogs, compound 3k emerged as a hit compound, demonstrating rapid bactericidal action and a significant post-antibacterial effect, with significant cytotoxicity towards human LO2 and HepG2 cells. In addition, compound 3k (10 mg/kg) showed comparable anti-MRSA efficacy to Ciprofloxacin (2 mg/kg) in a mouse model of abdominal infection. Overall, the present findings suggested that THßC derivatives based on the title compounds hold promising applications in the development of antibacterial drugs.
Asunto(s)
Antibacterianos , Carbolinas , Bacterias Gramnegativas , Bacterias Grampositivas , Pruebas de Sensibilidad Microbiana , Antibacterianos/farmacología , Antibacterianos/síntesis química , Antibacterianos/química , Carbolinas/farmacología , Carbolinas/química , Carbolinas/síntesis química , Humanos , Relación Estructura-Actividad , Animales , Ratones , Bacterias Grampositivas/efectos de los fármacos , Estructura Molecular , Bacterias Gramnegativas/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Células Hep G2 , Staphylococcus aureus Resistente a Meticilina/efectos de los fármacosRESUMEN
An unusual rhodium-catalyzed C-H activation/Lossen rearrangement/oxa-Michael addition tandem cyclization has been achieved along with a tunable well-known C-H activation/[4 + 2] annulation, leading to regio-, chemo-, and diastereoselective access to diverse pentacyclic α-carbolines and ß-carboline-1-one derivatives in moderate to good yields with significant anticancer activity.
Asunto(s)
Antineoplásicos , Carbolinas , Rodio , Rodio/química , Carbolinas/química , Carbolinas/síntesis química , Carbolinas/farmacología , Catálisis , Ciclización , Estructura Molecular , Antineoplásicos/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/química , Estereoisomerismo , Humanos , Ensayos de Selección de Medicamentos AntitumoralesRESUMEN
Triple-negative breast cancer is a highly aggressive and heterogeneous breast cancer subtype characterized by early metastasis, poor prognosis, and high recurrence. Targeting histone citrullination-mediated chromatin dysregulation to induce epigenetic alterations shows great promise in TNBC therapy. We report the synthesis, optimization, and evaluation of a novel series of ß-carboline-derived peptidyl arginine deiminase 4 inhibitors that exhibited potent inhibition of TNBC cell proliferation. The most outstanding PAD4 inhibitor, compound 28, hindered the PAD4-H3cit-NET signaling pathway and inhibited the growth of solid tumors and pulmonary metastatic nodules in the 4T1 in situ mouse model. Furthermore, 28 improved the tumor immune microenvironment by reshaping neutrophil phenotype, upregulating the proportions of dendritic cells and M1 macrophages, and reducing the amount of myeloid-derived suppressor cells. In conclusion, our work offered 28 as an efficacious PAD4 inhibitor that exerts a combination of conventional chemotherapy and immune-boosting effects, which represents a potential therapy strategy for TNBC.
Asunto(s)
Antineoplásicos , Carbolinas , Neutrófilos , Arginina Deiminasa Proteína-Tipo 4 , Neoplasias de la Mama Triple Negativas , Microambiente Tumoral , Neoplasias de la Mama Triple Negativas/tratamiento farmacológico , Neoplasias de la Mama Triple Negativas/patología , Neoplasias de la Mama Triple Negativas/inmunología , Carbolinas/farmacología , Carbolinas/química , Carbolinas/uso terapéutico , Carbolinas/síntesis química , Animales , Arginina Deiminasa Proteína-Tipo 4/antagonistas & inhibidores , Femenino , Humanos , Microambiente Tumoral/efectos de los fármacos , Ratones , Neutrófilos/efectos de los fármacos , Neutrófilos/metabolismo , Neutrófilos/inmunología , Antineoplásicos/farmacología , Antineoplásicos/química , Antineoplásicos/síntesis química , Antineoplásicos/uso terapéutico , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Ratones Endogámicos BALB C , Inhibidores Enzimáticos/farmacología , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/uso terapéutico , Fenotipo , Relación Estructura-ActividadRESUMEN
We discovered tetrahydro-γ-carboline sulfonamides as a new antischistosomal chemotype. The aryl sulfonamide and tetrahydro-γ-carboline substructures were required for high antischistosomal activity. Increasing polarity improved solubility and metabolic stability but decreased antischistosomal activity. We identified two compounds with IC50 values <5 µM against ex vivo Schistosoma mansoni.
