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1.
Cell Mol Life Sci ; 81(1): 395, 2024 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-39254764

RESUMO

The potent hallucinogen N,N-dimethyltryptamine (DMT) has garnered significant interest in recent years due to its profound effects on consciousness and its therapeutic psychopotential. DMT is an integral (but not exclusive) psychoactive alkaloid in the Amazonian plant-based brew ayahuasca, in which admixture of several ß-carboline monoamine oxidase A (MAO-A) inhibitors potentiate the activity of oral DMT, while possibly contributing in other respects to the complex psychopharmacology of ayahuasca. Irrespective of the route of administration, DMT alters perception, mood, and cognition, presumably through agonism at serotonin (5-HT) 1A/2A/2C receptors in brain, with additional actions at other receptor types possibly contributing to its overall psychoactive effects. Due to rapid first pass metabolism, DMT is nearly inactive orally, but co-administration with ß-carbolines or synthetic MAO-A inhibitors (MAOIs) greatly increase its bioavailability and duration of action. The synergistic effects of DMT and MAOIs in ayahuasca or synthetic formulations may promote neuroplasticity, which presumably underlies their promising therapeutic efficacy in clinical trials for neuropsychiatric disorders, including depression, addiction, and post-traumatic stress disorder. Advances in neuroimaging techniques are elucidating the neural correlates of DMT-induced altered states of consciousness, revealing alterations in brain activity, functional connectivity, and network dynamics. In this comprehensive narrative review, we present a synthesis of current knowledge on the pharmacology and neuroscience of DMT, ß-carbolines, and ayahuasca, which should inform future research aiming to harness their full therapeutic potential.


Assuntos
Banisteriopsis , Alucinógenos , Inibidores da Monoaminoxidase , Monoaminoxidase , N,N-Dimetiltriptamina , Inibidores da Monoaminoxidase/farmacologia , Inibidores da Monoaminoxidase/química , Banisteriopsis/química , N,N-Dimetiltriptamina/farmacologia , Humanos , Animais , Alucinógenos/farmacologia , Monoaminoxidase/metabolismo , Sinergismo Farmacológico , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Carbolinas/farmacologia , Carbolinas/química
2.
J Biol Chem ; 299(4): 104605, 2023 04.
Artigo em Inglês | MEDLINE | ID: mdl-36918100

RESUMO

Pseudorabies virus (PRV) has become a "new life-threatening zoonosis" since the human-originated PRV strain was first isolated in 2020. To identify novel anti-PRV agents, we screened a total of 107 ß-carboline derivatives and found 20 compounds displaying antiviral activity against PRV. Among them, 14 compounds showed better antiviral activity than acyclovir. We found that compound 45 exhibited the strongest anti-PRV activity with an IC50 value of less than 40 nM. Our in vivo studies showed that treatment with 45 significantly reduced the viral loads and protected mice challenged with PRV. To clarify the mode of action of 45, we conducted a time of addition assay, an adsorption assay, and an entry assay. Our results indicated that 45 neither had a virucidal effect nor affected viral adsorption while significantly inhibiting PRV entry. Using the FITC-dextran uptake assay, we determined that 45 inhibits macropinocytosis. The actin-dependent plasma membrane protrusion, which is important for macropinocytosis, was also suppressed by 45. Furthermore, the kinase DYRK1A (dual-specificity tyrosine phosphorylation-regulated kinase 1A) was predicted to be a potential target for 45. The binding of 45 to DYRK1A was confirmed by drug affinity responsive target stability and cellular thermal shift assay. Further analysis revealed that knockdown of DYRK1A by siRNA suppressed PRV macropinocytosis and the tumor necrosis factor alpha-TNF-induced formation of protrusions. These results suggested that 45 could restrain PRV macropinocytosis by targeting DYRK1A. Together, these findings reveal a unique mechanism through which ß-carboline derivatives restrain PRV infection, pointing to their potential value in the development of anti-PRV agents.


