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1.
Molecules ; 27(21)2022 Oct 28.
Artigo em Inglês | MEDLINE | ID: mdl-36364160

RESUMO

Kahweol and cafestol are two diterpenes extracted from Coffea arabica beans that have distinct biological activities. Recent research describes their potential activities, which include anti-inflammatory, anti-diabetic, and anti-cancer properties, among others. The two diterpenes have been shown to have anticancer effects in various in vitro and in vivo cancer models. This review aims to shed light on the recent developments regarding the potential effects of kahweol and cafestol on various cancers. A systematic literature search through Google Scholar and PubMed was performed between February and May 2022 to collect updates about the potential effects of cafestol and kahweol on different cancers in in vitro and in vivo models. The search terms "Kahweol and Cancer" and "Cafestol and Cancer" were used in this literature review as keywords; the findings demonstrated that kahweol and cafestol exhibit diverse effects on different cancers in in vitro and in vivo models, showing pro-apoptotic, cytotoxic, anti-proliferative, and anti-migratory properties. In conclusion, the diterpenes kahweol and cafestol display significant anticancer effects, while remarkably unaffecting normal cells. Our results show that both kahweol and cafestol exert their actions on various cancers via inducing apoptosis and inhibiting cell growth. Additionally, kahweol acts by inhibiting cell migration.


Assuntos
Coffea , Diterpenos , Neoplasias , Humanos , Diterpenos/farmacologia , Diterpenos/análise , Apoptose , Neoplasias/tratamento farmacológico , Café
2.
Int J Mol Sci ; 23(21)2022 Nov 02.
Artigo em Inglês | MEDLINE | ID: mdl-36362165

RESUMO

Ingenol mebutate (IM) is highly effective in the treatment of human papillomavirus (HPV)-induced anogenital warts (AGW) leading to fast ablation within hours. However, the exact mode of action is still largely unknown. We performed dermoscopy, in vivo confocal microscopy (CLM), histology, immunohistochemistry, and immunofluorescence to gain insights in mechanisms of IM treatment in AGW. In addition, we used in vitro assays (ELISA, HPV-transfection models) to further investigate in vivo findings. IM treatment leads to a strong recruitment of neutrophils with thrombosis of small skin vessels within 8 h, in a sense of immunothrombosis. In vivo and in vitro analyses showed that IM supports a prothrombotic environment by endothelial cell activation and von Willebrand factor (VWF) secretion, in addition to induction of neutrophil extracellular traps (NETosis). IM superinduces CXCL8/IL-8 expression in HPV-E6/E7 transfected HaCaT cells when compared to non-infected keratinocytes. Rapid ablation of warts after IM treatment can be well explained by the observed immunothrombosis. This new mechanism has so far only been observed in HPV-induced lesions and is completely different from the mechanisms we see in the treatment of transformed keratinocytes in actinic keratosis. Our initial findings indicate an HPV-specific effect, which could be also of interest for the treatment of other HPV-induced lesions. Larger studies are now needed to further investigate the potential of IM in different HPV tumors.


Assuntos
Condiloma Acuminado , Diterpenos , Ceratose Actínica , Infecções por Papillomavirus , Anormalidades da Pele , Verrugas , Humanos , Infecções por Papillomavirus/complicações , Infecções por Papillomavirus/tratamento farmacológico , Condiloma Acuminado/tratamento farmacológico , Diterpenos/farmacologia , Diterpenos/uso terapêutico , Ceratose Actínica/tratamento farmacológico , Papillomaviridae , Necrose
3.
Mar Drugs ; 20(11)2022 Nov 07.
Artigo em Inglês | MEDLINE | ID: mdl-36355021

RESUMO

Analytical scale chemical/cultivation profiling prioritized the Australian marine-derived fungus Aspergillus noonimiae CMB-M0339. Subsequent investigation permitted isolation of noonindoles A-F (5-10) and detection of eight minor analogues (i-viii) as new examples of a rare class of indole diterpene (IDT) amino acid conjugate, indicative of an acyl amino acid transferase capable of incorporating a diverse range of amino acid residues. Structures for 5-10 were assigned by detailed spectroscopic and X-ray crystallographic analysis. The metabolites 5-14 exhibited no antibacterial properties against G-ve and G+ve bacteria or the fungus Candida albicans, with the exception of 5 which exhibited moderate antifungal activity.


