RESUMO
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.
Assuntos
Antifúngicos , Carbolinas , Fusarium , Hidrazonas , Testes de Sensibilidade Microbiana , Carbolinas/química , Carbolinas/farmacologia , Carbolinas/síntese química , Antifúngicos/farmacologia , Antifúngicos/síntese química , Antifúngicos/química , Relação Estrutura-Atividade , Fusarium/efeitos dos fármacos , Hidrazonas/farmacologia , Hidrazonas/química , Hidrazonas/síntese química , Estrutura Molecular , HumanosRESUMO
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.
Assuntos
Carbolinas , Desacetilase 6 de Histona , Inibidores de Histona Desacetilases , Humanos , Carbolinas/química , Carbolinas/farmacologia , Carbolinas/síntese química , Linhagem Celular Tumoral , Cristalografia por Raios X , Relação Dose-Resposta a Droga , Desacetilase 6 de Histona/antagonistas & inibidores , Desacetilase 6 de Histona/metabolismo , Inibidores de Histona Desacetilases/química , Inibidores de Histona Desacetilases/farmacologia , Inibidores de Histona Desacetilases/síntese química , Modelos Moleculares , Estrutura Molecular , Relação Estrutura-Atividade , Morfolinas/síntese química , Morfolinas/química , Morfolinas/farmacologiaRESUMO
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.
Assuntos
Carbolinas , Carbolinas/química , Carbolinas/síntese química , Carbolinas/farmacologia , Humanos , Estrutura Molecular , Animais , Produtos Biológicos/química , Produtos Biológicos/farmacologia , Produtos Biológicos/síntese químicaRESUMO
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.
Assuntos
Antineoplásicos , Carbolinas , Complexos de Coordenação , Ensaios de Seleção de Medicamentos Antitumorais , Irídio , Fotoquimioterapia , Fármacos Fotossensibilizantes , Rutênio , Humanos , Irídio/química , Irídio/farmacologia , Rutênio/química , Rutênio/farmacologia , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/síntese química , Ligantes , Fármacos Fotossensibilizantes/farmacologia , Fármacos Fotossensibilizantes/química , Fármacos Fotossensibilizantes/síntese química , Complexos de Coordenação/farmacologia , Complexos de Coordenação/química , Complexos de Coordenação/síntese química , Carbolinas/química , Carbolinas/farmacologia , Carbolinas/síntese química , Estrutura Molecular , Relação Estrutura-Atividade , Proliferação de Células/efeitos dos fármacos , Piridinas/química , Piridinas/farmacologia , Piridinas/síntese química , Espécies Reativas de Oxigênio/metabolismo , Relação Dose-Resposta a Droga , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Apoptose/efeitos dos fármacosRESUMO
Light and pH dual-responsive ion transporters offer better applicability for cancer due to higher tunability and low cytotoxicity. Herein, we demonstrate the development of pH-responsive ß-carboline-based ionophores and photocleavable-linker appended ß-carboline-based proionophores to facilitate the controlled transport of Cl- across membranes, leading to apoptotic and autophagic cancer cell death.
Assuntos
Carbolinas , Luz , Carbolinas/química , Carbolinas/farmacologia , Humanos , Concentração de Íons de Hidrogênio , Apoptose/efeitos dos fármacos , Antineoplásicos/farmacologia , Antineoplásicos/química , Transporte de Íons/efeitos dos fármacos , Linhagem Celular Tumoral , Estrutura Molecular , Ionóforos/química , Ionóforos/farmacologia , Ensaios de Seleção de Medicamentos AntitumoraisRESUMO
BACKGROUND: ß-carboline alkaloids exert a distinguished ability to impair cell growth and induce cell death in a variety of cancers and the evaluation of such new therapeutic candidates may denote new possibilities for leukemia treatment. In this present study, we screened 12 ß-carboline derivatives containing different substituents at 1- and 3-positions of ß-carboline nucleus for their antineoplastic activities in a panel of leukemia cell lines. METHODS: The cytotoxic effects of the ß-carboline derivatives were evaluated in different leukemia cell lines as well as reactive oxygen species (ROS) generation, autophagy, and important signaling pathways. RESULTS: Treatment with the ß-carboline derivatives resulted in a potent antineoplastic activity leading to a reduced cell viability that was associated with increased cell death in a concentration-dependent manner. Interestingly, the treatment of primary mononuclear cells isolated from the peripheral blood of healthy donors with the ß-carboline derivatives showed a minor change in cell survival. The antineoplastic activity occurs by blocking ROS production causing consequent interruption of the PI3K/AKT and MAPK/ERK signaling and modulating autophagy processes. Notably, in vivo, AML burden was diminished in peripheral blood and bone marrow of a xenograft mouse model. CONCLUSIONS: Our results indicated that ß-carboline derivatives have an on-target malignant cell-killing activity and may be promising candidates for treating leukemia cells by disrupting crucial events that promote leukemia expansion and chemotherapy resistance.