Asunto(s)
Carbolinas/farmacología , Schistosoma mansoni/efectos de los fármacos , Sulfonamidas/farmacología , Animales , Carbolinas/síntesis química , Carbolinas/química , Relación Dosis-Respuesta a Droga , Estructura Molecular , Relación Estructura-Actividad , Sulfonamidas/síntesis química , Sulfonamidas/químicaRESUMEN
The natural product harmine, a representative ß-carboline alkaloid from the seeds of Peganum harmala L. (Zygophyllaceae), possesses a broad spectrum of biological activities. In this study, a novel series of harmine derivatives containing N-benzylpiperidine moiety were identified for the treatment of Alzheimer's disease (AD). The results showed that all the derivatives possessed significant anti-acetylcholinesterase (AChE) activity and good selectivity over butyrylcholinesterase (BChE). In particular, compound ZLWH-23 exhibited potent anti-AChE activity (IC50 = 0.27 µM) and selective BChE inhibition (IC50 = 20.82 µM), as well as acceptable glycogen synthase kinase-3 (GSK-3ß) inhibition (IC50 = 6.78 µM). Molecular docking studies and molecular dynamics simulations indicated that ZLWH-23 could form stable interaction with AChE and GSK-3ß. Gratifyingly, ZLWH-23 exhibited good selectivity for GSK-3ß over multi-kinases and very low cytotoxicity towards SH-SY5Y, HEK-293T, HL-7702, and HepG2 cell lines. Importantly, ZLWH-23 displayed efficient reduction against tau hyperphosphorylation on Ser-396 site in Tau (P301L) 293T cell model. Collectively, harmine-based derivatives could be considered as possible drug leads for the development of AD therapies.
Asunto(s)
Acetilcolinesterasa/metabolismo , Enfermedad de Alzheimer/tratamiento farmacológico , Antineoplásicos/química , Carbolinas/síntesis química , Inhibidores de la Colinesterasa/síntesis química , Glucógeno Sintasa Quinasa 3 beta/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/síntesis química , Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Carbolinas/farmacología , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Inhibidores de la Colinesterasa/farmacología , Diseño de Fármacos , Humanos , Simulación del Acoplamiento Molecular , Simulación de Dinámica Molecular , Unión Proteica , Inhibidores de Proteínas Quinasas/farmacología , Transducción de Señal , Relación Estructura-ActividadRESUMEN
So far, relatively few small molecules have been reported to promote tubulin degradation. Our previous studies have found that compound 2, a noncovalent colchicine-site ligand, was capable of promoting αß-tubulin degradation. To further improve its antiproliferative activity, 66 derivatives or analogues of 2 were designed and synthesized based on 2-tubulin cocrystal structure. Among them, 12b displayed nanomolar potency against a variety of tumor cells, including paclitaxel- and adriamycin-resistant cell lines. 12b binds to the colchicine site and promotes αß-tubulin degradation in a concentration-dependent manner via the ubiquitin-proteasome pathway. The X-ray crystal structure revealed that 12b binds in a similar manner as 2, but there is a slight conformation change of the B ring, which resulted in better interaction of 12b with surrounding residues. 12b effectively suppressed tumor growth at an i.v. dose of 40 mg/kg (3 times a week) on both A2780S (paclitaxel-sensitive) and A2780T (paclitaxel-resistant) ovarian xenograft models, with respective TGIs of 92.42 and 79.75% without obvious side effects, supporting its potential utility as a tumor-therapeutic compound.
Asunto(s)
Antineoplásicos/uso terapéutico , Carbolinas/uso terapéutico , Neoplasias/tratamiento farmacológico , Moduladores de Tubulina/uso terapéutico , Tubulina (Proteína)/metabolismo , Animales , Antineoplásicos/síntesis química , Antineoplásicos/metabolismo , Antineoplásicos/farmacocinética , Apoptosis/efectos de los fármacos , Sitios de Unión , Carbolinas/síntesis química , Carbolinas/metabolismo , Carbolinas/farmacocinética , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Diseño de Fármacos , Resistencia a Múltiples Medicamentos/efectos de los fármacos , Resistencia a Antineoplásicos/efectos de los fármacos , Femenino , Puntos de Control de la Fase G2 del Ciclo Celular/efectos de los fármacos , Humanos , Ratones Endogámicos BALB C , Ratones Desnudos , Estructura Molecular , Unión Proteica , Ratas , Relación Estructura-Actividad , Tubulina (Proteína)/química , Moduladores de Tubulina/síntesis química , Moduladores de Tubulina/metabolismo , Moduladores de Tubulina/farmacocinética , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
The discovery of antifungal agents with novel structure, broad-spectrum, low toxicity, and high efficiency has been the focus of medicinal chemists. Over the past decades, ß-carboline scaï¬old has attracted extensive attention in the scientific community due to its potent and diverse biological activities with nine successfully marketed ß-carboline-based drugs. In this review, we summarized the current states and advances in the antifungal activity of natural and synthetic ß-carbolines. Additionally, the structure-activity relationships and their antifungal mechanisms targeting bioï¬lm, cell wall, cell membrane, and fungal intracellular targets were also systematically discussed. In summary, ß-carbolines have the great potential to develop new efficient scaffolds to combat fungal infections.