Assuntos
Aminoácidos , Diterpenos , Austrália , Diterpenos/farmacologia , Candida albicans , Indóis/farmacologia , Estrutura Molecular , Testes de Sensibilidade Microbiana
4.
Int J Mol Sci ; 23(21)2022 Nov 04.
Artigo em Inglês | MEDLINE | ID: mdl-36362322

RESUMO

The incidence of diabetes mellitus (DM), one of the most common chronic metabolic disorders, has increased dramatically over the past decade and has resulted in higher rates of morbidity and mortality worldwide. The enzyme, α-Glucosidase (α-GLy), is considered a therapeutic target for the treatment of type 2 DM. Herein, we synthesized arylidene, heterocyclic, cyanoetoxy- and propargylated derivatives of quinopimaric acid (levopimaric acid diene adduct with p-benzoquinone) 1-50 and, first, evaluated their ability to inhibit α-GLy. Among the tested compounds, quinopimaric acid 1, 2,3-dihydroquinopimaric acid 8 and its amide and heterocyclic derivatives 9, 30, 33, 39, 44, with IC50 values of 35.57-65.98 µM, emerged as being good inhibitors of α-GLy. Arylidene 1ß-hydroxy and 1ß,13α-epoxy methyl dihydroquinopimarate derivatives 6, 7, 26-29, thiadiazole 32, 1a,4a-dehydroquinopimaric acid 40 and its indole, nitrile and propargyl hybrids 35-38, 42, 45, 48, and 50 showed excellent inhibitory activities. The most active compounds 38, 45, 48, and 50 displayed IC50 values of 0.15 to 0.68 µM, being 1206 to 266 more active than acarbose (IC50 of 181.02 µM). Kinetic analysis revealed the most active diterpene indole with an alkyne substituent 45 as a competitive inhibitor with Ki of 50.45 µM. Molecular modeling supported this finding and suggested that the indole core plays a key role in the binding. Compound 45 also has favorable pharmacokinetic and safety properties, according to the computational ADMET profiling. The results suggested that quinopimaric acid derivatives should be considered as potential candidates for novel alternative therapies in the treatment of type 2 diabetes.


Assuntos
Diabetes Mellitus Tipo 2 , Diterpenos , Humanos , alfa-Glucosidases/metabolismo , Diabetes Mellitus Tipo 2/tratamento farmacológico , Cinética , Diterpenos/farmacologia , Diterpenos/uso terapêutico , Indóis/uso terapêutico , Inibidores de Glicosídeo Hidrolases/farmacologia , Inibidores de Glicosídeo Hidrolases/química , Simulação de Acoplamento Molecular , Relação Estrutura-Atividade , Estrutura Molecular
5.
Molecules ; 27(20)2022 Oct 14.
Artigo em Inglês | MEDLINE | ID: mdl-36296494

RESUMO

Co-administered medicinal herbs can modify a drug's pharmacokinetics (PK), effectiveness, and toxicity. Andrographis paniculata (Burm. f.) ethanolic extract (APE) and andrographolide (AND) (a potent CYP2C9 inducer/inhibitor) can alter the pharmacokinetic parameters of glipizide (GLZ). This study aimed to determine the potential pharmacokinetics of herb-drug interactions between GLZ and APE/AND in the plasma of normal and diabetic rats using the HPLC bioanalysis method. The glipizide bioanalytical method established with RP-HPLC/UV instrument was validated following the EMA guidelines. GLZ was administered alone and in combination with APE or AND to normal and diabetic rats. The GLZ pharmacokinetic parameters were estimated according to the correlation between concentration and sampling time using the PK solver program. A simple and rapid GLZ bioanalysis technique with a lower limit of quantitation of 25 ng/mL was developed and presented the following parameters: accuracy (error ≤ 15%), precision (CV ≤ 15%), selectivity, stability, and linearity (R2 = 0.998) at concentrations ranging 25-1500 ng/mL. APE administration significantly improved the Cmax and AUC0-t/AUC0-∞ GLZ values in normal and diabetic rats (p < 0.05). AND significantly reduced the bioavailability of GLZ in diabetic rats with small values of T 1/2, Cmax, and AUC0-t/AUC0-∞ (p < 0.05). This combination can be considered in administering medications because it can influence the pharmacological effects of GLZ.


Assuntos
Andrographis , Diabetes Mellitus Experimental , Diterpenos , Hominidae , Animais , Ratos , Interações Ervas-Drogas , Glipizida , Andrographis paniculata , Cromatografia Líquida de Alta Pressão , Diabetes Mellitus Experimental/tratamento farmacológico , Indutores do Citocromo P-450 CYP2C9 , Extratos Vegetais/farmacologia , Diterpenos/farmacologia
6.
Molecules ; 27(20)2022 Oct 16.
Artigo em Inglês | MEDLINE | ID: mdl-36296525