Assuntos
Antineoplásicos , Carbolinas , Sobrevivência Celular , Leucemia Mieloide Aguda , Espécies Reativas de Oxigênio , Ensaios Antitumorais Modelo de Xenoenxerto , Carbolinas/farmacologia , Humanos , Animais , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/patologia , Camundongos , Espécies Reativas de Oxigênio/metabolismo , Linhagem Celular Tumoral , Antineoplásicos/farmacologia , Sobrevivência Celular/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Relação Dose-Resposta a DrogaRESUMO
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.
Assuntos
Carbolinas , Diabetes Mellitus Experimental , Inibidores de Glicosídeo Hidrolases , Semicarbazidas , alfa-Glucosidases , Inibidores de Glicosídeo Hidrolases/farmacologia , Inibidores de Glicosídeo Hidrolases/síntese química , Inibidores de Glicosídeo Hidrolases/química , Animais , alfa-Glucosidases/metabolismo , Carbolinas/farmacologia , Carbolinas/química , Carbolinas/síntese química , Semicarbazidas/farmacologia , Semicarbazidas/química , Semicarbazidas/síntese química , Camundongos , Relação Estrutura-Atividade , Diabetes Mellitus Experimental/tratamento farmacológico , Hipoglicemiantes/farmacologia , Hipoglicemiantes/síntese química , Hipoglicemiantes/química , Estrutura Molecular , Simulação de Acoplamento Molecular , Relação Dose-Resposta a Droga , Masculino , Glicemia/efeitos dos fármacos , Glicemia/metabolismo , Glicemia/análise , HumanosRESUMO
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.
Assuntos
Doença de Alzheimer , Carbolinas , Desacetilase 6 de Histona , Inibidores de Histona Desacetilases , Fármacos Neuroprotetores , Peixe-Zebra , Carbolinas/farmacologia , Carbolinas/química , Carbolinas/síntese química , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/metabolismo , Humanos , Animais , Desacetilase 6 de Histona/antagonistas & inibidores , Desacetilase 6 de Histona/metabolismo , Ratos , Inibidores de Histona Desacetilases/farmacologia , Inibidores de Histona Desacetilases/síntese química , Inibidores de Histona Desacetilases/química , Relação Estrutura-Atividade , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/síntese química , Fármacos Neuroprotetores/química , Estrutura Molecular , Relação Dose-Resposta a Droga , Células PC12 , Espécies Reativas de Oxigênio/metabolismoRESUMO
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.
