RESUMO
Although cancer and malaria are not etiologically nor pathophysiologically connected, due to their similarities successful repurposing of antimalarial drugs for cancer and vice-versa is known and used in clinical settings and drug research and discovery. With the growing resistance of cancer cells and Plasmodium to the known drugs, there is an urgent need to discover new chemotypes and enrich anticancer and antimalarial drug portfolios. In this paper, we present the design and synthesis of harmiprims, hybrids composed of harmine, an alkaloid of the ß-carboline type bearing anticancer and antiplasmodial activities, and primaquine, 8-aminoquinoline antimalarial drug with low antiproliferative activity, covalently bound via triazole or urea. Evaluation of their antiproliferative activities in vitro revealed that N-9 substituted triazole-type harmiprime was the most selective compound against MCF-7, whereas C1-substituted ureido-type hybrid was the most active compound against all cell lines tested. On the other hand, dimeric harmiprime was not toxic at all. Although spectrophotometric studies and thermal denaturation experiments indicated binding of harmiprims to the ds-DNA groove, cell localization showed that harmiprims do not enter cell nucleus nor mitochondria, thus no inhibition of DNA-related processes can be expected. Cell cycle analysis revealed that C1-substituted ureido-type hybrid induced a G1 arrest and reduced the number of cells in the S phase after 24 h, persisting at 48 h, albeit with a less significant increase in G1, possibly due to adaptive cellular responses. In contrast, N-9 substituted triazole-type harmiprime exhibited less pronounced effects on the cell cycle, particularly after 48 h, which is consistent with its moderate activity against the MCF-7 cell line. On the other hand, screening of their antiplasmodial activities against the erythrocytic, hepatic, and gametocytic stages of the Plasmodium life cycle showed that dimeric harmiprime exerts powerful triple-stage antiplasmodial activity, while computational analysis showed its binding within the ATP binding site of PfHsp90.
Assuntos
Antimaláricos , Antineoplásicos , Proliferação de Células , Ensaios de Seleção de Medicamentos Antitumorais , Harmina , Antimaláricos/farmacologia , Antimaláricos/química , Antimaláricos/síntese química , Humanos , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/síntese química , Harmina/farmacologia , Harmina/química , Harmina/síntese química , Proliferação de Células/efeitos dos fármacos , Relação Estrutura-Atividade , Plasmodium falciparum/efeitos dos fármacos , Estrutura Molecular , Descoberta de Drogas , Relação Dose-Resposta a Droga , Linhagem Celular Tumoral , Testes de Sensibilidade ParasitáriaRESUMO
Deregulation of dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A) plays a significant role in developmental brain defects, early-onset neurodegeneration, neuronal cell loss, dementia, and several types of cancer. Herein, we report the discovery of three new classes of N-heterocyclic DYRK1A inhibitors based on the potent, yet toxic kinase inhibitors, harmine and harmol. An initial inâ vitro evaluation of the small molecule library assembled revealed that the core heterocyclic motifs benzofuranones, oxindoles, and pyrrolones, showed statistically significant DYRK1A inhibition. Further, the utilization of a low cost, high-throughput functional genomic inâ vivo model system to identify small molecule inhibitors that normalize DYRK1A overexpression phenotypes is described. This inâ vivo assay substantiated the inâ vitro results, and the resulting correspondence validates generated classes as architectural motifs that serve as potential DYRK1A inhibitors. Further expansion and analysis of these core compound structures will allow discovery of safe, more effective chemical inhibitors of DYRK1A to ameliorate phenotypes caused by DYRK1A overexpression.