RESUMO

Euphorbia factors, lathyrane-type diterpenoids isolated from the medical herb Euphorbia lathyris L. (Euphorbiaceae), have been associated with intestinal irritation toxicity, but the mechanisms underlying this phenomenon are still unknown. The objective of this study was to evaluate the transcriptome and miRNA profiles of human colon adenocarcinoma Caco-2 cells in response to Euphorbia factors L1 (EFL1) and EFL2. Whole transcriptomes of mRNA and microRNA (miRNA) were obtained using second generation high-throughput sequencing technology in response to 200 µM EFL treatment for 72 h, and the differentially expressed genes and metabolism pathway were enriched. Gene structure changes were analyzed by comparing them with reference genome sequences. After 72 h of treatment, 16 miRNAs and 154 mRNAs were differently expressed between the EFL1 group and the control group, and 47 miRNAs and 1101 mRNAs were differentially expressed between the EFL2 group and the control. Using clusters of orthologous protein enrichment, the sequenced mRNAs were shown to be mainly involved in transcription, post-translational modification, protein turnover, chaperones, signal transduction mechanisms, intracellular trafficking, secretion, vesicular transport, and the cytoskeleton. The differentially expressed mRNA functions and pathways were enriched in transmembrane transport, T cell extravasation, the IL-17 signaling pathway, apoptosis, and the cell cycle. The differentially expressed miRNA EFLs caused changes in the structure of the gene, including alternative splicing, insertion and deletion, and single nucleotide polymorphisms. This study reveals the underlying mechanism responsible for the toxicity of EFLs in intestinal cells based on transcriptome and miRNA profiles of gene expression and structure.


Assuntos
Adenocarcinoma , Neoplasias do Colo , Diterpenos , Euphorbia , MicroRNAs , Humanos , Euphorbia/química , Transcriptoma , Células CACO-2 , Interleucina-17/genética , Neoplasias do Colo/genética , Diterpenos/farmacologia , Diterpenos/química , MicroRNAs/genética , MicroRNAs/metabolismo , RNA Mensageiro/genética , Perfilação da Expressão Gênica
7.
Cells ; 11(20)2022 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-36291112

RESUMO

Plectranthus ornatus Codd, the genus Plectranthus of the Lamiaceae family, has been used as traditional medicine in Africa, India and Australia. Pharmacological studies show the use of this plant to treat digestive problems. In turn, leaves were used for their antibiotic properties in some regions of Brazil to treat skin infections. The present study examines the anti-inflammatory, antioxidant and cytotoxic effects of the halimane and labdane diterpenes (11R*,13E)-11-acetoxyhalima-5,13-dien-15-oic acid (HAL) and 1α,6ß-diacetoxy-8α,13R*-epoxy-14-labden-11-one (PLEC) and the forskolin-like 1:1 mixture of 1,6-di-O-acetylforskolin and 1,6-di-O-acetyl-9-deoxyforskolin (MRC) isolated from P. ornatus on lung (A549) and leukemia (CCRF-CEM) cancer cell lines, and on normal human retinal pigment epithelial (ARPE-19) cell line in vitro. Additionally, molecular docking and computational approaches were used. ADMET properties were analysed through SwissADME and proTox-II-Prediction. The results indicate that all tested compounds significantly reduced the viability of the cancer cells and demonstrated no cytotoxic effects against the non-neoplastic cell line. The apoptosis indicators showed increased ROS levels for both the tested A549 and CCRF-CEM cancer cell lines after treatment. Furthermore, computational studies found HAL to exhibit moderate antioxidant activity. In addition, selected compounds changed mitochondrial membrane potential (MMP), and increased DNA damage and mitochondrial copy number for the CCRF-CEM cancer cell line; they also demonstrated anti-inflammatory effects on the ARPE-19 normal cell line upon lipopolysaccharide (LPS) treatment, which was associated with the modulation of IL-6, IL-8, TNF-α and GM-CSF genes expression. Docking studies gave indication about the lowest binding energy for 1,6-di-O-acetylforskolin docked into IL-6, TNF-α and GM-CSF, and 1,6-di-O-acetyl-9-deoxyforskolin docked into IL-8. The ADMET studies showed drug-likeness properties for the studied compounds. Thus, halimane and labdane diterpenes isolated from P. ornatus appear to offer biological potential; however, further research is necessary to understand their interactions and beneficial properties.


Assuntos
Diterpenos , Plectranthus , Humanos , Antibacterianos/farmacologia , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/metabolismo , Antioxidantes/metabolismo , Colforsina , Diterpenos/química , Diterpenos/isolamento & purificação , Diterpenos/farmacologia , Fator Estimulador de Colônias de Granulócitos e Macrófagos/metabolismo , Interleucina-6/metabolismo , Interleucina-8/metabolismo , Lipopolissacarídeos/metabolismo , Simulação de Acoplamento Molecular , Plectranthus/química , Plectranthus/metabolismo , Protoporfirinogênio Oxidase/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Pigmentos da Retina/metabolismo , Fator de Necrose Tumoral alfa/metabolismo
8.
Chem Pharm Bull (Tokyo) ; 70(10): 720-725, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36184455