Assuntos
Antibacterianos , Carbolinas , Bactérias Gram-Negativas , Bactérias Gram-Positivas , Testes de Sensibilidade Microbiana , Antibacterianos/farmacologia , Antibacterianos/síntese química , Antibacterianos/química , Carbolinas/farmacologia , Carbolinas/química , Carbolinas/síntese química , Humanos , Relação Estrutura-Atividade , Animais , Camundongos , Bactérias Gram-Positivas/efeitos dos fármacos , Estrutura Molecular , Bactérias Gram-Negativas/efeitos dos fármacos , Relação Dose-Resposta a Droga , Células Hep G2 , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacosRESUMO
AIM: Exploring the efficacy of ß-carboline-based molecular inhibitors in targeting microtubules for the development of novel anticancer therapeutics. MATERIALS AND METHODS: We synthesized a series of 1-Aryl-N-substituted-ß-carboline-3-carboxamide compounds and evaluated their cytotoxicity against human lung carcinoma (A549) cells using the MTT assay. Normal lung fibroblast cells (WI-38) were used to assess compound selectivity. The mechanism of action of MJ-211 was elucidated through Western blot analysis of key pro-apoptotic and cell cycle regulatory proteins. Additionally, the inhibitory effect of MJ-211 on multicellular 3D spheroid growth of A549 cells was evaluated. KEY FINDINGS: Lead compound MJ-211 exhibited remarkable cytotoxicity against A549 cells with an IC50 of 4.075 µM at 24 h treatment and IC50 of 1.7 nM after 72 h of treatment, while demonstrating selectivity towards normal WI-38 cells. MJ-211 activated pro-apoptotic factors Bim and p53, and suppressed Cyclin B1, Phospho HSP 27, BubR1, Mad 2, ERK1/2, and NF-κB, indicating its potent antimitotic and pro-apoptotic effects. MJ-211 significantly suppressed the migration of cells and inhibited the growth of A549 cell-derived multicellular 3D spheroids, highlighting its efficacy in a more physiologically relevant model. SIGNIFICANCE: Cytotoxic effect of MJ-211 against cancer cells, selectivity towards normal cells, and ability to modulate key regulatory proteins involved in apoptosis and cell cycle progression underscore its potential as a promising template for further anticancer lead optimization. Moreover, the inhibitory effect of MJ-211 on multicellular spheroid growth suggests its efficacy in combating tumor heterogeneity and resistance mechanisms, thereby offering a promising avenue for future anticancer drug development.
Assuntos
Carbolinas , Microtúbulos , NF-kappa B , Humanos , Carbolinas/farmacologia , NF-kappa B/metabolismo , Microtúbulos/efeitos dos fármacos , Microtúbulos/metabolismo , Células A549 , Antimitóticos/farmacologia , Regulação para Baixo/efeitos dos fármacos , Apoptose/efeitos dos fármacos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Antineoplásicos/farmacologia , Proliferação de Células/efeitos dos fármacosRESUMO
Demyelination is generated in several nervous system illnesses. Developing strategies for effective clinical treatments requires the discovery of promyelinating drugs. Increased GABAergic signaling through γ-aminobutyric acid type A receptor (GABAAR) activation in oligodendrocytes has been proposed as a promyelinating condition. GABAAR expressed in oligodendroglia is strongly potentiated by n-butyl-ß-carboline-3-carboxylate (ß-CCB) compared to that in neurons. Here, mice were subjected to 0.3% cuprizone (CPZ) added in the food to induce central nervous system demyelination, a well-known model for multiple sclerosis. Then ß-CCB (1 mg/Kg) was systemically administered to analyze the remyelination status in white and gray matter areas. Myelin content was evaluated using Black-Gold II (BGII) staining, immunofluorescence (IF), and magnetic resonance imaging (MRI). Evidence indicates that ß-CCB treatment of CPZ-demyelinated animals promoted remyelination in several white matter structures, such as the fimbria, corpus callosum, internal capsule, and cerebellar peduncles. Moreover, using IF, it was observed that CPZ intake induced an increase in NG2+ and a decrease in CC1+ cell populations, alterations that were importantly retrieved by ß-CCB treatment. Thus, the promyelinating character of ß-CCB was confirmed in a generalized demyelination model, strengthening the idea that it has clinical potential as a therapeutic drug.
Assuntos
Carbolinas , Cuprizona , Doenças Desmielinizantes , Modelos Animais de Doenças , Remielinização , Animais , Cuprizona/toxicidade , Remielinização/efeitos dos fármacos , Camundongos , Doenças Desmielinizantes/induzido quimicamente , Doenças Desmielinizantes/patologia , Doenças Desmielinizantes/metabolismo , Carbolinas/farmacologia , Carbolinas/administração & dosagem , Bainha de Mielina/metabolismo , Bainha de Mielina/efeitos dos fármacos , Masculino , Camundongos Endogâmicos C57BL , Oligodendroglia/efeitos dos fármacos , Oligodendroglia/metabolismo , Esclerose Múltipla/tratamento farmacológico , Esclerose Múltipla/metabolismo , Esclerose Múltipla/induzido quimicamente , Esclerose Múltipla/patologia , Substância Branca/efeitos dos fármacos , Substância Branca/metabolismo , Substância Branca/patologia , Imageamento por Ressonância MagnéticaRESUMO
Herpes simplex virus (HSV) infections are highly widespread among humans, producing symptoms ranging from ulcerative lesions to severe diseases such as blindness and life-threatening encephalitis. At present, there are no vaccines available, and some existing antiviral treatments can be ineffective or lead to adverse effects. As a result, there is a need for new anti-HSV drugs. In this report, the in vitro anti-HSV effect of 9,9'-norharmane dimer (nHo-dimer), which belongs to the ß-carboline (ßC) alkaloid family, was evaluated. The dimer exhibited no virucidal properties and did not impede either the attachment or penetration steps of viral particles. The antiviral effect was only exerted under the constant presence of the dimer in the incubation media, and the mechanism of action was found to involve later events of virus infection. Analysis of fluorescence lifetime imaging data showed that the nHo-dimer internalized well into the cells when present in the extracellular incubation medium, with a preferential accumulation into perinuclear organelles including mitochondria. After washing the host cells with fresh medium free of nHo-dimer, the signal decreased, suggesting the partial release of the compound from the cells. This agrees with the observation that the antiviral effect is solely manifested when the alkaloid is consistently present in the incubation media.