Assuntos
Proteínas de Drosophila/antagonistas & inibidores , Harmina/análogos & derivados , Harmina/farmacologia , Compostos Heterocíclicos/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Proteínas Tirosina Quinases/antagonistas & inibidores , Animais , Relação Dose-Resposta a Droga , Drosophila , Proteínas de Drosophila/genética , Proteínas de Drosophila/metabolismo , Desenho de Fármacos , Harmina/síntese química , Harmina/química , Compostos Heterocíclicos/síntese química , Compostos Heterocíclicos/química , Humanos , Estrutura Molecular , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Tirosina Quinases/genética , Proteínas Tirosina Quinases/metabolismo , Relação Estrutura-Atividade , Quinases DyrkRESUMO
As cancer remains one of the major health burdens worldwide, novel agents, due to the development of resistance, are needed. In this work, we designed and synthesized harmirins, which are hybrid compounds comprising harmine and coumarin scaffolds, evaluated their antiproliferative activity, and conducted cell localization and cell cycle analysis experiments. Harmirins were prepared from the corresponding alkynes and azides under mild reaction conditions using Cu(I) catalyzed azide-alkyne cycloaddition, leading to the formation of the 1H-1,2,3-triazole ring. Antiproliferative activity of harmirins was evaluated in vitro against four human cancer cell lines (MCF-7, HCT116, SW620, and HepG2) and one human non-cancer cell line (HEK293T). The most pronounced activities were exerted against MCF-7 and HCT116 cell lines (IC50 in the single-digit micromolar range), while the most selective harmirins were 5b and 12b, substituted at C-3 and O-7 of the ß-carboline core and bearing methyl substituent at position 6 of the coumarin ring (SIs > 7.2). Further experiments demonstrated that harmirin 12b is localized exclusively in the cytoplasm. In addition, it induced a strong G1 arrest and reduced the percentage of cells in the S phase, suggesting that it might exert its antiproliferative activity through inhibition of DNA synthesis, rather than DNA damage. In conclusion, harmirin 12b is a novel harmine and coumarin hybrid with significant antiproliferative activity and warrants further evaluation as a potential anticancer agent.
Assuntos
Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Cumarínicos/química , Harmina/síntese química , Harmina/farmacologia , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Técnicas de Química Sintética , Relação Dose-Resposta a Droga , Harmina/análogos & derivados , Humanos , Estrutura MolecularRESUMO
Alzheimer's disease (AD) is a chronic and progressive neurodegenerative disease, characterized by irreversible cognitive impairment, memory loss and behavioral disturbances, ultimately leading to death. Glycogen synthase kinase 3ß (GSK-3ß) and dual-specificity tyrosine phosphorylation regulated kinase1A (DYRK1A) have gained a lot of attention for its role in tau pathology. To search for potential dual GSK-3ß/DYRK1A inhibitors, we focused on harmine, a natural ß-carboline alkaloid, which has been extensively studied for its various biological effects on the prevention of AD. In this study, a new series of harmine derivatives were designed, synthesized and evaluated as dual GSK-3ß/DYRK1A inhibitors for their multiple biological activities. The in vitro results indicated that most of them displayed promising activity against GSK-3ß and DYRK1A. Among them, compound ZDWX-25 showed potent inhibitory effects on GSK-3ß and DYRK1A with IC50 values of 71 and 103 nM, respectively. Molecular modelling and kinetic studies verified that ZDWX-25 could interact with the ATP binding pocket of GSK-3ß and DYRK1A. Western blot analysis revealed that ZDWX-25 inhibited hyperphosphorylation of tau protein in okadaic acid (OKA)-induced SH-SY5Y cells. In addition, ZDWX-25 showed good blood-brain barrier penetrability in vitro. More importantly, ZDWX-25 could ameliorate the impaired learning and memory in APP/PS1/Tau transgenic mice. These results indicated that the harmine-based compounds could be served as promising dual-targeted candidates for AD.
Assuntos
Doença de Alzheimer/tratamento farmacológico , Glicogênio Sintase Quinase 3 beta/antagonistas & inibidores , Harmina/farmacologia , Fármacos Neuroprotetores/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Proteínas Tirosina Quinases/antagonistas & inibidores , Doença de Alzheimer/metabolismo , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Desenho de Fármacos , Glicogênio Sintase Quinase 3 beta/metabolismo , Harmina/síntese química , Harmina/química , Humanos , Modelos Moleculares , Estrutura Molecular , Fármacos Neuroprotetores/síntese química , Fármacos Neuroprotetores/química , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Tirosina Quinases/metabolismo , Relação Estrutura-Atividade , Quinases DyrkRESUMO
Recently, our group identified that harmine is able to induce ß-cell proliferation both in vitro and in vivo, mediated via the DYRK1A-NFAT pathway. Since, harmine suffers from a lack of selectivity, both against other kinases and CNS off-targets, we therefore sought to expand structure-activity relationships for harmine's DYRK1A activity, to enhance selectivity for off-targets while retaining human ß-cell proliferation activity. We carried out optimization of the 9-N-position of harmine to synthesize 29 harmine-based analogs. Several novel inhibitors showed excellent DYRK1A inhibition and human ß-cell proliferation capability. An optimized DYRK1A inhibitor, 2-2c, was identified as a novel, efficacious in vivo lead candidate. 2-2c also demonstrates improved selectivity for kinases and CNS off-targets, as well as in vivo efficacy for ß-cell proliferation and regeneration at lower doses than harmine. Collectively, these findings demonstrate that 2-2c is a much improved in vivo lead candidate as compared to harmine for the treatment of diabetes.