Assuntos
Antivirais , Carbolinas , Herpesvirus Suídeo 1 , Animais , Humanos , Camundongos , Aciclovir/farmacologia , Aciclovir/toxicidade , Antivirais/química , Antivirais/farmacologia , Antivirais/uso terapêutico , Carbolinas/química , Carbolinas/farmacologia , Carbolinas/uso terapêutico , Técnicas de Silenciamento de Genes , Herpesvirus Suídeo 1/efeitos dos fármacos , Concentração Inibidora 50 , Pinocitose/efeitos dos fármacos , Proteínas Tirosina Quinases/antagonistas & inibidores , Pseudorraiva/tratamento farmacológico , Pseudorraiva/prevenção & controle , Pseudorraiva/virologia , Internalização do Vírus/efeitos dos fármacos , Células HeLa , Modelos Químicos , Quinases Dyrk
3.
Mol Pharm ; 21(7): 3553-3565, 2024 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-38816926

RESUMO

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 fármacos
4.
J Org Chem ; 89(19): 13923-13936, 2024 10 04.
Artigo em Inglês | MEDLINE | ID: mdl-39284576

RESUMO

Herein, we describe a novel reaction between C-2-substituted indoles and 2-nitroacetophenones leading to a variety of indole-containing heterocyclic scaffolds. At 60 °C in AcOH with H2SO4 as catalyst, C-2 aryl indoles give 3-(2-nitrovinyl)-indoles with high Z or E geometric selectivity depending on the type of substrate utilized. These compounds undergo an electrocyclization process in a sealed vial in a microwave apparatus in DMF at 250 °C to give benzo[a]carbazoles and naphtho[2,1-a]carbazoles depending on whether the C-2 aromatic moiety is phenyl or naphthyl. Utilization of 2-methylindoles in the reaction with 2-nitroacetophenones and performing the reaction in a sealed vial in a microwave apparatus in AcOH at 200 °C leads to 1-hydroxy-ß-carbolines. Selected compounds from each scaffold were tested for antiproliferative activities against MDA-MB-231 triple-negative breast cancer cells under normoxic and hypoxic conditions, and three compounds belonging to the 3-(2-nitrovinyl)-indole and 1-hydroxy-ß-carboline series were identified to have single-digit micromolar IC50 values.


Assuntos
Antineoplásicos , Carbazóis , Carbolinas , Proliferação de Células , Indóis , Indóis/química , Indóis/farmacologia , Indóis/síntese química , Humanos , Carbazóis/química , Carbazóis/síntese química , Carbazóis/farmacologia , Proliferação de Células/efeitos dos fármacos , Carbolinas/química , Carbolinas/síntese química , Carbolinas/farmacologia , Antineoplásicos/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Estrutura Molecular , Linhagem Celular Tumoral , Ensaios de Seleção de Medicamentos Antitumorais , Relação Estrutura-Atividade
5.
Bioorg Med Chem Lett ; 109: 129822, 2024 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-38823728

RESUMO

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 fármacos
6.
Inorg Chem ; 63(41): 19140-19155, 2024 Oct 14.
Artigo em Inglês | MEDLINE | ID: mdl-39361042

RESUMO

Despite advances in Ir(III) and Ru(II) photosensitizers (PSs), their lack of selectivity for cancer cells has hindered their use in photodynamic therapy (PDT). We disclose the synthesis and characterization of two pairs of Ir(III) and Ru(II) polypyridyl complexes bearing two ß-carboline ligands (N^N') functionalized with -COOMe (L1) or -COOH (L2), resulting in PSs of formulas [Ir(C^N)2(N^N')]Cl (Ir-Me: C^N = ppy, N^N' = L1; Ir-H: C^N = ppy, N^N' = L2) and [Ru(N^N)2(N^N')](Cl)2 (Ru-Me: N^N = bpy, N^N' = L1; Ru-H: N^N = bpy, N^N' = L2). To enhance their selectivity toward cancer cells, Ir-H and Ru-H were coupled to a bombesin derivative (BN3), resulting in the metallopeptides Ir-BN and Ru-BN. Ir(III) complexes showed higher anticancer activity than their Ru(II) counterparts, particularly upon blue light irradiation, but lacked cancer cell selectivity. In contrast, Ir-BN and Ru-BN exhibited selective photocytoxicity against prostate cancer cells, with a lower effect against nonmalignant fibroblasts. All compounds generated ROS and induced severe mitochondrial toxicity upon photoactivation, leading to apoptosis. Additionally, the ability of Ir-Me to oxidize NADH was demonstrated, suggesting a mechanism for mitochondrial damage. Our findings indicated that the conjugation of metal PSs with BN3 creates efficient PDT agents, achieving selectivity through targeting bombesin receptors and local photoactivation.


