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1.
Int J Pharm ; : 121296, 2021 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-34793932

RESUMO

Treatment of acute myeloid leukaemia (AML) relies on decades-old drugs, and while recent years have seen some breakthroughs, AML is still characterised by poor prognosis and survival rate. Drug repurposing can expedite the preclinical development of new therapies, and by nanocarrier encapsulation, the number of potentially viable drug candidates can be further expanded. The anti-psychotic drug chlorpromazine (CPZ) has been identified as a candidate for repurposing for AML therapy. Nanoencapsulation may improve the suitability of CPZ for the treatment of AML by reducing its effect on the central nervous system. Using the emulsion-evaporation technique, we have developed PEGylated PLGA nanoparticles loaded with CPZ for AML therapy. The nanoparticles were characterised to be between 150 and 300 nm by DLS, of spherical morphology by TEM, with a drug loading of at least 6.0% (w/w). After an initial burst release of adsorbed drug, the remaining 80% of the drug was retained in the PLGA nanoparticles for at least 24 hours. The CPZ-loaded nanoparticles had equal cytotoxic potential towards AML cells to free CPZ, but acted more slowly, in line with the protracted drug release. Crucially, nanoparticles injected intravenously into zebrafish larvae did not accumulate in the brain, and nanoencapsulation also prevented CPZ from crossing an artificial membrane model. This demonstrates that the purpose for nanoencapsulation of CPZ is fulfilled, namely avoiding effects on the central nervous system while retaining the anti-AML activity of the drug.

2.
ACS Omega ; 6(38): 24619-24629, 2021 Sep 28.
Artigo em Inglês | MEDLINE | ID: mdl-34604644

RESUMO

Graphene-based drug carriers provide a promising addition to current cancer drug delivery options. Increased accessibility of high-quality graphene made by plasma-enhanced chemical vapor deposition (PE-CVD) makes it an attractive material to revisit in comparison to the widely studied graphene oxide (GO) in drug delivery. Here, we show the potential of repurposing the metabolic drug phenformin for cancer treatment in terms of stability, binding, and pH-responsive release. Using covalent attachment of poly(ethylene glycol) (PEG) onto pristine (PE-CVD) graphene, we show that PEG stabilized graphene nanosheets (PGNS) are stable in aqueous solutions and exhibit higher binding affinity toward phenformin than GO. Moreover, we experimentally demonstrate an improved drug release from PGNS than GO at pH levels lower than physiological conditions, yet comparable to that found in tumor microenvironments.

3.
Physiol Plant ; 173(2): 612-623, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34085279

RESUMO

In addition to the rapidly expanding field of using microalgae for food and feed, microalgae represent a tremendous potential for new bioactive compounds with health-promoting effects. One field where new therapeutics is needed is cancer therapy. As cancer therapy often cause severe side effects and loose effect due to development of drug resistance, new therapeutic agents are needed. Treating cancer by modulating the immune response using peptides has led to unprecedented responses in patients. In this review, we want to elucidate the potential for microalgae as a source of new peptides for possible use in cancer management. Among the limited studies on anti-cancer effects of peptides, positive results were found in a total of six different forms of cancer. The majority of studies have been performed with different strains of Chlorella, but effects have also been found using peptides from other species. This is also the case for peptides with immunomodulating effects and peptides with other health-promoting effects (e.g., role in cardiovascular diseases). However, the active peptide sequence has been determined in only half of the studies. In many cases, the microalga strain and the cultivation conditions used for producing the algae have not been reported. The low number of species that have been explored, as opposed to the large number of species available, is a clear indication that the potential for new discoveries is large. Additionally, the availability and cost-effectiveness of microalgae make them attractive in the search for bioactive peptides to prevent cancer.