Assuntos
Harmina/análogos & derivados , Harmina/farmacologia , Células Secretoras de Insulina/efeitos dos fármacos , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Proteínas Tirosina Quinases/antagonistas & inibidores , Animais , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Harmina/síntese química , Humanos , Células Secretoras de Insulina/citologia , Células Secretoras de Insulina/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Simulação de Acoplamento Molecular , Sistema Nervoso/efeitos dos fármacos , Sistema Nervoso/metabolismo , Inibidores de Proteínas Quinases/síntese química , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Tirosina Quinases/metabolismo , Ratos Wistar , Quinases DyrkRESUMO
Previously, we reported for the first time that harmala alkaloids harmine and tetrahydroharmine exhibit activity against plant viruses, and we developed an analogue, designated NK0209, that efficiently prevents and controls plant virus diseases. Here, to investigate the influence of the spatial configuration of NK0209 on its antiviral activities, we synthesized its four optical isomers, determined their configurations, and evaluated their activities against tobacco mosaic virus. All four isomers were significantly more active than ningnanmycin, which is one of the most successful commercial antiviral agents, with in vivo inactivation, cure, and protection rates of 57.3 ± 1.9, 54.2 ± 3.3, and 55.0 ± 4.1% at 500 µg/mL. Furthermore, analysis of structure-activity relationships demonstrated for the first time that the spatial conformation of NK0209 is an important determinant of its antiviral activity, and our results provide information about the possible optimum configuration for interaction of this molecule with its target protein.
Assuntos
Antivirais/química , Antivirais/farmacologia , Harmina/química , Harmina/farmacologia , Vírus de Plantas/efeitos dos fármacos , Vírus do Mosaico do Tabaco/efeitos dos fármacos , Antivirais/síntese química , Desenho de Fármacos , Harmina/síntese química , Isomerismo , Conformação Molecular , Doenças das Plantas/virologia , Vírus de Plantas/crescimento & desenvolvimento , Relação Estrutura-Atividade , Vírus do Mosaico do Tabaco/crescimento & desenvolvimentoRESUMO
Mycobacterium tuberculosis is still the deadliest bacterial pathogen worldwide and the increasing number of multidrug-resistant tuberculosis cases further complicates this global health issue. M. tuberculosis phosphoserine phosphatase SerB2 is a promising target for drug design. Besides being a key essential metabolic enzyme of the pathogen's serine pathway, it appears to be involved in immune evasion mechanisms. In this work, a malachite green-based phosphatase assay has been used to screen 122 compounds from an internal chemolibrary. Trisubstituted harmine derivatives were found among the best hits that inhibited SerB2 activity. Synthesis of an original compound helped to discuss a brief structure activity relationship evaluation. Kinetics experiments showed that the most potent derivatives inhibit the phosphatase in a parabolic competitive fashion with apparent inhibition constants ( K i ) values in the micromolar range. Their interaction modes with the enzyme were investigated through induced fit docking experiments, leading to results consistent with the experimental data. Cellular assays showed that the selected compounds also inhibited M. tuberculosis growth in vitro. Those promising results may provide a basis for the development of new antimycobacterial agents targeting SerB2.