RESUMO

Five podophyllotoxin derivatives (1-5), two diterpenoids (6 and 7), three diterpenoid xylosides (8-10), a flavanonol glycoside (11), flavonol (12), and biflavonoid (13) were isolated from the leaves of Thujopsis dolabrata (Cupressaceae). Compounds 1, 6, and 8 were named (-)-ß-isopeltatin, epi-nootkastatin 2, and acetoxyanticopalol 15-O-ß-D-xylopyranoside, respectively. The structures of the isolated compounds were determined based on a detailed analysis of NMR spectroscopic data and through chromatographic and spectroscopic analyses following specific chemical transformations. The isolated compounds (1-5 and 7-11) were evaluated for their cytotoxicity toward HL-60 human promyelocytic leukemia cells and Caki-1 human kidney carcinoma cells. The podophyllotoxin derivatives (1-5) exhibited cytotoxicity against both HL-60 and Caki-1 cells with IC50 values ranging from 0.00069 to 5.4 µM, and the diterpenoid derivatives (7-10) demonstrated cytotoxicity against HL-60 cells with IC50 values ranging from 4.5 to 11 µM. HL-60 cells treated with 8 exhibited apoptosis characteristics, such as accumulation of sub-G1 cells and nuclear chromatin condensation.


Assuntos
Antineoplásicos Fitogênicos , Biflavonoides , Cupressaceae , Diterpenos , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/farmacologia , Cromatina , Cupressaceae/química , Diterpenos/farmacologia , Flavonóis , Glicosídeos/análise , Células HL-60 , Humanos , Folhas de Planta/química , Podofilotoxina/análise
9.
Molecules ; 27(19)2022 Oct 08.
Artigo em Inglês | MEDLINE | ID: mdl-36235222

RESUMO

Human glioblastoma multiforme (GBM) is one of the most malignant brain tumors, with a high mortality rate worldwide. Conventional GBM treatment is now challenged by the presence of the blood-brain barrier (BBB), drug resistance, and post-treatment adverse effects. Hence, developing bioactive compounds isolated from plant species and identifying molecular pathways in facilitating effective treatment has become crucial in GBM. Based on pharmacodynamic studies, andrographolide has sparked the interest of cancer researchers, who believe it may alleviate difficulties in GBM therapy; however, it still requires further study. Andrographolide is a bicyclic diterpene lactone derived from Andrographis paniculata (Burm.f.) Wallich ex Nees that has anticancer properties in various cancer cell lines. The present study aimed to evaluate andrographolide's anticancer effectiveness and potential molecular pathways using a DBTRG-05MG cell line. The antiproliferative activity of andrographolide was determined using the WST-1 assay, while scratch assay and clonogenic assay were used to evaluate andrographolide's effectiveness against the cancer cell line by examining cell migration and colony formation. Flowcytometry was also used to examine the apoptosis and cell cycle arrest induced by andrographolide. The mRNA and protein expression level involved in the ERK1/2/c-Myc/p53 signaling pathway was then assessed using qRT-PCR and Western blot. The protein-protein interaction between c-Myc and p53 was determined by a reciprocal experiment of the co-immunoprecipitation (co-IP) using DBTRG-05MG total cell lysate. Andrographolide significantly reduced the viability of DBTRG-05MG cell lines in a concentration- and time-dependent manner. In addition, scratch and clonogenic assays confirmed the effectiveness of andrographolide in reducing cell migration and colony formation of DBTRG-05MG, respectively. Andrographolide also promoted cell cycle arrest in the G2/M phase, followed by apoptosis in the DBTRG-05MG cell line, by inducing ERK1/2, c-Myc, and p53 expression at the mRNA level. Western blot results demonstrated that c-Myc overexpression also increased the production of the anti-apoptotic protein p53. Our findings revealed that c-Myc and p53 positively interact in triggering the apoptotic signaling pathway. This study successfully discovered the involvement of ERK1/2/c-Myc/p53 in the suppression of the DBTRG-05MG cell line via cell cycle arrest followed by the apoptosis signaling pathway following andrographolide treatment.


Assuntos
Diterpenos , Glioblastoma , Apoptose , Proteínas Reguladoras de Apoptose/metabolismo , Pontos de Checagem do Ciclo Celular , Linhagem Celular Tumoral , Proliferação de Células , Diterpenos/farmacologia , Diterpenos/uso terapêutico , Pontos de Checagem da Fase G2 do Ciclo Celular , Glioblastoma/metabolismo , Humanos , Lactonas/farmacologia , Sistema de Sinalização das MAP Quinases , RNA Mensageiro/metabolismo , Transdução de Sinais , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo
10.
Int J Mol Sci ; 23(19)2022 Sep 27.
Artigo em Inglês | MEDLINE | ID: mdl-36232690