Assuntos
Chlorella , Microalgas , Sequência de Aminoácidos , Humanos , Peptídeos
4.
Physiol Plant ; 173(2): 639-650, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34145585

RESUMO

Cyanobacteria produce a variety of chemically diverse cyclic lipopeptides with potent antifungal activities. These cyclic lipopeptides have an amphipathic structure comprised of a polar peptide cycle and hydrophobic fatty acid side chain. Many have antibiotic activity against a range of human and plant fungal pathogens. This review article aims to summarize the present knowledge on the chemical diversity and cellular effects of cyanobacterial cyclic lipopeptides that display antifungal activity. Cyclic antifungal lipopeptides from cyanobacteria commonly fall into four structural classes; hassallidins, puwainaphycins, laxaphycins, and anabaenolysins. Many of these antifungal cyclic lipopeptides act through cholesterol and ergosterol-dependent disruption of membranes. In many cases, the cyclic lipopeptides also exert cytotoxicity in human cells, and a more extensive examination of their biological activity and structure-activity relationship is warranted. The hassallidin, puwainaphycin, laxaphycin, and anabaenolysin structural classes are unified through shared complex biosynthetic pathways that encode a variety of unusual lipoinitiation mechanisms and branched biosynthesis that promote their chemical diversity. However, the biosynthetic origins of some cyanobacterial cyclic lipopeptides and the mechanisms, which drive their structural diversification in general, remain poorly understood. The strong functional convergence of differently organized chemical structures suggests that the production of lipopeptide confers benefits for their producer. Whether these benefits originate from their antifungal activity or some other physiological function remains to be answered in the future. However, it is clear that cyanobacteria encode a wealth of new cyclic lipopeptides with novel biotechnological and therapeutic applications.


Assuntos
Antifúngicos , Cianobactérias , Antibacterianos , Antifúngicos/farmacologia , Lipopeptídeos/farmacologia , Peptídeos Cíclicos/farmacologia
5.
RSC Med Chem ; 12(5): 767-778, 2021 Apr 19.
Artigo em Inglês | MEDLINE | ID: mdl-34124675

RESUMO

Novel chemotherapeutic strategies for acute myeloid leukemia (AML) treatment are called for. We have recently demonstrated that the phenazine 5,10-dioxide natural products iodinin (3) and myxin (4) exhibit potent and hypoxia-selective cell death on MOLM-13 human AML cells, and that the N-oxide functionalities are pivotal for the cytotoxic activity. Very few structure-activity relationship studies dedicated to phenazine 5,10-dioxides exist on mammalian cell lines and the present work describes our efforts regarding in vitro lead optimizations of the natural compounds iodinin (3) and myxin (4). Prodrug strategies reveal carbamate side chains to be the optimal phenol-attached group. Derivatives with no oxygen-based substituent (-OH or -OCH3) in the 6th position of the phenazine skeleton upheld potency if alkyl or carbamate side chains were attached to the phenol in position 1. 7,8-Dihalogenated- and 7,8-dimethylated analogs of 1-hydroxyphenazine 5,10-dioxide (21) displayed increased cytotoxic potency in MOLM-13 cells compared to all the other compounds studied. On the other hand, dihalogenated compounds displayed high toxicity towards the cardiomyoblast H9c2 cell line, while MOLM-13 selectivity of the 7,8-dimethylated analogs were less affected. Further, a parallel artificial membrane permeability assay (PAMPA) demonstrated the majority of the synthesized compounds to penetrate cell membranes efficiently, which corresponded to their cytotoxic potency. This work enhances the understanding of the structural characteristics essential for the activity of phenazine 5,10-dioxides, rendering them promising chemotherapeutic agents.

6.
Physiol Plant ; 173(2): 507-513, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-33709388

RESUMO

NordAqua is a multidisciplinary Nordic Center of Excellence funded by NordForsk Bioeconomy program (2017-2022). The research center promotes Blue Bioeconomy and endeavours to reform the use of natural resources in a environmentally sustainable way. In this short communication, we summarize particular outcomes of the consortium. The key research progress of NordAqua includes (1) improving of photosynthetisis, (2) developing novel photosynthetic cell factories that function in a "solar-driven direct CO2 capture to target bioproducts" mode, (3) promoting the diversity of Nordic cyanobacteria and algae as an abundant and resilient alternative for less sustainable forest biomass and for innovative production of biochemicals, and (4) improving the bio-based wastewater purification and nutrient recycling technologies to provide new tools for integrative circular economy platforms.