Assuntos
Reposicionamento de Medicamentos , Inibidores Enzimáticos/farmacologia , Harmina/farmacologia , Mycobacterium tuberculosis/efeitos dos fármacos , Monoéster Fosfórico Hidrolases/antagonistas & inibidores , Antituberculosos/síntese química , Antituberculosos/química , Antituberculosos/farmacologia , Avaliação Pré-Clínica de Medicamentos , Inibidores Enzimáticos/análise , Inibidores Enzimáticos/síntese química , Harmina/síntese química , Harmina/química , Cinética , Testes de Sensibilidade Microbiana , Simulação de Acoplamento Molecular , Monoéster Fosfórico Hidrolases/metabolismo , TermodinâmicaRESUMO
Harmicines constitute novel hybrid compounds that combine two agents with reported antiplasmodial properties, namely ß-carboline harmine and a cinnamic acid derivative (CAD). Cu(I) catalyzed azide-alkyne cycloaddition was employed for the preparation of three classes of hybrid molecules: N-harmicines 6a-i, O-harmicines 7a-i and N,O-bis-harmicines 8a-g,i. In vitro antiplasmodial activities of harmicines against the erythrocytic stage of Plasmodium falciparum (chloroquine-sensitive Pf3D7 and chloroquine-resistant PfDd2 strains) and hepatic stage of P. berghei, as well as cytotoxicity against human liver hepatocellular carcinoma cell line (HepG2), were evaluated. Remarkably, most of the compounds exerted significant activities against both stages of the Plasmodium life cycle. The conjugation of various CADs to harmine resulted in the increased antiplasmodial activity relative to harmine. In general, O-harmicines 7 exhibited the highest activity against the erythrocytic stage of both P. falciparum strains, whereas N,O-bis harmicines 8 showed the most pronounced activity against P. berghei hepatic stages. For the latter compound, molecular dynamics simulations confirmed binding within the ATP binding site of PfHsp90, while the weaker binders, namely 6b and harmine, were found to be positioned away from this structural element. In addition, decomposition of the computed binding free energies into contributions from individual residues suggested guidelines for further derivatization of harmine towards more efficient compounds. Cytotoxicity screening revealed N-harmicines 6 as the least, and O-harmicines 7 as the most toxic compounds. Harmicines 6g, 8b and 6d exerted the most selective action towards Plasmodium over human cells, respectively. These results establish harmicines as hits for future optimisation and development of novel antiplasmodial agents.
Assuntos
Antimaláricos/farmacologia , Cinamatos/farmacologia , Harmina/farmacologia , Alcaloides Indólicos/farmacologia , Plasmodium berghei/efeitos dos fármacos , Plasmodium falciparum/efeitos dos fármacos , Antimaláricos/síntese química , Antimaláricos/química , Cinamatos/síntese química , Cinamatos/química , Relação Dose-Resposta a Droga , Harmina/síntese química , Harmina/química , Alcaloides Indólicos/síntese química , Alcaloides Indólicos/química , Simulação de Dinâmica Molecular , Estrutura Molecular , Testes de Sensibilidade Parasitária , Relação Estrutura-AtividadeRESUMO
Thirty-three new quaternization harman analogues were synthesized and their antibacterial activity against four Gram-positive and two Gram-negative bacteria were evaluated. The structure-activity relationships were summarized and compounds 4f, 4i, 4l, 4u, 4w, 4x and 5c showed excellent antibacterial activity, low cytotoxicity, good thermal stability and "drug-like" properties. In particular, compound 4x exhibited better bactericidal effect (4-fold superiority against methicillin-resistant Staphylococcus aureus) than standard drugs fosfomycin sodium and ampicillin sodium (minimum inhibitory concentrationâ¯=â¯50â¯nmol/mL). Scanning electron microscopy revealed morphological changes of the bacterial cell surface and the docking evaluation provided a good total score (6.4952) for 4x which is close to the score of ciprofloxacin (6.9723). The results indicated that the quaternization harman analogues might exert their bactericidal effect by damaging bacterial cell membrane and wall, and disrupting the function of type II topoisomerase. In addition, the in vivo antibacterial assay with a protective efficacy of 81.3% further demonstrated the potential of these derivatives as new bactericides and antibiotics.