RESUMO

Human nucleolin (hNcl) is a multifunctional protein involved in the progression of various cancers and plays a key role in other pathologies. Therefore, there is still unsatisfied demand for hNcl modulators. Recently, we demonstrated that the plant ent-kaurane diterpene oridonin inhibits hNcl but, unfortunately, this compound is quite toxic for healthy cells. Trachylobane diterpene 6,19-dihydroxy-ent-trachiloban-17-oic acid (compound 12) extracted from Psiadia punctulata (DC.) Vatke (Asteraceae) emerged as a ligand of hNcl from a cellular thermal shift assay (CETSA)-based screening of a small library of diterpenes. Effective interaction between this compound and the protein was demonstrated to occur both in vitro and inside two different types of cancer cells. Based on the experimental and computational data, a model of the hNcl/compound 12 complex was built. Because of this binding, hNcl mRNA chaperone activity was significantly reduced, and the level of phosphorylation of the protein was affected. At the biological level, cancer cell incubation with compound 12 produced a cell cycle block in the subG0/G1 phase and induced early apoptosis, whereas no cytotoxicity towards healthy cells was observed. Overall, these results suggested that 6,19-dihydroxy-ent-trachiloban-17-oic could represent a selective antitumoral agent and a promising lead for designing innovative hNcl inhibitors also usable for therapeutic purposes.


Assuntos
Asteraceae , Diterpenos do Tipo Caurano , Diterpenos , Neoplasias , Asteraceae/química , Diterpenos/química , Diterpenos/farmacologia , Diterpenos do Tipo Caurano/química , Diterpenos do Tipo Caurano/farmacologia , Humanos , Ligantes , Neoplasias/tratamento farmacológico , Fosfoproteínas , Fosforilação , RNA Mensageiro , Proteínas de Ligação a RNA
11.
Int J Mol Sci ; 23(19)2022 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-36232954

RESUMO

Since cancer treatment by radio- and chemotherapy has been linked to safety concerns, there is a need for new and alternative anticancer drugs; as such, compounds isolated from plants represent promising candidates. The current study investigates the anticancer features of halimane (11R*,13E)-11-acetoxyhalima-5,13-dien-15-oic acid (HAL) and the labdane diterpenes 1α,6ß-diacetoxy-8α,13R*-epoxy-14-labden-11-one (PLEC) and forskolin-like 1:1 mixture of 1,6-di-O-acetylforskolin and 1,6-di-O-acetyl-9-deoxyforskolin (MRC) isolated from Plectranthus ornatus in MCF7 and FaDu cancer cell lines. Cytotoxicity was assessed by MTT assay, ROS production by Di-chloro-dihydro-fluorescein diacetate assay (DCFH) or Red Mitochondrial Superoxide Indicator (MitoSOX) and Mitochondrial Membrane Potential (MMP) by fluorescent probe JC-1 (5',6,6'-tetrachloro-1,1',3,3'-tetraethylbenzimidazolylcarbocyanine iodide). In addition, the relative amounts of mitochondrial DNA (mtDNA) were determined using quantitative Real-Time-PCR (qRT-PCR) and damage to mitochondrial DNA (mtDNA) and nuclear DNA (nDNA) by semi-long run quantitative Real-Time-PCR (SLR-qRT-PCR). Gene expression was determined using Reverse-Transcription-qPCR. Caspase-3/7 activity by fluorescence was assessed. Assessment of General In Vivo Toxicity has been determined by Brine Shrimp Lethality Bioassay. The studied HAL and PLEC were found to have a cytotoxic effect in MCF7 with IC50 = 13.61 µg/mL and IC50 = 17.49 µg/mL and in FaDu with IC50 = 15.12 µg/mL and IC50 = 32.66 µg/mL cancer cell lines. In the two tested cancer cell lines, the phytochemicals increased ROS production and mitochondrial damage in the ND1 and ND5 gene regions and reduced MMP (ΔΨm) and mitochondrial copy numbers. They also changed the expression of pro- and anti-apoptotic genes (Bax, Bcl-2, TP53, Cas-3, Cas-8, Cas-9, Apaf-1 and MCL-1). Studies demonstrated increase in caspase 3/7 activity in tested cancer cell lines. In addition, we showed no toxic effect in in vivo test for the compounds tested. The potential mechanism of action may have been associated with the induction of apoptosis in MCF7 and FaDu cancer cells via the mitochondrial pathway; however, further in vivo research is needed to understand the mechanisms of action and potential of these compounds.