Asunto(s)
Antifúngicos/química , Productos Biológicos/química , Carbolinas/síntesis química , Micosis/tratamiento farmacológico , Animales , Antifúngicos/farmacología , Productos Biológicos/farmacología , Carbolinas/farmacología , Descubrimiento de Drogas , Femenino , Humanos , Masculino , Ratones , Pruebas de Sensibilidad Microbiana , Modelos Moleculares , Estructura Molecular , Unión Proteica , Transducción de Señal , Relación Estructura-ActividadRESUMEN
Malaria is still one of the most dangerous infectious diseases and the emergence of drug resistant parasites only worsens the situation. A series of new tetrahydro-ß-carbolines were designed, synthesized by the Pictet-Spengler reaction, and characterized. Further, the compounds were screened for their in vitro antiplasmodial activity against chloroquine-sensitive (D10) and chloroquine-resistant (W2) strains of Plasmodium falciparum. Moreover, molecular modeling studies were performed to assess the potential action of the designed molecules and toxicity assays were conducted on the human microvascular endothelial (HMEC-1) cell line and human red blood cells. Our studies identified N-(3,3-dimethylbutyl)-1-octyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b] indole-3-carboxamide (7) (a mixture of diastereomers) as the most promising compound endowed with the highest antiplasmodial activity, highest selectivity, and lack of cytotoxicity. In silico simulations carried out for (1S,3R)-7 provided useful insights into its possible interactions with enzymes essential for parasite metabolism. Further studies are underway to develop the optimal nanosized lipid-based delivery system for this compound and to determine its precise mechanism of action.
Asunto(s)
Antimaláricos/química , Antimaláricos/farmacología , Carbolinas/química , Carbolinas/farmacología , Plasmodium falciparum/efectos de los fármacos , Antimaláricos/síntesis química , Carbolinas/síntesis química , Línea Celular , Diseño de Fármacos , Humanos , Malaria Falciparum/tratamiento farmacológico , Simulación del Acoplamiento Molecular , Plasmodium falciparum/enzimología , Plasmodium falciparum/metabolismoRESUMEN
Herein we report an organocatalytic enantioselective functionalization of heterocyclic carboxaldehydes via the Pictet-Spengler reaction. Through careful pairing of novel squaramide and Brønsted acid catalysts, our method tolerates a breadth of heterocycles, enabling preparation of a series of heterocycle conjugated ß-(tetrahydro)carbolines in good yield and enantioselectivity. Careful selection of carboxylic acid co-catalyst is essential for toleration of a variety of regioisomeric heterocycles. Utility is demonstrated via the three-step stereoselective preparation of pyridine-containing analogues of potent selective estrogen receptor downregulator and U.S. FDA approved drug Tadalafil.
Asunto(s)
Aldehídos/química , Compuestos Heterocíclicos/química , Nitrógeno/química , Benzaldehídos/química , Carbolinas/síntesis química , Carbolinas/química , Ácidos Carboxílicos/química , Catálisis , Enlace de Hidrógeno , EstereoisomerismoRESUMEN
1, 2, 3, 4-Tetrahydro-ß-carboline (THßC) scaffold is widespread in many natural products (NPs) and synthetic compounds which show a variety of pharmacological activities. In this article, we reviewed the design, structures and biological characteristics of reported synthetic THßC compounds, and structure and activity relationship (SAR) of them were also discussed. This work might provide a reference for subsequent drug development based on THßC.
Asunto(s)
Carbolinas/síntesis química , Analgésicos/síntesis química , Analgésicos/química , Analgésicos/farmacología , Antimaláricos/síntesis química , Antimaláricos/química , Antimaláricos/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/química , Antineoplásicos/farmacología , Antiprotozoarios/síntesis química , Antiprotozoarios/química , Antiprotozoarios/farmacología , Antivirales/síntesis química , Antivirales/química , Antivirales/farmacología , Carbolinas/química , Carbolinas/farmacología , Química Farmacéutica , Fungicidas Industriales/síntesis química , Fungicidas Industriales/química , Fungicidas Industriales/farmacología , Humanos , Estructura MolecularRESUMEN
To discover the promising antitumor agents, a series of ß-carboline derivatives with nitrogen mustard moieties were designed and synthesized. Most target derivatives showed antiproliferative activity against MCF-7 and MDA-MB-231 cells. Among them, (1-methyl-9H-pyrido[3,4-b]indol-3-yl)methyl (S)-3-(4-(bis(2-chloroethyl)amino)phenyl)-2-formamidopropanoate possessed the most potent antiproliferative activity with IC50 values of 1.79 µM and 4.96 µM, respectively, which were significantly higher than that of the parent compounds, and the efficacy was comparable to that of the positive control doxorubicin. More importantly, it showed weak cytotoxicity against human normal breast cell line MCF-10A (IC50 > 20 µM), exhibiting certain selectivity. Subsequently, further mechanism exploration indicated that it induced G2/M phase cell cycle arrest and apoptosis in MDA-MB-231 cells. The DCFH-DA fluorescent probe assay and comet assay showed that this compound could cause intracellular ROS accumulation and DNA damage. In addition, it exerted potent inhibitory effect on the migration, invasion and adhesion of MDA-MB-231 cells in vitro. In short, (1-methyl-9H-pyrido[3,4-b]indol-3-yl)methyl (S)-3-(4-(bis(2-chloroethyl)amino)phenyl)-2-formamidopropanoate was considered as a promising compound for anti-breast cancer.