Assuntos
Antineoplásicos , Bombesina , Carbolinas , Irídio , Fotoquimioterapia , Fármacos Fotossensibilizantes , Neoplasias da Próstata , Rutênio , Fármacos Fotossensibilizantes/química , Fármacos Fotossensibilizantes/farmacologia , Fármacos Fotossensibilizantes/síntese química , Humanos , Irídio/química , Irídio/farmacologia , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/patologia , Masculino , Rutênio/química , Rutênio/farmacologia , Carbolinas/química , Carbolinas/farmacologia , Carbolinas/síntese química , Antineoplásicos/química , Antineoplásicos/farmacologia , Antineoplásicos/síntese química , Bombesina/química , Bombesina/farmacologia , Complexos de Coordenação/química , Complexos de Coordenação/farmacologia , Complexos de Coordenação/síntese química , Ensaios de Seleção de Medicamentos Antitumorais , Estrutura Molecular , Sobrevivência Celular/efeitos dos fármacos , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos
7.
Bioorg Med Chem ; 111: 117841, 2024 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-39094526

RESUMO

3-Tetrazolyl-ß-carbolines were prepared by the Pictet-Spengler approach using a tryptophan analogue as building block, in which the carboxylic acid was replaced by the bioisosteric tetrazole group. Knowing that ß-carbolines are often associated with psychopharmacological effects, the study of the 3-tetrazolyl-ß-carbolines as potential neuroprotective agents against Parkinson's disease was investigated. The evaluation of neuroprotective effects against 1-methyl-4-phenylpyridin-1-ium (MPP+)-induced cytotoxicity allowed to identify compounds with relevant neuroprotective activity. One derivative, 3-(1-benzyl-1H-tetrazol-5-yl)-1-(p-dimethylaminophenyl)-ß-carboline, stood out for its low cytotoxicity and excellent performance, preventing cell death induced by this neurotoxin. The most promising compounds were also evaluated for their neuroprotective properties against iron (III)-induced cytotoxicity. However, only one 3-tetrazolyl-ß-carboline derivative slightly reduced iron-induced cytotoxicity. Overall, the neuroprotective properties of 3-tetrazolyl-ß-carbolines have been demonstrated and this finding may contribute to the development of new therapies for Parkinson's disease.


Assuntos
Carbolinas , Fármacos Neuroprotetores , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/química , Fármacos Neuroprotetores/síntese química , Carbolinas/química , Carbolinas/farmacologia , Carbolinas/síntese química , Relação Estrutura-Atividade , Humanos , Estrutura Molecular , Sobrevivência Celular/efeitos dos fármacos , Tetrazóis/química , Tetrazóis/farmacologia , Tetrazóis/síntese química , Relação Dose-Resposta a Droga , Animais
8.
Bioorg Chem ; 145: 107216, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38387396

RESUMO

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 Molecular
9.
Bioorg Chem ; 151: 107648, 2024 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-39032406

RESUMO

Non-small cell lung cancer (NSCLC) is the most common type of lung cancer and remains the leading cause of cancer deaths. Much progress has been made to treat NSCLC, however, only limited patients can benefit from current treatments. Thus, more efforts are needed to pursue novel molecular modalities for NSCLC treatment. It was demonstrated that pseudo-natural products (PNP) are a critical source for antitumor drug discovery. Herein, we describe a CH activation protocol for the expedient construction of a focused library utilizing the PNP rational design strategy. This protocol features a rhodium-catalyzed CH activation/ [4+2] annulation reaction between N-OAc-indole-2-carboxamide and alkynyl quinols, enabling facile access to diverse quinol substituted ß-carboline derivatives (31 examples). The anticancer activities were assessed in vitro against NSCLC cell line A549, yielding a potent antiproliferative ß-carboline derivative (8r) with an IC50 value of 0.8 ± 0.1 µM. Further investigation revealed that this compound could decrease the expression of Caspase 3, and increase the expression of autophagic protein Cyclin B1, thus markedly inducing autophagy and apoptosis. Mechanistic study suggested that 8r could be a potent anti-NSCLC agent through the AKT/mTOR signaling pathway in A549 cells. Moreover, the anticancer activities were also assessed against three other cancer cell lines, and 8r exhibits a broader inhibitory effect on cell proliferation in all cancer cell lines tested. These results indicated that carboline-based PNPs show great potential to induce cell autophagy and apoptosis, which serve as good leads for further drug discovery.