Assuntos
Antineoplásicos , Diterpenos , Plectranthus , Antineoplásicos/farmacologia , Apoptose , Caspase 3/genética , Caspase 3/metabolismo , Linhagem Celular Tumoral , Colforsina/farmacologia , DNA Mitocondrial/metabolismo , Diterpenos/farmacologia , Corantes Fluorescentes/farmacologia , Iodetos , Potencial da Membrana Mitocondrial , Proteína de Sequência 1 de Leucemia de Células Mieloides/metabolismo , Compostos Fitoquímicos/metabolismo , Compostos Fitoquímicos/farmacologia , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Superóxidos , Proteína X Associada a bcl-2/metabolismo
12.
J Nat Prod ; 85(10): 2372-2384, 2022 10 28.
Artigo em Inglês | MEDLINE | ID: mdl-36215157

RESUMO

A new strategy for the semisynthesis of the aromatic cassane-type diterpene taepeenin F (6) is reported. The introduction of the methyl group at C-14, characteristic of the target compound, was achieved via dienone 13, easily prepared from abietic acid (10), the major compound in renewable rosin. Biological assays of selected compounds are reported. The antiproliferative activity against HT29, B16-F10, and HepG2 tumor cell lines has been investigated. Salicylaldehyde 21 was the most active compound (IC50 = 7.72 µM). Products 16 and 21 displayed apoptotic effects in B16-F10 cells, with total apoptosis rates of 46 and 38.4%, respectively. This apoptotic process involves a significant arrest of the B16-F10 cell cycle, blocking the G0/G1 phase. Dienone 16 did not cause any loss of the mitochondrial membrane potential (MMP), while salicylaldehyde 21 caused a partial loss of the MMP. The anti-inflammatory activity of the selected compounds was investigated with the LPS-stimulated RAW 264.7 macrophages. All compounds showed potent NO inhibition, with percentages between 80 and 99% at subcytotoxic concentrations. Dienone 16 inhibited LPS-induced differentiation of RAW 264.7 cells, by increasing the proportion of cells in the S phase. In addition, salicylaldehyde 21 had effects on the cell cycle, recovering the cells from the G0/G1 full arrest produced in response to LPS action.


Assuntos
Antineoplásicos , Diterpenos , Lipopolissacarídeos/farmacologia , Potencial da Membrana Mitocondrial , Apoptose , Linhagem Celular Tumoral , Diterpenos/farmacologia , Anti-Inflamatórios/farmacologia , Proliferação de Células , Antineoplásicos/farmacologia
13.
Biomolecules ; 12(10)2022 10 09.
Artigo em Inglês | MEDLINE | ID: mdl-36291655

RESUMO

Corneal opacification due to fibrosis is a leading cause of blindness worldwide. Fibrosis occurs from many causes including trauma, photorefractive surgery, microbial keratitis (infection of the cornea), and chemical burns, yet there is a paucity of therapeutics to prevent or treat corneal fibrosis. This study aimed to determine if andrographolide, a labdane diterpenoid found in Andrographis paniculate, has anti-fibrotic properties. Furthermore, we evaluated if andrographolide could prevent the differentiation of fibroblasts to myofibroblasts in vitro, given that the transforming growth factor beta-1(TGF-ß1) stimulated persistence of myofibroblasts in the cornea is a primary component of fibrosis. We demonstrated that andrographolide inhibited the upregulation of alpha smooth muscle actin (αSMA) mRNA and protein in rabbit corneal fibroblasts (RCFs), thus, demonstrating a reduction in the transdifferentiation of myofibroblasts. Immunofluorescent staining of TGF-ß1-stimulated RCFs confirmed a dose-dependent decrease in αSMA expression when treated with andrographolide. Additionally, andrographolide was well tolerated in vivo and had no impact on corneal epithelialization in a rat debridement model. These data support future studies investigating the use of andrographolide as an anti-fibrotic in corneal wound healing.


Assuntos
Diterpenos , Fator de Crescimento Transformador beta1 , Coelhos , Ratos , Animais , Fator de Crescimento Transformador beta1/metabolismo , Miofibroblastos/metabolismo , Actinas/metabolismo , Células Cultivadas , Fibroblastos/metabolismo , Diterpenos/farmacologia , Córnea/metabolismo , Fibrose , RNA Mensageiro/genética
14.
Chem Biodivers ; 19(11): e202200793, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-36215180

RESUMO

Icetexane diterpenoids are a diverse family of natural products sourced from several species of terrestrial plants. Icetexanes exhibit a broad array of biological activities and together with their complex 6-7-6 tricyclic scaffolds, they have piqued the interest of synthetic organic chemists, natural products chemists, and biological investigators over the past four decades and were reviewed 13 years ago. This review summarizes icetexane natural products isolated since 2009, provides an overview of new synthetic approaches to the icetexane problem, and proposes an additional classification of icetexanes based on novel structures that are unlike previously isolated materials.