Assuntos
Antivirais , Antivirais/farmacologia , Antivirais/química , Chlorocebus aethiops , Humanos , Células Vero , Animais , Simplexvirus/efeitos dos fármacos , Simplexvirus/fisiologia , Herpes Simples/tratamento farmacológico , Herpes Simples/virologia , Carbolinas/farmacologia , Carbolinas/química , Herpesvirus Humano 1/efeitos dos fármacos , Herpesvirus Humano 1/fisiologia , Harmina/farmacologia , Harmina/química , Harmina/análogos & derivadosRESUMO
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.
Assuntos
Antineoplásicos , Carbolinas , Neutrófilos , Proteína-Arginina Desiminase do Tipo 4 , Neoplasias de Mama Triplo Negativas , Microambiente Tumoral , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/patologia , Neoplasias de Mama Triplo Negativas/imunologia , Carbolinas/farmacologia , Carbolinas/química , Carbolinas/uso terapêutico , Carbolinas/síntese química , Animais , Proteína-Arginina Desiminase do Tipo 4/antagonistas & inibidores , Feminino , Humanos , Microambiente Tumoral/efeitos dos fármacos , Camundongos , Neutrófilos/efeitos dos fármacos , Neutrófilos/metabolismo , Neutrófilos/imunologia , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/síntese química , Antineoplásicos/uso terapêutico , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Camundongos Endogâmicos BALB C , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/química , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/uso terapêutico , Fenótipo , Relação Estrutura-AtividadeRESUMO
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.
Assuntos
Antineoplásicos , Carbolinas , Ródio , Ródio/química , Carbolinas/química , Carbolinas/síntese química , Carbolinas/farmacologia , Catálise , Ciclização , Estrutura Molecular , Antineoplásicos/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Estereoisomerismo , Humanos , Ensaios de Seleção de Medicamentos AntitumoraisRESUMO
Chemo-photodynamic therapy is a treatment method that combines chemotherapy and photodynamic therapy and has demonstrated significant potential in cancer treatment. However, the development of chemo-photodynamic therapeutic agents with fewer side effects still poses a challenge. Herein, we designed and synthesized a novel series of ß-carboline/furylmalononitrile hybrids 10a-i and evaluated their chemo-photodynamic therapeutic effects. Most of the compounds were photodynamically active and exhibited cytotoxic effects in four cancer cells. In particular, 10f possessed type-I/II photodynamic characteristics, and its 1O2 quantum yield increased by 3-fold from pH 7.4 to 4.5. Most interestingly, 10f exhibited robust antiproliferative effects by tumor-selective cytotoxicities and hypoxic-overcoming phototoxicities. In addition, 10f generated intracellular ROS and induced hepatocellular apoptosis, mitochondrial damage, and autophagy. Finally, 10f demonstrated extremely low acute toxicity (LD50 = 1415 mg/kg) and a high tumor-inhibitory rate of 80.5% through chemo-photodynamic dual therapy. Our findings may provide a promising framework for the design of new photosensitizers for chemo-photodynamic therapy.