Asunto(s)
Antineoplásicos/farmacología , Carbolinas/farmacología , Diseño de Fármacos , Mecloretamina/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/química , Apoptosis/efectos de los fármacos , Carbolinas/síntesis química , Carbolinas/química , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Femenino , Humanos , Mecloretamina/química , Estructura Molecular , Relación Estructura-ActividadRESUMEN
On the occasion of receiving the Pharmaceutical Society of Japan Award 2020, I explained our research activities on the total syntheses of polycyclic alkaloids as an invited review. The structure of lundurine B, which has an unstable cyclopropane fused indoline skeleton, was proved firstly by the total synthesis. I also describe the total syntheses of optically active lundurine B and rapidilectine B utilizing asymmetric desymmetrization of the spiro intermediate. We developed an intramolecular bond formation reaction between the 2-position of the furan ring to the iminium cation (furane-iminium cation cyclization) to synthesize manzamine alkaloids. The reaction was applied to the total synthesis of the core skeleton of nakadomarin A and ircinal A. A ring-closing metathesis reaction effectively applied to the synthesis of medium and large heterocyclic rings containing the cis double bond found in the structures of nakadomarin A and ircinal A. The total synthesis of schizocommunin, a metabolite of Schizophyllum commune isolated from a patient with human allergenic bronchopulmonary mycosis, was accomplished. We could correct the error in the proposed structure by total synthesis of the natural product. A part of the mechanism of cytotoxicity expression was clarified using newly synthesized shizocommunin.
Asunto(s)
Alcaloides/síntesis química , Productos Biológicos/síntesis química , Ciclopropanos/síntesis química , Compuestos Policíclicos/síntesis química , Alcaloides/química , Productos Biológicos/química , Carbolinas/síntesis química , Carbolinas/química , Ciclización , Ciclopropanos/química , Humanos , Alcaloides Indólicos/síntesis química , Alcaloides Indólicos/química , Indoles/síntesis química , Indoles/química , Aspergilosis Pulmonar Invasiva/metabolismo , Compuestos Policíclicos/químicaRESUMEN
Natural ß-carboline alkaloids are ideal models for the discovery of pharmaceutically important entities. Various 1-substituted ß-carbolines were synthesized from commercially inexpensive tryptophan and demonstrated significant in vitro antifungal activity against G. graminis. Significantly, compound 4m (EC50 = 0.45 µM) with carboxamide at 1-position displayed the best efficacy and nearly 20 folds enhancement in antifungal potential compared to Silthiopham (EC50 = 8.95 µM). Moreover, compounds 6, 7, and 4i exhibited excellent in vitro antifungal activities and in vivo protective and curative activities against B. cinerea and F. graminearum. Preliminary mechanism studies revealed that compound 4m caused reactive oxygen species accumulation, cell membrane destruction, and deregulation of histone acetylation. These findings indicated that 1-carbamoyl ß-carboline can be selected as a promising model for the discovery of novel and broad-spectrum fungicide candidates.
Asunto(s)
Antifúngicos/farmacología , Botrytis/efectos de los fármacos , Carbolinas/farmacología , Descubrimiento de Drogas , Fusarium/efectos de los fármacos , Antifúngicos/síntesis química , Antifúngicos/química , Carbolinas/síntesis química , Carbolinas/química , Relación Dosis-Respuesta a Droga , Pruebas de Sensibilidad Microbiana , Estructura Molecular , Relación Estructura-ActividadRESUMEN
We describe our efforts to identify structurally diverse leads in the triazole-containing N1-carboline series of bromodomain and extra-terminal inhibitors. Replacement of the N5 "cap" phenyl moiety with various heteroaryls, coupled with additional modifications to the carboline core, provided analogs with similar potency, improved pharmacokinetic properties, and increased solubility compared to our backup lead, BMS-986225 (2). Rapid SAR exploration was enabled by a convergent, synthetic route. These efforts provided a potent BET inhibitor, 3-fluoropyridyl 12, that demonstrated robust efficacy in a multiple myeloma mouse tumor model at 1 mg/kg.