Assuntos
Antibacterianos/farmacologia , Desenho de Fármacos , Harmina/análogos & derivados , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Antibacterianos/síntese química , Antibacterianos/química , Membrana Celular/efeitos dos fármacos , Parede Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Harmina/síntese química , Harmina/química , Harmina/farmacologia , Staphylococcus aureus Resistente à Meticilina/citologia , Testes de Sensibilidade Microbiana , Estrutura Molecular , Relação Estrutura-AtividadeRESUMO
AIM: There is little information available on the monoamine oxidase isoform selectivity of N-alkyl harmine analogs, which exhibit a myriad of activities including MAO-A, DYRK1A and cytotoxicity to several select cancer cell lines. RESULTS: Compounds 3e and 4c exhibited an IC50 of 0.83 ± 0.03 and 0.43 ± 0.002 µM against MAO-A and an IC50 of 0.26 ± 0.04 and 0.36 ± 0.001 µM against MAO-B, respectively. Molecular docking studies revealed π-π interactions between the synthesized molecules and aromatic amino acid residues. Conclusion & future perspective: The current study delineates the structural requirements for MAO-A selectivity and such information may be helpful in designing selective analogs for kinase, DYRK1A and harmine-based cytotoxics without apparent MAO enzyme inhibition.
Assuntos
Harmina/análogos & derivados , Harmina/farmacologia , Inibidores da Monoaminoxidase/química , Inibidores da Monoaminoxidase/farmacologia , Monoaminoxidase/metabolismo , Triazóis/química , Triazóis/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/farmacologia , Química Click , Harmina/síntese química , Humanos , Cinética , Simulação de Acoplamento Molecular , Inibidores da Monoaminoxidase/síntese química , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Isoformas de Proteínas/antagonistas & inibidores , Isoformas de Proteínas/metabolismo , Relação Estrutura-Atividade , Triazóis/síntese químicaRESUMO
Harmine, one of the natural ß-carboline alkaloids extracted from Peganum harmala L., exhibits broad spectrum but limited insecticidal ability against many pests. So there is an urgent need to synthesize novel derivatives with high efficiency. In the present study, a new synthetic compound, [1-(2-naphthyl)-3-(2-thioxo-1,3,4-oxadiazol-5-yl) ß-carboline] (ZC-14), showed a strong proliferation inhibition effect against the Spodoptera frugiperda Sf9 cell line in a dose-dependent manner. Simultaneously, apoptosis induced by 7.5 µg/mL ZC-14 was confirmed with physiological and biochemical evidence, including typical apoptosis characteristics with shrinkage, apoptotic bodies, nuclear condensation/fragmentation, a clear DNA ladder, and a series of apoptotic rates. In addition, mitochondria were confirmed to be involved in apoptosis induced by ZC-14 accompanied with the loss of mitochondrial membrane potential (Δψm), the release of cytochrome c from mitochondria into the cytosol and increased expression of cleaved-caspase-3. However, harmine could not induce apoptosis at the same concentration. In summary, these data indicated that compound ZC-14 has a higher cytotoxicity than harmine against Sf9 cells. Besides, it exhibited an anti-proliferative effect in Sf9 cells via inducing apoptosis in which the mitochondrial apoptotic pathway plays a crucial role.
Assuntos
Apoptose/efeitos dos fármacos , Citotoxinas/toxicidade , Harmina/análogos & derivados , Animais , Proliferação de Células/efeitos dos fármacos , Citotoxinas/síntese química , Harmina/síntese química , Harmina/toxicidade , Potencial da Membrana Mitocondrial , Mitocôndrias/efeitos dos fármacos , Células Sf9 , SpodopteraRESUMO
Dual-specificity tyrosine-phosphorylation-regulated kinaseâ 1A (DYRK1A) is an emerging biological target with implications in diverse therapeutic areas such as neurological disorders (Down syndrome, in particular), metabolism, and oncology. Harmine, a natural product that selectively inhibits DYRK1A amongst kinases, could serve as a tool compound to better understand the biological processes that arise from DYRK1A inhibition. On the other hand, harmine is also a potent inhibitor of monoamine oxidaseâ A (MAO-A). Using structure-based design, we synthesized a collection of harmine analogues with tunable selectivity toward these two enzymes. Modifications at the 7-position typically decreased affinity for DYRK1A, whereas substitution at the 9-position had a similar effect on MAO-A inhibition but DYRK1A inhibition was maintained. The resulting collection of compounds can help to understand the biological role of DYRK1A and also to assess the interference in the biological effect originating in MAO-A inhibition.