Assuntos
Apoptose , Carbolinas , Nitrilas , Fotoquimioterapia , Fármacos Fotossensibilizantes , Espécies Reativas de Oxigênio , Fármacos Fotossensibilizantes/farmacologia , Fármacos Fotossensibilizantes/química , Fotoquimioterapia/métodos , Humanos , Carbolinas/química , Carbolinas/farmacologia , Nitrilas/química , Nitrilas/farmacologia , Apoptose/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Linhagem Celular Tumoral , Animais , Camundongos , Proliferação de Células/efeitos dos fármacos , Antineoplásicos/farmacologia , Antineoplásicos/química , Autofagia/efeitos dos fármacosRESUMO
ß-Carboline nucleus is therapeutically valuable in medicinal chemistry for the treatment of varied number of diseases, most importantly cancer. The potent and wide-ranging activity of ß-carboline has established them as imperative pharmacological scaffolds especially in the cancer treatment. Numerous derivatives such as Tetrahydro ß-carbolines, metal complexed ß-carbolines, mono, di and tri substituted ß-carbolines have been reported to possess dynamic anticancer activity. These different substituted ß-carboline derivatives had shown different mechanism of action and plays important role in anticancer drug discovery and development. The review is an update of the chemistry of ß-carbolines, both synthetic and natural origin acting through various targets against cancerous cells. In addition to this, studies of multitarget molecules designed by coupling ß-carbolines along with other mechanisms for treatment of neoplasm are also summarized.
Assuntos
Antineoplásicos , Carbolinas , Neoplasias , Carbolinas/química , Carbolinas/farmacologia , Humanos , Antineoplásicos/química , Antineoplásicos/farmacologia , Neoplasias/tratamento farmacológico , Neoplasias/patologia , AnimaisRESUMO
AIM: Through network pharmacology, molecular docking, molecular dynamics in combination with experimentation, we explored the mechanism whereby 1-ethoxycarbonyl-beta-carboline (EBC) regulates the M2 polarization of tumor-associated macrophages. METHODS: Network pharmacology was adopted for analyzing the targets and signaling pathways related to the M2 polarization of EBC-macrophages, small molecular-protein docking was employed to analyze the possibility of EBC bonding to related protein, and molecular dynamics was introduced to analyze the binding energy between EBC and HDAC2. The M2 polarization of RAW264.7 macrophages was triggered in vitro by IL-4. After EBC intervention, the expressions of M1/M2 polarization-related cytokines were detected, and the mechanism of EBC action was explored in HDAC2-knockout RAW264.7 macrophages. A tumor-bearing mouse model was established in vitro to find the impact of EBC on tumor-associated M2 macrophages. RESULTS: As revealed by the network pharmacology, molecular docking and molecular dynamics analyses, EBC was associated with 51 proteins, including HDAC2, NF-κB and HDAC4. Molecular docking and dynamics analyses suggested that HDAC2 was the main target of EBC. In vitro experiments discovered that EBC could hinder the M2 polarization of RAW264.7 macrophages, which exerted insignificant effect on the M1-associated cytokines, but could lower the levels of M2-associated cytokines. After knocking out HDAC2, EBC could not further inhibit the M2 polarization of macrophages. At the mouse level, EBC could hinder the tumor growth and the tissue levels of M2 macrophages, whose effect was associated with HDAC2. CONCLUSION: Our study combining multiple methods finds that EBC inhibits the HDAC2-mediated M2 polarization of macrophages, thereby playing an anti-tumor role.
Assuntos
Farmacologia em Rede , Macrófagos Associados a Tumor , Animais , Camundongos , Simulação de Acoplamento Molecular , Macrófagos Associados a Tumor/metabolismo , Citocinas/metabolismo , Carbolinas/farmacologia , Carbolinas/uso terapêuticoRESUMO
INTRODUCTION AND HYPOTHESIS: Phosphodiesterase enzymes are widely distributed in female urogenital tissues. Yet, the understanding of their physiological roles and the impact of phosphodiesterase inhibitors on lower urinary tract symptoms in women remains limited. Current hypotheses are conflicting: one suggests that vasodilation might expand the periurethral vascular plexus, leading to increased urethral pressure, whereas the other proposes a relaxation of urethral musculature, resulting in decreased pressure. To further clarify this, we investigated the effect of tadalafil on the opening urethral pressure and voiding function in healthy women. METHODS: We conducted a randomized, double-blind, placebo-controlled crossover trial involving 24 healthy women. Participants were randomly assigned to receive a single dose of tadalafil (40 mg) or placebo during their initial visit and then switched to the alternative treatment during their second visit. Opening urethral pressure was measured with urethral pressure reflectometry during both resting and squeezing conditions of the pelvic floor. Subsequently, voiding parameters were recorded. RESULTS: Compared with placebo, a single dose of tadalafil significantly reduced opening urethral pressure during both resting (-6.8 cmH20; 95% confidence interval [CI], -11.8 to -1.9; p = 0.009) and squeezing conditions (-8.8 cmH20; 95% CI, -14.6 to -3.1; p = 0.005). Voiding parameters did not show significant differences (average flow rate: -0.8 ml/s [95% CI, -2.0 to 0.4; p = 0.2]; maximum flow rate: -1.7 ml/s [95% CI, -4.8 to 1.5; p = 0.3]). CONCLUSIONS: A single dose of 40 mg tadalafil moderately reduced urethral pressure in healthy women, without affecting voiding parameters. The clinical implications of this are yet to be determined.