Assuntos
Produtos Biológicos , Diterpenos , Salvia , Produtos Biológicos/farmacologia , Produtos Biológicos/química , Salvia/química , Diterpenos/farmacologia , Diterpenos/química , Plantas/química
15.
Mar Drugs ; 20(10)2022 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-36286428

RESUMO

The first investigation of the South China Sea soft coral Sarcophyton boettgeri afforded five new capnosane diterpenes, sarboettgerins A-E (1-5), together with one known related compound, pavidolide D (6). Their structures, including absolute configurations, were elucidated by the extensive spectroscopic analysis, 13C NMR calculations, and X-ray diffraction. Among them, new compounds 1-5 were featured by the rarely encountered Z-geometry double bond Δ1 within the 5/11-fused bicyclic capnosane carbon framework. Plausible biogenetic relationships of all isolates were proposed, and they might give an insight into future biomimetic synthesis of these novel compounds. In an in vitro bioassay, compound 5 displayed potent anti-neuroinflammatory activity against LPS-induced NO release in BV-2 microglial cells, which might be developed as a new type of potential neuroprotective agent in future.


Assuntos
Antozoários , Diterpenos , Fármacos Neuroprotetores , Animais , Antozoários/química , Fármacos Neuroprotetores/farmacologia , Lipopolissacarídeos , Diterpenos/farmacologia , Diterpenos/química , China , Carbono , Estrutura Molecular
16.
Mar Drugs ; 20(10)2022 Oct 14.
Artigo em Inglês | MEDLINE | ID: mdl-36286463

RESUMO

In recent decades, aquaculture techniques for soft corals have made remarkable progress in terms of conditions and productivity. Researchers have been able to obtain larger quantities of soft corals, thus larger quantities of biologically active metabolites, allowing them to study their biological activity in many pharmacological assays and even produce sufficient quantities for clinical trials. In this review, we summarize 201 secondary metabolites that have been identified from cultured soft corals in the era from 2002 to September 2022. Various types of diterpenes (eunicellins, cembranes, spatanes, norcembranes, briaranes, and aquarianes), as well as biscembranes, sterols, and quinones were discovered and subjected to bioactivity investigations in 53 different studies. We also introduce a more in-depth discussion of the potential biological effects (anti-cancer, anti-inflammatory, and anti-microbial) and the mechanisms of action of the identified secondary metabolites. We hope this review will shed light on the untapped potential applications of aquaculture to produce valuable secondary metabolites to tackle current and emerging health conditions.


Assuntos
Antozoários , Diterpenos , Animais , Antozoários/metabolismo , Diterpenos/farmacologia , Esteróis/metabolismo , Aquicultura , Quinonas
17.
Biochem Pharmacol ; 205: 115254, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-36210604

RESUMO

Glioma is one of the most common malignant primary brain tumors, with poor prognosis and high recurrence. There are currently few drugs approved for brain tumors; thus, it is necessary to develop new effective drugs. Natural diterpenoids have important biological activities, including antiinflammatory, antioxidative, and antitumor effects. In this study, 7α,14ß-dihydroxy-ent-kaur-17-dimethylamino-3,15-dione (DGA), a diterpenoid compound modified from glaucocalyxin A, inhibited the proliferation of many tumor cells, especially glioma. Flow cytometry analysis showed that DGA induced apoptosis in glioma cells. DGA also inhibited xenograft tumors in nude mice. It affected the expression of ceramide synthases (CerS) in glioma cells; CerS1 decreased, and CerS2 and CerS5 increased, resulting in a change in the composition of glycosphingolipids containing varying acyl chain lengths. In glioma cells treated with DGA, the gene transcription of activating transcription factor 4 (ATF4), X-box binding protein-1 (XBP1), and C/EBP-homologous protein (CHOP) in unfolded protein response pathways was upregulated. Meanwhile, the ratio of proapoptotic protein Bcl-2-associated X protein (BAX) to antiapoptotic protein B-cell lymphoma 2 (Bcl-2) also increased. This suggested that an imbalance of glycosphingolipids caused by DGA induced severe endoplasmic reticulum stress and triggered cell apoptosis. Moreover, Western blotting showed DGA inhibited the signal transducers and activators of transcription 3 (STAT3) signaling pathway by reducing the phosphorylation of STAT3 and its upstream kinases, which also promoted the apoptosis of glioma cells. Together, these results explored the anticancer activities of DGA and highlighted it as a potential candidate for treating glioma.


Assuntos
Neoplasias Encefálicas , Diterpenos , Glioma , Camundongos , Animais , Humanos , Estresse do Retículo Endoplasmático , Proteína X Associada a bcl-2/metabolismo , Camundongos Nus , Glicoesfingolipídeos/farmacologia , Glicoesfingolipídeos/uso terapêutico , Fator 4 Ativador da Transcrição/genética , Fator 4 Ativador da Transcrição/metabolismo , Fator de Transcrição CHOP/genética , Fator de Transcrição CHOP/metabolismo , Apoptose , Glioma/patologia , Diterpenos/farmacologia , Diterpenos/uso terapêutico , Neoplasias Encefálicas/tratamento farmacológico , Ceramidas/uso terapêutico , Fator de Transcrição STAT3/metabolismo
18.
Med Oncol ; 40(1): 7, 2022 Oct 29.
Artigo em Inglês | MEDLINE | ID: mdl-36308574