Assuntos
Fotossíntese , Biomassa
7.
iScience ; 23(11): 101649, 2020 Nov 20.
Artigo em Inglês | MEDLINE | ID: mdl-33103086

RESUMO

The receptor tyrosine kinase AXL is associated with epithelial plasticity in several solid tumors including breast cancer and AXL-targeting agents are currently in clinical trials. We hypothesized that AXL is a driver of stemness traits in cancer by co-option of a regulatory function normally reserved for stem cells. AXL-expressing cells in human mammary epithelial ducts co-expressed markers associated with multipotency, and AXL inhibition abolished colony formation and self-maintenance activities while promoting terminal differentiation in vitro. Axl-null mice did not exhibit a strong developmental phenotype, but enrichment of Axl + cells was required for mouse mammary gland reconstitution upon transplantation, and Axl-null mice had reduced incidence of Wnt1-driven mammary tumors. An AXL-dependent gene signature is a feature of transcriptomes in basal breast cancers and reduced patient survival irrespective of subtype. Our interpretation is that AXL regulates access to epithelial plasticity programs in MaSCs and, when co-opted, maintains acquired stemness in breast cancer cells.

8.
Immun Inflamm Dis ; 8(3): 342-359, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32578964

RESUMO

BACKGROUND: Glioblastoma (GBM) is an aggressive malignant brain tumor where median survival is approximately 15 months after best available multimodal treatment. Recurrence is inevitable, largely due to O6 methylguanine DNA methyltransferase (MGMT) that renders the tumors resistant to temozolomide (TMZ). We hypothesized that pretreatment with bortezomib (BTZ) 48 hours prior to TMZ to deplete MGMT levels would be safe and tolerated by patients with recurrent GBM harboring unmethylated MGMT promoter. The secondary objective was to investigate whether 26S proteasome blockade may enhance differentiation of cytotoxic immune subsets to impact treatment responses measured by radiological criteria and clinical outcomes. METHODS: Ten patients received intravenous BTZ 1.3 mg/m2 on days 1, 4, and 7 during each 4th weekly TMZ-chemotherapy starting on day 3 and escalated from 150 mg/m2 per oral 5 days/wk via 175 to 200 mg/m2 in cycles 1, 2, and 3, respectively. Adverse events and quality of life were evaluated by CTCAE and EQ-5D-5L questionnaire, and immunological biomarkers evaluated by flow cytometry and Luminex enzyme-linked immunosorbent assay. RESULTS: Sequential BTZ + TMZ therapy was safe and well tolerated. Pain and performance of daily activities had greatest impact on patients' self-reported quality of life and were inversely correlated with Karnofsky performance status. Patients segregated a priori into three groups, where group 1 displayed stable clinical symptoms and/or slower magnetic resonance imaging radiological progression, expanded CD4+ effector T-cells that attenuated cytotoxic T-lymphocyte associated protein-4 and PD-1 expression and secreted interferon γ and tumor necrosis factor α in situ and ex vivo upon stimulation with PMA/ionomycin. In contrast, rapidly progressing group 2 patients exhibited tolerised T-cell phenotypes characterized by fourfold to sixfold higher interleukin 4 (IL-4) and IL-10 Th-2 cytokines after BTZ + TMZ treatment, where group 3 patients exhibited intermediate clinical/radiological responses. CONCLUSION: Sequential BTZ + TMZ treatment is safe and promotes Th1-driven immunological responses in selected patients with improved clinical outcomes (Clinicaltrial.gov (NCT03643549)).


Assuntos
Glioblastoma , Adulto , Antineoplásicos Alquilantes/uso terapêutico , Bortezomib/uso terapêutico , Dacarbazina/uso terapêutico , Combinação de Medicamentos , Feminino , Glioblastoma/tratamento farmacológico , Humanos , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia , Qualidade de Vida , Temozolomida/uso terapêutico
9.
Int J Pharm ; 584: 119391, 2020 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-32376444