Assuntos
Desenho de Fármacos , Harmina/farmacologia , Inibidores da Monoaminoxidase/farmacologia , Monoaminoxidase/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Tirosina Quinases/metabolismo , Relação Dose-Resposta a Droga , Harmina/síntese química , Harmina/química , Humanos , Modelos Moleculares , Estrutura Molecular , Inibidores da Monoaminoxidase/síntese química , Inibidores da Monoaminoxidase/química , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Relação Estrutura-Atividade , Quinases DyrkRESUMO
BACKGROUND: The emergence of artemisinin-resistant Plasmodium falciparum strains poses a serious challenge to the control of malaria. This necessitates the development of new anti-malarial drugs. Previous studies have shown that the natural beta-carboline alkaloid harmine is a promising anti-malarial agent targeting the P. falciparum heat-shock protein 90 (PfHsp90). The aim of this study was to test the anti-malarial activity of harmine analogues. METHODS: Forty-two harmine analogues were synthesized and the binding of these analogues to P. falciparum heat shock protein 90 was investigated. The in vitro anti-malarial activity of two of the analogues, 17A and 21A, was evaluated using a 72-h growth inhibition assay. The in vivo anti-malarial activity was tested in Plasmodium berghei infection of BALB/c mice. The potential of 21A for a combination treatment with artemisinin was evaluated using in vivo combination study with dihydro-artemisinin in BALB/c mice. Cytotoxicity of the harmine analogues was tested in vitro using HepG2 and HeLa cell lines. RESULTS: 17A and 21A bound to PfHsp90 with average IC50 values of 12.2 ± 2.3 and 23.1 ± 8.8 µM, respectively. They also inhibited the P. falciparum W2 strain with average IC50 values of 4.2 ± 1.3 and 5.7 ± 1.7 µM, respectively. In vivo, three daily injections of P. berghei-infected BALB/c mice with 100 mg/kg of either 17A or 21A showed significant reduction in parasitaemia with a 51.5 and 56.1% reduction, respectively. Mice treated with 17A and 21A showed a median survival time of 11 and 14 days, respectively, while the vehicle control mice survived a median of only 8.5 days. A dose-ranging experiment with 21A showed that the compound has a dose-dependent anti-malarial effect. Furthermore, treatment of infected mice with a combination of 21A and dihydroartemisinin (DHA) showed a dramatic reduction in parasitaemia compared to treatment with DHA alone. CONCLUSION: A novel and non-toxic harmine analogue has been synthesized which binds to PfHsp90 protein, inhibits P. falciparum in vitro at micromolar concentration, reduces parasitaemia and prolongs survival of P. berghei-infected mice with an additive anti-malarial effect when combined with DHA.
Assuntos
Antimaláricos/farmacologia , Artemisininas/farmacologia , Sinergismo Farmacológico , Proteínas de Choque Térmico HSP90/antagonistas & inibidores , Harmina/farmacologia , Plasmodium berghei/efeitos dos fármacos , Plasmodium falciparum/efeitos dos fármacos , Animais , Antimaláricos/administração & dosagem , Antimaláricos/síntese química , Antimaláricos/química , Artemisininas/administração & dosagem , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Modelos Animais de Doenças , Feminino , Harmina/administração & dosagem , Harmina/síntese química , Harmina/química , Humanos , Concentração Inibidora 50 , Malária/tratamento farmacológico , Camundongos Endogâmicos BALB C , Plasmodium falciparum/crescimento & desenvolvimento , Ligação Proteica , Proteínas de Protozoários/antagonistas & inibidores , Resultado do TratamentoRESUMO
A series of novel harmine derivatives bearing a benzylindine substituent in position-1 of ß-carboline ring were synthesized and evaluated as antitumor agents. The N2-benzylated ß-carboline derivatives 3a-g represented the most interesting anticancer activities and compound 3c was found to be the most active agent to diverse cancer cell lines such as gastric carcinoma, melanoma and colorectal cancer. Notably, compound 3c showed low toxicity to normal cells. The treatment significantly induced cell apoptosis. Mechanistically, PI3K/AKT signaling pathway mediated compound 3c-induced apoptosis. Compound 3c inhibited phosphorylation of AKT and promoted the production of reactive oxygen species (ROS). The ROS scavenger, LNAC and GSH, could disturb the effect of compound 3c induced apoptosis and PI3K activity inhibitor LY294002 synergistically enhanced compound 3c efficacy. Moreover, the results from nude mice xenograft model showed that compound 3c treatment effectively inhibited tumor growth and decreased tumor weight. Collectively, our results demonstrated that compound 3c exerts apoptotic effect in cancer cells via suppression of phosphorylated AKT and evocation of ROS generation, which suggested that compound 3c might be served as a promising therapeutic agent for cancer treatment.