Assuntos
Sintomas do Trato Urinário Inferior , Uretra , Feminino , Humanos , Tadalafila/farmacologia , Tadalafila/uso terapêutico , Estudos Cross-Over , Micção , Sintomas do Trato Urinário Inferior/tratamento farmacológico , Método Duplo-Cego , Carbolinas/farmacologia , Carbolinas/uso terapêuticoRESUMO
ß-Carboline alkaloids are natural and synthetic products with outstanding antitumor activity. C3 substituted and dimerized ß-carbolines exert excellent antitumor activity. In the present research, 37 ß-carboline derivatives were synthesized and characterized. Their cytotoxicity, cell cycle, apoptosis, and CDK2- and DNA-binding affinity were evaluated. ß-Carboline monomer M3 and dimer D4 showed selective activity and higher cytotoxicity in tumor cells than in normal cells. Structure-activity relationships (SAR) indicated that the amide group at C3 enhanced the antitumor activity. M3 blocked the A549 (IC50 = 1.44 ± 1.10 µM) cell cycle in the S phase and inhibited A549 cell migration, while D4 blocked the HepG2 (IC50 = 2.84 ± 0.73 µM) cell cycle in the G0/G1 phase, both of which ultimately induced apoptosis. Furthermore, associations of M3 and D4 with CDK2 and DNA were proven by network pharmacology analysis, molecular docking, and western blotting. The expression level of CDK2 was downregulated in M3-treated A549 cells and D4-treated HepG2 cells. Moreover, M3 and D4 interact with DNA and CDK2 at sub-micromolar concentrations in endothermic interactions caused by entropy-driven adsorption processes, which means that the favorable entropy change (ΔS > 0) overcomes the unfavorable enthalpy change (ΔH > 0) and drives the spontaneous reaction (ΔG < 0). Overall, these results clarified the antitumor mechanisms of M3 and D4 through disrupting the cell cycle by binding DNA and CDK2, which demonstrated the potential of M3 and D4 as novel antiproliferative drugs targeting mitosis.
Assuntos
Antineoplásicos , Proliferação de Células , Simulação de Acoplamento Molecular , Ciclo Celular , Relação Estrutura-Atividade , Antineoplásicos/farmacologia , Antineoplásicos/química , DNA , Carbolinas/farmacologia , Carbolinas/química , Linhagem Celular Tumoral , Ensaios de Seleção de Medicamentos Antitumorais , Estrutura MolecularRESUMO
The ß-Carboline FG-7142 is a partial inverse agonist at the benzodiazepine allosteric site on the GABA-A receptor that induces anxiogenic, proconvulsant, and appetite-reducing effects in many species, including humans. Seizure-kindling effects have been well studied, however anxiogenic properties are relatively unexplored. This study aimed to investigate concentration-dependent effects of FG-7142 on anxiety-like behaviour and fear responses in zebrafish (Danio rerio) using the open-field test (OF) and novel object approach test (NOA). A U-shaped distribution was found with maximal responses in increased immobility and reduced distance moved at 10 µM in the NOA but not the OF. Follow up experiments demonstrated a lack of effect in repeated OF testing and no changes in opercular movements. Furthermore, the effect of FG-7142 was reversed with ethanol treatment. These results suggest that FG-7142 elicits a 'freezing' response in zebrafish via the introduction of novelty, suggesting fear-induction. These findings indicate that FG-7142 may act as an agent to promote acute fear responses in zebrafish.