RESUMO

The antipsychotic drug chlorpromazine (CPZ) has potential for the treatment of acute myeloid leukemia, if central nervous system side-effects resulting from its passage through the blood-brain barrier can be prevented. A robust drug delivery system for repurposed CPZ would be drug-in-cyclodextrin-in-liposome that would redirect the drug away from the brain while avoiding premature release in the circulation. As a first step, CPZ complexation with cyclodextrin (CD) has been studied. The stoichiometry, binding constant, enthalpy, and entropy of complex formation between CPZ and a panel of CDs was investigated by isothermal titration calorimetry (ITC). All the tested CDs were able to include CPZ, in the form of 1:1, 1:2 or a mixture of 1:1 and 1:2 complexes. In particular, a substituted γ-CD, sugammadex (the octasodium salt of octakis(6-deoxy-6-S-(2-carboxyethyl)-6-thio)cyclomaltooctaose), formed exclusively 1:2 complexes with an extremely high association constant of 6.37 × 109 M-2. Complexes were further characterized by heat capacity changes, one- and two-dimensional (ROESY) nuclear magnetic resonance (NMR) spectroscopy and molecular dynamics simulations. Finally, protection of CPZ against photodegradation by CDs was assessed. This was accelerated rather than reduced by complexation with CD. Altogether these results provide a molecular basis for the use of CD in delayed release formulations for CPZ.


Assuntos
Química Farmacêutica/métodos , Clorpromazina/administração & dosagem , Ciclodextrinas/química , Lipossomos/química , Clorpromazina/química , Preparações de Ação Retardada , Portadores de Fármacos/química , Reposicionamento de Medicamentos , Estabilidade de Medicamentos , Espectroscopia de Ressonância Magnética , Simulação de Dinâmica Molecular , Sugammadex/química , Termodinâmica , beta-Ciclodextrinas/química , gama-Ciclodextrinas/química
10.
Bioorg Med Chem ; 28(10): 115461, 2020 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-32245563

RESUMO

Cyclin-dependent kinase 8 (CDK8) plays a vital role in regulating cell transcription either through its association with the mediator complex or by the phosphorylation of transcription factors. CDK8-mediated activation of oncogenes has proved to be important in a variety of cancer types including hematological malignancies. We have designed and synthesized a series of new synthetic steroids. The compounds were evaluated as CDK8 inhibitors in vitro. The three most potent compounds exhibit Kd-values towards CDK8 in the low nanomolar range (3.5-18 nM). Furthermore, the compounds displayed selectivity for CDK8 in a panel of 465 different kinases. The cell studies indicated a selectivity to kill AML-cancer cell lines compared to normal cell lines.


Assuntos
Antineoplásicos/farmacologia , Quinase 8 Dependente de Ciclina/antagonistas & inibidores , Desenho de Fármacos , Inibidores de Proteínas Quinases/farmacologia , Esteroides/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Quinase 8 Dependente de Ciclina/metabolismo , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Estrutura Molecular , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Esteroides/síntese química , Esteroides/química , Relação Estrutura-Atividade
11.
Toxins (Basel) ; 12(1)2019 12 24.
Artigo em Inglês | MEDLINE | ID: mdl-31878347

RESUMO

Cyanobacteria are photosynthetic organisms that produce a large diversity of natural products with interesting bioactivities for biotechnological and pharmaceutical applications. Cyanobacterial extracts exhibit toxicity towards other microorganisms and cancer cells and, therefore, represent a source of potentially novel natural products for drug discovery. We tested 62 cyanobacterial strains isolated from various Brazilian biomes for antileukemic and antimicrobial activities. Extracts from 39 strains induced selective apoptosis in acute myeloid leukemia (AML) cancer cell lines. Five of these extracts also exhibited antifungal and antibacterial activities. Chemical and dereplication analyses revealed the production of nine known natural products. Natural products possibly responsible for the observed bioactivities and five unknown, chemically related chlorinated compounds present only in Brazilian cyanobacteria were illustrated in a molecular network. Our results provide new information on the vast biosynthetic potential of cyanobacteria isolated from Brazilian environments.