Assuntos
Antineoplásicos , Harmina , Neoplasias/tratamento farmacológico , Células A549 , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/farmacologia , Cromonas , Harmina/análogos & derivados , Harmina/síntese química , Harmina/química , Harmina/farmacologia , Células HeLa , Células Hep G2 , Humanos , Camundongos , Camundongos Nus , Morfolinas , Neoplasias/metabolismo , Neoplasias/patologia , Fosfatidilinositol 3-Quinases/metabolismo , Inibidores de Fosfoinositídeo-3 Quinase , Proteínas Proto-Oncogênicas c-akt/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
A series of N(9)-substituted harmine derivatives were synthesized and evaluated for their anticancer activity on a panel of cancer cell lines, their apoptosis induction and their cell cycle effects. The results showed that N(9)-substituted harmine derivatives had anticancer effects. In particular, N(9)-haloalkyl derivatives 9a-9c and N(9)-acyl harmine derivatives 11c and 11d, with IC50 values less than 1µM, were more potent than doxorubicin against A-549 and/or MCF-7 cell lines. Moreover, structure-activity relationships (SARs) indicated that introducing a haloalkyl or benzenesulfonyl group in the N(9)-position of harmine could significantly increase the anticancer activity. The most active compound (11d) caused cell cycle arrest in the G2/M phase, and induced cell apoptosis in a dose-dependent manner.
Assuntos
Antineoplásicos/síntese química , Harmina/química , Células A549 , Antineoplásicos/química , Antineoplásicos/toxicidade , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Ensaios de Seleção de Medicamentos Antitumorais , Pontos de Checagem da Fase G2 do Ciclo Celular/efeitos dos fármacos , Harmina/síntese química , Harmina/toxicidade , Humanos , Pontos de Checagem da Fase M do Ciclo Celular/efeitos dos fármacos , Células MCF-7 , Relação Estrutura-AtividadeRESUMO
We synthesized two series of new hydrazide harmine derivatives. The reaction of harmine 1 with ethyl acetate chloride afforded the corresponding ethyl ester 2. The treatment of 2 with hydrazine hydrate gave the hydrazide 3 which further converted into hydrazones 4a-j and dihydrazides 5a-c. A series of new triazoles 7a-f has also been prepared from the suitable propargyl harmine 6. The synthesized derivatives were characterized by 1H-NMR, 13C-NMR, and HRMS and evaluated for their activities against MCF7, HCT116 OVCAR-3, acetylcholinesterase and 5-lipoxygenase. The most hydrazones derivatives 4a-j have a good cytotoxic activity against all cell lines, when 4a, 4d, 4f and 4 g are more active than 1 (against OVCAR-3 IC50 16.7-2.5 µM). The compound 6 was the most active (IC50 = 1.9 µM) against acetylcholinesterase. Some compounds exhibited significant activity against 5-lipoxygenase (IC50 = 30.9-63.1 µM).
Assuntos
Acetilcolinesterase/metabolismo , Antineoplásicos/farmacologia , Inibidores da Colinesterase/farmacologia , Harmina/análogos & derivados , Inibidores de Lipoxigenase/farmacologia , Lipoxigenase/metabolismo , Antineoplásicos/síntese química , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/química , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Harmina/síntese química , Harmina/química , Humanos , Inibidores de Lipoxigenase/síntese química , Inibidores de Lipoxigenase/química , Estrutura Molecular , Relação Estrutura-AtividadeRESUMO
Harmine 1 was extracted from the seeds of Peganum harmala. From this natural molecule, a new series of isoxazole derivatives with complete regiospecificity were prepared using 1,3-dipolar cycloaddition reactions with various arylnitrile oxides. Harmine and its derivatives were characterized by (1)H NMR, (13)C NMR and HRMS. The evaluation of their anti-acetylcholinesterase (AChE), anti-5-lipoxygenase (5-LOX), anti-xanthine oxidase (XOD) and anticancer activities were studied in vitro against AChE, 5-LOX and XOD enzymes, respectively, and in HTC-116, MCF7 and OVCAR-3 cancer cell lines. The prepared derivatives were shown to be inactive against the XOD enzyme (0-38.3 ± 1.9% at 100 µM). Compound 2 exhibited the best anti-AChE activity (IC50=1.9 ± 1.5 µM). Derivatives 3a, 3b and 3d had moderate cytotoxic activities (IC50=5.0 ± 0.3 µM (3a) and IC50=6.3 ± 0.4 µM (3b) against HCT 116 cells, IC50=5.0 ± 1.0 µM (3d) against MCF7 cells).