RESUMO

Cellular c-FLIP prevents apoptosis mediated by death receptor through inhibiting activation of caspase-8. Therefore, when c-FLIP is downregulated or eliminated, caspase-8 activation is promoted, and death receptor ligand-induced apoptosis is activated. It was reported that triptolide (TPL) sensitized tumor cells to TNF-α-induced apoptosis by blocking TNF-α-induced activation of NF-κB and transcription of c-IAP1 and c-IAP2. However, the effect of TPL on basal c-FLIP expression was not understood. In this study, we found that the combination of TNF-α and TPL accelerated apoptosis in human hepatocellular carcinoma cells and TNF-α-induced elevated as well as basal level of FLIPS protein were downregulated by TPL. Additionally, we demonstrated that the basal level of FLIPS in Huh7 cells was continuously downregulated following the incubation of TPL and downregulated more when dosage of TPL for treatment was increased. Subsequently, we showed that TPL reduced FLIPS level in a transcription- and degradation-independent mechanism. Our findings suggest that TPL induces loss of FLIPS at the post-transcriptional level independently of proteasome-mediated pathway, an additional mechanism of TPL sensitizing cancer cells to TNF-α-induced apoptosis.


Assuntos
Carcinoma Hepatocelular , Diterpenos , Neoplasias Hepáticas , Humanos , Caspase 8/metabolismo , Caspase 8/farmacologia , Complexo de Endopeptidases do Proteassoma/metabolismo , Complexo de Endopeptidases do Proteassoma/farmacologia , Regulação para Baixo , Fator de Necrose Tumoral alfa/farmacologia , Carcinoma Hepatocelular/tratamento farmacológico , Diterpenos/farmacologia , Apoptose , Neoplasias Hepáticas/tratamento farmacológico , Receptores de Morte Celular/metabolismo , Linhagem Celular Tumoral
19.
Bioorg Med Chem ; 73: 117020, 2022 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-36182801

RESUMO

The diterpene glucoside fusicoccin-A (FC-A) is a fungal phytotoxin that stabilizes the interaction of plant 14-3-3 protein and plasma membrane H+-ATPase by forming a stable ternary complex. Previous studies demonstrated that structurally modified FC-A derivatives exhibit significant antitumor activities but their synthesis involves an explosive reagent, limiting their utility and opportunities for further structure-activity-relationship studies. In this study, we synthesized a series of FC derivatives by introducing various substituents on the fusicoccan scaffold and on the glucoside moiety, and evaluated their stabilization effects on the binding of 14-3-3 to fluorescently labeled mode-1 and mode-3 phosphopeptides. The results showed that introducing an amino group at the 6'-position of the glucoside moiety improves stabilization. Furthermore, cell-based evaluation demonstrated that 6'-amino benzyl 21b exhibits higher antiproliferative activity than previously developed FC agents.


Assuntos
Proteínas 14-3-3 , Diterpenos , Proteínas 14-3-3/metabolismo , Diterpenos/farmacologia , Glucosídeos , Glicosídeos/metabolismo , Fosfopeptídeos/metabolismo , ATPases Translocadoras de Prótons/metabolismo
20.
Eur J Med Chem ; 243: 114713, 2022 Dec 05.
Artigo em Inglês | MEDLINE | ID: mdl-36087386

RESUMO

Pleuromutilins, the unique fungal metabolites possessing 5/6/8 tricyclic skeleton, are potent antibacterial leading compounds for the development of new antibiotics. We applied the MS/MS molecular networking technique and the combinatorial biosynthesis approach to discover new pleuromutilin analogues. Ten pleuromutilin derivatives including seven new compounds (1-7) were obtained from the solid culture of Omphalina mutila. The gene cluster for the biosynthesis of pleuromutilins in the mushroom of O. mutila was identified and further expressed in yeast. Nine pleuromutilin-type diterpenes including three new "unnatural" pleuromutilins (16-18) were generated in a GGPP-engineered Saccharomyces cerevisiae. The antimicrobial bioassays indicated that compounds 3, 9, 10, 15, and 17 exhibited potent inhibition against methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococcus faecalis (VRE). Several pleuromutilins were found to show immunomodulatory activities by promoting the cell viability, enhancing the ROS and NO production, or increasing the levels of proinflammatory cytokines IL-6 and TNF-α in the macrophage RAW 264.7. The structure-activity relationship for pleuromutilins was analyzed.


Assuntos
Diterpenos , Staphylococcus aureus Resistente à Meticilina , Compostos Policíclicos , Espectrometria de Massas em Tandem , Compostos Policíclicos/farmacologia , Diterpenos/farmacologia , Antibacterianos/farmacologia , Testes de Sensibilidade Microbiana
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