Assuntos
Anti-Infecciosos/farmacologia , Antineoplásicos/farmacologia , Produtos Biológicos/farmacologia , Cianobactérias/química , Antibacterianos/farmacologia , Anti-Infecciosos/isolamento & purificação , Antifúngicos/farmacologia , Antineoplásicos/isolamento & purificação , Produtos Biológicos/química , Brasil , Linhagem Celular Tumoral , Cianobactérias/classificação , Cianobactérias/genética , Descoberta de Drogas , Ensaios de Seleção de Medicamentos Antitumorais , Redes Reguladoras de Genes , Humanos , Leucemia Mieloide Aguda/tratamento farmacológico , Testes de Sensibilidade Microbiana
12.
Ther Drug Monit ; 41(6): 766-771, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31725695

RESUMO

AIM: The aim of this pilot study was to investigate whether psychotropic drugs frequently analyzed in a routine therapeutic drug monitoring laboratory bind to low-density lipoproteins/very-low-density lipoproteins (LDL/VLDL) in human serum. METHODS: Drug concentrations in 20 serum sample pools containing one psychotropic drug each, and in the LDL/VLDL fractions extracted from the same samples, were measured by triple quadrupole liquid chromatography tandem mass spectrometry. The membrane permeability of the drugs was measured using a Parallel Artificial Membrane Permeability Assay. RESULTS: Of the 20 antidepressants, antipsychotics, and antiepileptics examined, 7 drugs were detected in both the pooled serum samples and in the LDL/VLDL fraction. Binding of drugs to LDL/VLDL significantly correlated with high octanol: water partition coefficient (logP), high degree of protein binding, and a low polar surface area. The drugs found in LDL/VLDL, with the exception of aripiprazole, were also characterized by high or intermediate membrane permeability. CONCLUSIONS: The present results indicate that psychotropic drugs with certain characteristics bind to LDL/VLDL in blood. This further implies that lipoproteins could play an important role in drug transport.


Assuntos
Lipoproteínas LDL/química , Lipoproteínas VLDL/química , Psicotrópicos/química , Humanos , Membranas Artificiais , Projetos Piloto , Ligação Proteica , Psicotrópicos/sangue
13.
Sci Rep ; 9(1): 13789, 2019 09 24.
Artigo em Inglês | MEDLINE | ID: mdl-31551444

RESUMO

The exchange proteins directly activated by cAMP 1 and 2 (Epac1 and Epac2) are expressed in a cell specific manner in the liver, but their biological functions in this tissue are poorly understood. The current study was undertaken to begin to determine the potential roles of Epac1 and Epac2 in liver physiology and disease. Male C57BL/6J mice in which expression of Epac1 and/or Epac2 are deleted, were subjected to partial hepatectomy and the regenerating liver was analyzed with regard to lipid accumulation, cell replication and protein expression. In response to partial hepatectomy, deletion of Epac1 and/or Epac2 led to increased hepatocyte proliferation 36 h post surgery, and the transient steatosis observed in wild type mice was virtually absent in mice lacking both Epac1 and Epac2. The expression of the protein cytochrome P4504a14, which is implicated in hepatic steatosis and fibrosis, was substantially reduced upon deletion of Epac1/2, while a number of factors involved in lipid metabolism were significantly decreased. Moreover, the number of Küpffer cells was affected, and Epac2 expression was increased in the liver of wild type mice in response to partial hepatectomy, further supporting a role for these proteins in liver function. This study establishes hepatic phenotypic abnormalities in mice deleted for Epac1/2 for the first time, and introduces Epac1/2 as regulators of hepatocyte proliferation and lipid accumulation in the regenerative process.


Assuntos
Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , AMP Cíclico/metabolismo , Fatores de Troca do Nucleotídeo Guanina/metabolismo , Regeneração Hepática/fisiologia , Animais , Proliferação de Células/fisiologia , Fígado Gorduroso/metabolismo , Fibrose/metabolismo , Hepatectomia/métodos , Metabolismo dos Lipídeos/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL
14.
Biochim Biophys Acta Biomembr ; 1861(8): 1510-1521, 2019 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-31226245

RESUMO

Hassallidins are cyclic glycolipopeptides produced by cyanobacteria and other prokaryotes. The hassallidin structure consists of a peptide ring of eight amino acids where a fatty acid chain, additional amino acids, and sugar moieties are attached. Hassallidins show antifungal activity against several opportunistic human pathogenic fungi, but does not harbor antibacterial effects. However, they have not been studied on mammalian cells, and the mechanism of action is unknown. We purified hassallidin D from cultured cyanobacterium Anabaena sp. UHCC 0258 and characterized its effect on mammalian and fungal cells. Ultrastructural analysis showed that hassallidin D disrupts cell membranes, causing a lytic/necrotic cell death with rapid presence of disintegrated outer membrane, accompanied by internalization of small molecules such as propidium iodide into the cells. Furthermore, artificial liposomal membrane assay showed that hassallidin D selectively targets sterol-containing membranes. Finally, in silico membrane modeling allowed us to study the interaction between hassallidin D and membranes in detail, and confirm the role of cholesterol for hassallidin-insertion into the membrane. This study demonstrates the mechanism of action of the natural compound hassallidin, and gives further insight into how bioactive lipopeptide metabolites selectively target eukaryotic cell membranes.