Assuntos
Doença de Alzheimer/tratamento farmacológico , Anti-Inflamatórios não Esteroides/farmacologia , Antineoplásicos/farmacologia , Harmina/análogos & derivados , Harmina/farmacologia , Isoxazóis/farmacologia , Anti-Inflamatórios não Esteroides/síntese química , Antineoplásicos/síntese química , Espectroscopia de Ressonância Magnética Nuclear de Carbono-13 , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/farmacologia , Reação de Cicloadição , Células HCT116 , Harmina/síntese química , Humanos , Isoxazóis/síntese química , Inibidores de Lipoxigenase/síntese química , Inibidores de Lipoxigenase/farmacologia , Células MCF-7 , Peganum , Espectroscopia de Prótons por Ressonância Magnética , Relação Estrutura-Atividade , Tamoxifeno/farmacologia , Xantina Oxidase/antagonistas & inibidoresRESUMO
Iodobenzene diacetate was employed as a mild and efficient reagent for one-pot oxidative decarboxylation of tetrahydro-ß-carboline acids and dehydrogenation of tetrahydro-ß-carbolines to access the corresponding aromatic ß-carbolines. To the best of our knowledge this is the first synthesis of ß-carbolines via a one-pot oxidative decarboxylation at ambient temperature. The utility of this protocol has been demonstrated in the synthesis of ß-carboline alkaloids norharmane (2o), harmane (2p), eudistomin U (9) and eudistomin I (12).
Assuntos
Acetatos/química , Carbolinas/química , Carbolinas/síntese química , Harmina/análogos & derivados , Iodobenzenos/química , Descarboxilação , Harmina/síntese química , Harmina/química , Estrutura Molecular , OxirreduçãoRESUMO
Harmine is a beta-carboline alkaloid found in medicinal plant PeganumHarmala, which has served as a folk anticancer medicine. However, clinical applications of harmine were limited by its low pharmacological effects and noticeable neurotoxicity. In this study, we modified harmine to increase the therapeutic efficacy and to decrease the systemic toxicity. Specifically, two tumor targeting harmine derivatives 2DG-Har-01 and MET-Har-02 were synthesized by modifying substituent in position-2, -7 and -9 of harmine ring with two different targeting group2-amino-2-deoxy-D-glucose (2DG) and Methionine (Met), respectively. Their therapeutic efficacy and toxicity were investigated both in vitro and in vivo. Results suggested that the two new harmine derivatives displayed much higher therapeutic effects than non-modified harmine. In particular, MET-Har-02 was more potent than 2DG-Har-01 with promising potential for targeted cancer therapy.
Assuntos
Antineoplásicos/uso terapêutico , Harmina/análogos & derivados , Terapia de Alvo Molecular , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/farmacologia , Antineoplásicos/toxicidade , Apoptose/efeitos dos fármacos , Divisão Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Forma Celular/efeitos dos fármacos , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Ensaios de Seleção de Medicamentos Antitumorais , Harmina/síntese química , Harmina/química , Harmina/farmacologia , Harmina/uso terapêutico , Harmina/toxicidade , Coração/efeitos dos fármacos , Humanos , Rim/efeitos dos fármacos , Pulmão/efeitos dos fármacos , Camundongos , Estrutura Molecular , Células PC12 , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Ratos , Ensaio Tumoral de Célula-TroncoRESUMO
A method to prepare 1-substituted N-Boc-tetrahydro-ß-carbolines was developed by lithiation followed by electrophilic substitution. The deprotonation to give the organolithium was optimized by in situ IR spectroscopy and showed that the Boc group rotates slowly at low temperature. The chemistry was applied to the synthesis of 9-methyleleagnine (N-methyltetrahydroharman) and 11-methylharmicine.