Assuntos
Antineoplásicos , Carbolinas , Proliferação de Células , Desenho de Fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Proteínas Proto-Oncogênicas c-akt , Transdução de Sinais , Serina-Treonina Quinases TOR , Humanos , Carbolinas/química , Carbolinas/farmacologia , Carbolinas/síntese química , Serina-Treonina Quinases TOR/metabolismo , Serina-Treonina Quinases TOR/antagonistas & inibidores , Antineoplásicos/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Proliferação de Células/efeitos dos fármacos , Relação Estrutura-Atividade , Transdução de Sinais/efeitos dos fármacos , Estrutura Molecular , Relação Dose-Resposta a Droga , Produtos Biológicos/farmacologia , Produtos Biológicos/química , Produtos Biológicos/síntese química , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral
10.
Bioorg Chem ; 151: 107676, 2024 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-39068716

RESUMO

Dual-specificity tyrosine phosphorylation-regulated kinase A (DYRK1A) is a potential drug target for diabetes. The DYRK1A inhibitor can promote ß cells proliferation, increase insulin secretion and reduce blood sugar in diabetes. In this paper, a series ß-carboline-cinnamic acid skeletal derivatives were designed, synthesized and evaluated to inhibit the activity of DYRK1A and promote pancreatic islet ß cell proliferation. Pharmacological activity showed that all of the compounds could effectively promote pancreatic islet ß cell proliferation at a concentration of 1 µM, and the cell viability of compound A1, A4 and B4 reached to 381.5 %, 380.2 % and 378.5 %, respectively. Compound A1, A4 and B4 could also inhibit the expression of DYRK1A better than positive drug harmine. Further mechanistic studies showed that compound A1, A4 and B4 could inhibit DYRK1A protein expression via promoting its degradation and thus enhancing the expression of proliferative proteins PCNA and Ki67. Molecular docking showed that ß-carboline scaffold of these three compounds was fully inserted into the ATP binding site and formed hydrophobic interactions with the active pocket. Besides, these three compounds were predicted to possess better drug-likeness properties using SwissADME. In conclusion, compounds A1, A4 and B4 were potent pancreatic ß cell proliferative agents as DYRK1A inhibitors and might serve as promising candidates for the treatment of diabetes.


Assuntos
Carbolinas , Proliferação de Células , Cinamatos , Relação Dose-Resposta a Droga , Desenho de Fármacos , Quinases Dyrk , Simulação de Acoplamento Molecular , Inibidores de Proteínas Quinases , Proteínas Serina-Treonina Quinases , Proteínas Tirosina Quinases , Proteínas Tirosina Quinases/antagonistas & inibidores , Proteínas Tirosina Quinases/metabolismo , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Proteínas Serina-Treonina Quinases/metabolismo , Carbolinas/farmacologia , Carbolinas/química , Carbolinas/síntese química , Proliferação de Células/efeitos dos fármacos , Relação Estrutura-Atividade , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Estrutura Molecular , Cinamatos/farmacologia , Cinamatos/química , Cinamatos/síntese química , Células Secretoras de Insulina/efeitos dos fármacos , Células Secretoras de Insulina/metabolismo , Hipoglicemiantes/farmacologia , Hipoglicemiantes/síntese química , Hipoglicemiantes/química , Humanos , Animais , Diabetes Mellitus/tratamento farmacológico , Diabetes Mellitus/metabolismo , Sobrevivência Celular/efeitos dos fármacos
11.
Int J Mol Sci ; 25(9)2024 May 02.
Artigo em Inglês | MEDLINE | ID: mdl-38732185

RESUMO

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 & derivados
12.
Molecules ; 29(15)2024 Jul 29.
Artigo em Inglês | MEDLINE | ID: mdl-39124974

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 , Humanos
13.
Molecules ; 29(18)2024 Sep 11.
Artigo em Inglês | MEDLINE | ID: mdl-39339297

RESUMO

The discovery of a lead compound against Candida albicans is urgently needed because of the lack of clinically available antifungal drugs and the increase in drug resistance. Herein, a ß-carboline alkaloid methylaervine (MET) exhibited potential activity against C. albicans (MIC = 16-128 µg/mL), no hemolytic toxicity, and a low tendency to induce drug resistance. An antifungal mechanism study indicated that MET effectively inhibited the biofilm formation and disrupted the mature biofilm. Moreover, filamentation formation and spore germination were also weakened. The electron microscopy analysis revealed that MET could damage the cell structure, including the cell wall, membrane, and cytoplasm. In particular, the permeability and integrity of the cell membrane were destroyed. When it entered the fungi cell, it interfered with the redox homeostasis and DNA function. Overall, MET can inhibit the growth of C. albicans from multiple channels, such as biofilm, filamentation, cell structure, and intracellular targets, which are difficult to mutate at the same time to generate drug resistance. This work provides a promising lead compound for the creation of new antifungal agents against C. albicans.