Assuntos
Antifúngicos/metabolismo , Antineoplásicos/metabolismo , Glicolipídeos/metabolismo , Glicopeptídeos/metabolismo , Lipopeptídeos/metabolismo , Lipídeos de Membrana/metabolismo , Esteróis/metabolismo , Anabaena/química , Antifúngicos/isolamento & purificação , Antifúngicos/farmacologia , Antineoplásicos/isolamento & purificação , Antineoplásicos/farmacologia , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Ensaios de Seleção de Medicamentos Antitumorais , Glicopeptídeos/isolamento & purificação , Glicopeptídeos/farmacologia , Humanos , Lipopeptídeos/isolamento & purificação , Lipopeptídeos/farmacologia , Membranas Mitocondriais/efeitos dos fármacos
15.
Curr Med Chem ; 26(28): 5278-5292, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31099318

RESUMO

Acute Myeloid Leukaemia (AML) is the neoplastic transformation of Hematopoietic Stem Cells (HSC) and relapsed disease is a major challenge in the treatment. Despite technological advances in the field of medicine and our heightened knowledge regarding the pathogenesis of AML, the initial therapy of "7+3" Cytarabine and Daunorubicin has remained mainly unchanged since 1973. AML is a disease of the elderly, and increased morbidity in this patient group does not allow the full use of the treatment and drug-resistant relapse is common. Nanocarriers are drug-delivery systems that can be used to transport drugs to the bone marrow and target Leukemic Stem Cells (LSC), conferring less side-effects compared to the free-drug alternative. Nanocarriers also can be used to favour the transport of drugs that otherwise would not have been used clinically due to toxicity and poor efficacy. Liposomes are a type of nanocarrier that can be used as a dedicated drug delivery system, which can also have active ligands on the surface in order to interact with antigens on the target cells or tissues. In addition to using small molecules, it is possible to attach antibodies to the liposome surface, generating so-called immunoliposomes. By using immunoliposomes as a drug-delivery system, it is possible to minimize the toxic side effects caused by the chemotherapeutic drug on healthy organs, and at the same time direct the drugs towards the remaining AML blasts and stem cells. This article aims to explore the possibilities of using immunoliposomes as a drug carrier in AML therapy. Emphasis will be on possible target molecules on the AML cells, leukaemic stem cells, as well as bone marrow constituents relevant to AML therapy. Further, some conditions and precautions that must be met for immunoliposomes to be used in AML therapy will be discussed.


Assuntos
Antineoplásicos/uso terapêutico , Citarabina/uso terapêutico , Daunorrubicina/uso terapêutico , Portadores de Fármacos/química , Leucemia Mieloide Aguda/tratamento farmacológico , Animais , Antineoplásicos/química , Citarabina/química , Daunorrubicina/química , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Leucemia Mieloide Aguda/patologia , Lipossomos/química , Nanopartículas/química
16.
Phytochemistry ; 164: 67-77, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31100654

RESUMO

For more than four centuries, the intake of Narthecium ossifragum has been associated with poisoning in domesticated animals. Saponins occurring in flowering tops of the plant are considered to cause kidney damage in calves. At present, there are more than 30 papers on the saponins of N. ossifragum in the literature, although the structures of these compounds have hitherto not been determined. Here, we identify the saponins of N. ossifragum as sarsasapogenin, sarsasapogenin-3-O-ß-galactopyranoside, sarsasapogenin-3-O-(2'-O-ß-glucopyranosyl-ß-galactopyranoside) and sarsasapogenin-3-O-(2'-O-ß-glucopyranosyl-3'-O-α-arabinopyranosyl-ß-galactopyranoside). Moreover, six aromatic natural products were isolated and characterized from the methanolic extract from flowers of N. ossifragum. Five of these aromatic compounds, chrysoeriol 6-C-ß-arabinofuranoside-8-C-ß-glucopyranoside, chrysoeriol 6-C-ß-arabinopyranosyl-8-C-ß-glucopyranoside, chrysoeriol 6-C-ß-xylopyranosyl-8-C-ß-galactopyranoside, chrysoeriol 6-C-ß-galactopyranosyl-8-C-ß-glucopyranoside and chrysoeriol 6-C-ß-glucopyranosyl-8-C-ß-galactopyranoside are undescribed. All compounds were tested for cytotoxicity in mammalian cell lines derived from the heart, kidney, and haematological tissues. The saponins exhibited cytotoxicity in the micromolar range, with proportionally increasing cytotoxicity with increasing number of glycosyl substituents. The most potent compound was the main saponin sarsasapogenin-3-O-(2'-O-ß-glucopyranosyl-3'-O-α-arabinopyranosyl-ß-galactopyranoside), which produced cell death at concentrations below 3-4 µM in all three cell lines tested. This indicates that the saponins are the toxicants mainly responsible for kidney damage observed in cattle after ingestion of N. ossifragum. Our findings also pave the way for analysis of individual compounds isolated during the biopsies of intoxicated animals.


Assuntos
Produtos Biológicos/farmacologia , Topos Floridos/química , Magnoliopsida/química , Saponinas/farmacologia , Animais , Produtos Biológicos/química , Produtos Biológicos/isolamento & purificação , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Relação Dose-Resposta a Droga , Conformação Molecular , Ratos , Saponinas/química , Saponinas/isolamento & purificação , Relação Estrutura-Atividade
17.
Heliyon ; 5(3): e01369, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30963118

RESUMO

Neoglaziovia variegata is endemic to northeastern Brazil. The drought resistant plant produces edible fruits and is used as a fibre plant by rural communities in the Caatinga region where a variety of products are made from the white, soft and flexible fibres. Extracts of N. variegata have been reported to be of low toxicity and to exhibit antinociceptive effect, photoprotective potential, antioxidant effect, gastroprotective effects and antibacterial effect against both Gram-positive and Gram-negative bacteria, however, the chemical constituents of this species are mainly unknown. The novel poly-oxygenated flavone glucoside 5,6,7,4'-tetrahydroxy-3',5'-dimethoxy-flavone 7-O-ß-glucopyranoside in addition to the rare poly-oxygenated flavone 5,4'-dihydroxy-6,7,3'-trimethoxyflavone 4'-O-ß-glucopyranoside and the flavonol quercetin 3-O-(6''-rhamnopyranosyl-ß-glucopyranoside) have been characterised from the leaves of N. variegata. 5,6,7,4'-tetrahydroxy-3',5'-dimethoxy-flavone, which comprises the core structure of the novel compound, is a new flavonoid aglycone in nature. The structure determinations were based on extensive use of 2D NMR spectroscopic techniques and high-resolution mass spectrometry. Both substances exhibited toxicity towards MOLM-13 acute myeloid leukaemia cells.

18.
Mol Cancer Ther ; 18(3): 567-578, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30679386

RESUMO

More than 40 years ago, the present standard induction therapy for acute myeloid leukemia (AML) was developed. This consists of the metabolic inhibitor cytarabine (AraC) and the cytostatic topoisomerase 2 inhibitor daunorubucin (DNR). In light of the high chance for relapse, as well as the large heterogeneity, novel therapies are needed to improve patient outcome. We have tested the anti-AML activity of 15 novel compounds based on the scaffolds pyrrolo[2,3-a]carbazole-3-carbaldehyde, pyrazolo[3,4-c]carbazole, pyrazolo[4,3-a]phenanthridine, or pyrrolo[2,3-g]indazole. The compounds were inhibitors of Pim kinases, but could also have inhibitory activity against other protein kinases. Ser/Thr kinases like the Pim kinases have been identified as potential drug targets for AML therapy. The compound VS-II-173 induced AML cell death with EC50 below 5 µmol/L, and was 10 times less potent against nonmalignant cells. It perturbed Pim-kinase-mediated AML cell signaling, such as attenuation of Stat5 or MDM2 phosphorylation, and synergized with DNR to induce AML cell death. VS-II-173 induced cell death also in patients with AML blasts, including blast carrying high-risk FLT3-ITD mutations. Mutation of nucleophosmin-1 was associated with good response to VS-II-173. In conclusion new scaffolds for potential AML drugs have been explored. The selective activity toward patient AML blasts and AML cell lines of the pyrazolo-analogue VS-II-173 make it a promising drug candidate to be further tested in preclinical animal models for AML.