Assuntos
Antifúngicos , Biofilmes , Candida albicans , Testes de Sensibilidade Microbiana , Candida albicans/efeitos dos fármacos , Candida albicans/crescimento & desenvolvimento , Antifúngicos/farmacologia , Antifúngicos/química , Biofilmes/efeitos dos fármacos , Carbolinas/farmacologia , Carbolinas/química , Membrana Celular/efeitos dos fármacos
14.
Molecules ; 29(19)2024 Sep 27.
Artigo em Inglês | MEDLINE | ID: mdl-39407516

RESUMO

The genus Lentzea is a prolific source of bioactive and structurally diverse secondary metabolites. We isolated a novel strain, Lentzea sp. JNUCC 0626, from Hwasun Gotjawal on Jeju Island, Korea. Based on 16S rRNA partial gene sequence analysis, strain JNUCC 0626 is closely related to Lentzea isolaginshaensis NX62 (99.41% similarity), Lentzea pudingi DHS C021 (99.31%), and Lentzea cavernae SYSU K10001 (99.26%). From the fermentation broth of JNUCC 0626, we isolated 1-acetyl-ß-carboline, whose structure was established using IR, HR-ESI-MS, and 1D- and 2D-NMR techniques. 1-acetyl-ß-carboline was found to activate melanogenesis in mouse B16F10 cells without cytotoxicity at concentrations up to 50 µM. At this concentration, the compound increased melanin content by 27.44% and tyrosinase activity by 240.64% compared to the control, by upregulating key melanogenic enzymes, including tyrosinase, TRP-1, TRP-2, and microphthalmia-associated transcription factor (MITF), a central regulator of melanogenesis. In addition, 1-acetyl-ß-carboline significantly inhibited ERK phosphorylation, reducing it by 20.79% at a concentration of 12.5 µM and by 25.63% at 25 µM. This inhibition supports the hypothesis that 1-acetyl-ß-carboline enhances melanin synthesis by upregulating MITF and melanogenic enzymes via the ERK signaling pathway. This study aimed to isolate and identify 1-acetyl-ß-carboline from a novel strain of Lentzea sp. JNUCC 0626, discovered in Gotjawal, Jeju Island, and to evaluate its effect on melanin production in B16F10 melanoma cells. Skin irritation tests on 32 subjects confirmed its safety for topical use, and the findings suggest that 1-acetyl-ß-carboline, which enhances melanogenesis without cytotoxicity, holds promise as a therapeutic agent for hypopigmentation-related conditions or as a cosmetic ingredient.


Assuntos
Carbolinas , Melaninas , Melanoma Experimental , Animais , Carbolinas/farmacologia , Carbolinas/química , Carbolinas/isolamento & purificação , Camundongos , Melaninas/biossíntese , Melaninas/metabolismo , Melanoma Experimental/tratamento farmacológico , Melanoma Experimental/patologia , Melanoma Experimental/metabolismo , Linhagem Celular Tumoral , Monofenol Mono-Oxigenase/metabolismo , Monofenol Mono-Oxigenase/antagonistas & inibidores , Monofenol Mono-Oxigenase/genética , Fator de Transcrição Associado à Microftalmia/metabolismo , Fator de Transcrição Associado à Microftalmia/genética
15.
Nat Chem Biol ; 17(3): 335-343, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33168978

RESUMO

Mitochondrial DNA (mtDNA) mutations are the major cause of mitochondrial diseases. Cells harboring disease-related mtDNA mutations exhibit various phenotypic abnormalities, such as reduced respiration and elevated lactic acid production. Induced pluripotent stem cell (iPSC) lines derived from patients with mitochondrial disease, with high proportions of mutated mtDNA, exhibit defects in maturation into neurons or cardiomyocytes. In this study, we have discovered a small-molecule compound, which we name tryptolinamide (TLAM), that activates mitochondrial respiration in cybrids generated from patient-derived mitochondria and fibroblasts from patient-derived iPSCs. We found that TLAM inhibits phosphofructokinase-1 (PFK1), which in turn activates AMPK-mediated fatty-acid oxidation to promote oxidative phosphorylation, and redirects carbon flow from glycolysis toward the pentose phosphate pathway to reinforce anti-oxidative potential. Finally, we found that TLAM rescued the defect in neuronal differentiation of iPSCs carrying a high ratio of mutant mtDNA, suggesting that PFK1 represents a potential therapeutic target for mitochondrial diseases.