Assuntos
Carbazóis/química , Indazóis/química , Leucemia Mieloide Aguda/tratamento farmacológico , Inibidores de Proteínas Quinases/farmacologia , Apoptose/efeitos dos fármacos , Carbazóis/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Citarabina/química , Citarabina/farmacologia , Humanos , Indazóis/farmacologia , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patologia , Mutação/efeitos dos fármacos , Fosforilação/efeitos dos fármacos , Inibidores de Proteínas Quinases/química , Proteínas Proto-Oncogênicas c-pim-1/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-pim-1/genética , Transdução de Sinais/efeitos dos fármacos , Inibidores da Topoisomerase II/química , Inibidores da Topoisomerase II/farmacologia
19.
Bioconjug Chem ; 29(2): 493-502, 2018 02 21.
Artigo em Inglês | MEDLINE | ID: mdl-29299922

RESUMO

Enzyme replacement therapy (ERT) is a therapeutic approach envisioned decades ago for the correction of genetic disorders, but ERT has been less successful for the correction of disorders with neurological manifestations. In this work, we have tested the functionality of nanoparticles (NP) composed of maltodextrin with a lipid core to bind and stabilize tyrosine hydroxylase (TH). This is a complex and unstable brain enzyme that catalyzes the rate-limiting step in the synthesis of dopamine and other catecholamine neurotransmitters. We have characterized these TH-loaded NPs to evaluate their potential for ERT in diseases associated with TH dysfunction. Our results show that TH can be loaded into the lipid core maltodextrin NPs with high efficiency, and both stability and activity are maintained through loading and are preserved during storage. Binding to NPs also favored the uptake of TH to neuronal cells, both in cell culture and in the brain. The internalized NP-bound TH was active as we measured an increase in intracellular L-Dopa synthesis following NP uptake. Our approach seems promising for the use of catalytically active NPs in ERT to treat neurodegenerative and neuropsychiatric disorders characterized by dopamine deficiency, notably Parkinson's disease.


Assuntos
Encéfalo/metabolismo , Portadores de Fármacos/química , Nanopartículas/química , Neurônios/metabolismo , Polissacarídeos/química , Tirosina 3-Mono-Oxigenase/administração & dosagem , Tirosina 3-Mono-Oxigenase/farmacocinética , Animais , Linhagem Celular , Estabilidade Enzimática , Terapia Enzimática , Feminino , Humanos , Masculino , Modelos Moleculares , Doença de Parkinson/tratamento farmacológico , Doença de Parkinson/enzimologia
20.
J Enzyme Inhib Med Chem ; 33(1): 370-375, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-29336193

RESUMO

Phenazine is known to regroup planar nitrogen-containing heterocyclic compounds. It was used here to enhance the bioavailability of the biologically important compound iodinin, which is near insoluble in aqueous solutions. Its water solubility has led to the development of new formulations using diverse amphiphilic α-cyclodextrins (CDs). With the per-[6-desoxy-6-(3-perfluorohexylpropanethio)-2,3-di-O-methyl]-α-CD, we succeeded to get iodinin-loaded nanoformulations with good parameters such as a size of 97.9 nm, 62% encapsulation efficiency and efficient control release. The study presents an interesting alternative to optimizing the water solubility of iodinin by chemical modifications of iodinin.


Assuntos
Nanopartículas/química , Fenazinas/química , alfa-Ciclodextrinas/química , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Relação Dose-Resposta a Droga , Estrutura Molecular , Tamanho da Partícula , Fenazinas/farmacologia , Ratos , Solubilidade , Relação Estrutura-Atividade , Propriedades de Superfície , alfa-Ciclodextrinas/farmacologia
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