Assuntos
Amidas/farmacologia , Carbolinas/farmacologia , Fibroblastos/efeitos dos fármacos , Células-Tronco Pluripotentes Induzidas/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Fosfofrutoquinase-1/genética , Proteínas Quinases Ativadas por AMP/genética , Proteínas Quinases Ativadas por AMP/metabolismo , Amidas/química , Carbolinas/química , Diferenciação Celular/efeitos dos fármacos , Respiração Celular/efeitos dos fármacos , Respiração Celular/genética , Quimera/genética , Quimera/metabolismo , DNA Mitocondrial/genética , DNA Mitocondrial/metabolismo , Fibroblastos/metabolismo , Fibroblastos/patologia , Regulação da Expressão Gênica , Glicólise/efeitos dos fármacos , Glicólise/genética , Células HEK293 , Células HeLa , Humanos , Células-Tronco Pluripotentes Induzidas/metabolismo , Células-Tronco Pluripotentes Induzidas/patologia , Mitocôndrias/genética , Mitocôndrias/metabolismo , Mitocôndrias/patologia , Doenças Mitocondriais/tratamento farmacológico , Doenças Mitocondriais/genética , Doenças Mitocondriais/metabolismo , Doenças Mitocondriais/patologia , Mutação , Neurônios/metabolismo , Neurônios/patologia , Fosforilação Oxidativa/efeitos dos fármacos , Via de Pentose Fosfato/genética , Fosfofrutoquinase-1/antagonistas & inibidores , Fosfofrutoquinase-1/metabolismo
16.
Photochem Photobiol Sci ; 22(3): 487-501, 2023 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-36402936

RESUMO

Harmaline (1) and harmalol (2) represent two 3,4-dihydro-ß-carboline (DHßCs) most frequently reported in a vast number of living systems. Fundamental aspects including the photosensitizing properties, cellular uptake, as well as the cyto- and phototoxicity of 1 and 2 were investigated herein. The molecular basis underlying the investigated processes are elucidated. Data reveal that both alkaloids show a distinctive pattern of extracellular DNA photodamage. Compound 1 induces a DNA photodamage profile dominated by oxidised purines and sites of base loss (AP sites), whereas 2 mostly induces single-strand breaks (SSBs) in addition to a small extent of purine oxidative damage. In both cases, DNA oxidative damage would occur through type I mechanism. In addition, a concerted hydrolytic attack is suggested as an extra mechanism accounting for the SSBs formation photoinduced by 2. Subcellular internalisation, cyto- and phototoxicity of 1 and 2 and the corresponding full-aromatic derivatives harmine (3) and harmol (4) also showed quite distinctive patterns in a structure-dependent manner. These results are discussed in the framework of the potential biological, biomedical and/or pharmacological roles reported for these alkaloids. The subtle structural difference (i.e., the exchange of a methoxy group for a hydroxyl substituent at C(7)) between harmaline and harmalol, gives rise to distinctive photosensitizing and subcellular localisation patterns.


Assuntos
Alcaloides , Harmalina , Harmalina/farmacologia , Harmalina/química , Carbolinas/farmacologia , Carbolinas/química , DNA
17.
Bioorg Chem ; 133: 106401, 2023 04.
Artigo em Inglês | MEDLINE | ID: mdl-36746025

RESUMO

Bis-ß-carboline alkaloids are widely distributed in natural products and represent a promising drug-like scaffold for discovering drugs and bioactive molecules. In this study, we utilized the structural simplification strategy to construct a novel bis-ß-carboline scaffold via "one-pot" condensation-Mannich reaction. The simplified bis-ß-carboline derivatives were obtained in good yield. Antitumor evaluation revealed most compounds, especially 3m, displayed potent antitumor activity (IC50 values for 3m: 0.96 µM âˆ¼ 1.52 µM). More importantly, 3m displayed valuable antitumor properties including anti-migration and anti-invasion activity against cancer cells, antiangiogenic and vascular-disrupting properties. Mechanistic studies revealed 3m potently inhibited both Top1 and Top2 activity, thus interfering with DNA synthesis in cancer cells. Taken together, this study developed a new synthetic methodology to construct a novel bis-ß-carboline scaffold, which represents a promising lead structure for antitumor drug discovery.


Assuntos
Alcaloides , Antineoplásicos , Carbolinas , Alcaloides/farmacologia , Alcaloides/química , Antineoplásicos/farmacologia , Antineoplásicos/química , Carbolinas/farmacologia , Carbolinas/química , Estrutura Molecular , Relação Estrutura-Atividade
18.
Bioorg Chem ; 131: 106313, 2023 02.
Artigo em Inglês | MEDLINE | ID: mdl-36516521

RESUMO

In a quest for effective cancer targeted drug therapy, a series of new ß-carboline tethered indole-3-glyoxylamide derivatives, conjoining salient pharmacophoric properties with prominent cytotoxicity, were synthesized. The in vitro cytotoxic ability of the compounds was established, and many of the compounds exhibited remarkable cytotoxicity (IC50 < 10 µM) on human cancer cell lines like HCT116, A549, SK-MEL-28, and MCF7. Precisely, compound 12x expressed the best cytotoxic potential against melanoma cancer cell line (SK-MEL-28) with an IC50 value of 4.37 µM. In addition, cytotoxicity evaluation against normal kidney cell line (NRK52E) entrenched the cytospecificity and selectivity index of 12x. The traditional apoptosis assays advised morphological and nuclear alterations such as apoptotic body formation, condensed/horseshoe-shaped/fragmented nuclei, and generation of ROS. The flow cytometric analysis revealed significant early and slight late-stage induction of apoptosis. The target-based physiochemical assays indicated the ability of compound 12x to bind with DNA and inhibition of Topoisomerase II. Moreover, molecular modeling studies affirm the excellent DNA intercalation potential and stabilized interactions of 12x with DNA base pairs. In silico prediction of physicochemical parameters revealed the promising drug-like properties of the synthesized derivatives.


Assuntos
Antineoplásicos , Neoplasias , Humanos , Estrutura Molecular , Relação Estrutura-Atividade , DNA/química , Antineoplásicos/química , Carbolinas/farmacologia , Carbolinas/química , Simulação por Computador , DNA Topoisomerases Tipo II/metabolismo , Ensaios de Seleção de Medicamentos Antitumorais , Proliferação de Células , Apoptose , Linhagem Celular Tumoral
19.
Arch Pharm (Weinheim) ; 356(7): e2300091, 2023 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-37021551

RESUMO

As flavin adenine dinucleotide (FAD)-dependent enzymes, monoamine oxidases (MAOs) catalyze the oxidative deamination of various endogenous and exogenous amines. MAO-A inhibitors are thought to be effective therapeutic agents for treating neurological diseases including depression and anxiety. Due to the academic challenge of developing new human (h) MAO-A inhibitors and the potential for discovering substances with remarkable properties compared to existing MAO-A inhibitors, numerous research groups are looking into novel classes of chemical compounds that may function as selective hMAO-A inhibitors. ß-Carbolines are reported to be a prominent class of bioactive molecules exhibiting MAO-A inhibition. Chemically, ß-carboline is a tricyclic pyrido-3,4-indole ring. It has only recently been discovered that this chemotype has highly effective and specific MAO-A inhibitory activity. In this review, structure-activity relationship studies included in particular research publications from the 1960s to the present are discussed with regard to ß-carboline and its analogs. This comprehensive information helps to design and develop a new family of MAO-A inhibitors for the management of depressive disorders.


Assuntos
Inibidores da Monoaminoxidase , Monoaminoxidase , Humanos , Inibidores da Monoaminoxidase/farmacologia , Inibidores da Monoaminoxidase/química , Relação Estrutura-Atividade , Monoaminoxidase/metabolismo , Carbolinas/farmacologia , Carbolinas/química
20.
Bioorg Med Chem Lett ; 59: 128546, 2022 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-35031451

RESUMO

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.


Assuntos
Carbolinas/farmacologia , Schistosoma mansoni/efeitos dos fármacos , Sulfonamidas/farmacologia , Animais , Carbolinas/síntese química , Carbolinas/química , Relação Dose-Resposta a Droga , Estrutura Molecular , Relação Estrutura-Atividade , Sulfonamidas/síntese química , Sulfonamidas/química
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