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1.
J Nat Prod ; 85(11): 2541-2546, 2022 11 25.
Artigo em Inglês | MEDLINE | ID: mdl-36367222

RESUMO

Cladoxanthones A (1) and B (2), two xanthone-derived metabolites featuring a new spiro[cyclopentane-1,2'-[3,9a]ethanoxanthene]-2,4',9',11'(4a'H)-tetraone skeleton, were isolated from cultures of the ascomycete fungus Cladosporium sp., together with the known mangrovamide J (3). Their structures were elucidated primarily by NMR experiments. The absolute configurations of 1 and 2 were assigned by X-ray crystallography using Cu Kα radiation. Compound 1 could be generated from the hypothetical precursors related to α-methylene ketone and dihydro-xanthone via a Diels-Alder reaction, while 2 could be an oxidative coupling product resulting from 1 and 3. Compounds 1 and 2 showed weakly cytotoxic effects.


Assuntos
Antineoplásicos , Cladosporium , Ciclopentanos , Xantonas , Humanos , Antineoplásicos/química , Antineoplásicos/isolamento & purificação , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Cladosporium/química , Cristalografia por Raios X , Ciclopentanos/química , Ciclopentanos/isolamento & purificação , Ciclopentanos/farmacologia , Estrutura Molecular , Xantonas/química , Xantonas/isolamento & purificação , Xantonas/farmacologia
2.
J Nat Prod ; 85(11): 2592-2602, 2022 11 25.
Artigo em Inglês | MEDLINE | ID: mdl-36288556

RESUMO

In this work, four new cyclodepsipeptides, fusarihexins C-E (1-3) and enniatin Q (4), four new cyclopentane derivatives, fusarilins A-D (5-8), together with eight known compounds (9-16), were isolated from cultures of the endophytic fungus Fusarium sp. The structures of the isolated compounds were elucidated by analysis of HRMS and NMR spectroscopic data. The absolute configurations were determined using Marfey's method, a modified Mosher's method, single-crystal X-ray diffraction analysis, and ECD analysis. The antitumor activities of the isolated compounds in vitro were evaluated. Cyclodepsipeptides displayed cytotoxicities against the Huh-7, MRMT-1, and HepG-2 cell lines. Compounds 4, 9, 10, and 12 with IC50 values of 1.0-9.1 µM exhibited the most potent cytotoxicities against the three cell lines as compared to the positive control-5-fluorouracil. Compounds 1-3 and 11 exhibited moderate cytotoxic activities (IC50 values of 10.7-20.1 µM).


Assuntos
Antineoplásicos , Ciclopentanos , Depsipeptídeos , Fusarium , Antineoplásicos/química , Antineoplásicos/isolamento & purificação , Antineoplásicos/farmacologia , Cristalografia por Raios X , Ciclopentanos/química , Ciclopentanos/isolamento & purificação , Ciclopentanos/farmacologia , Depsipeptídeos/química , Fusarium/química , Estrutura Molecular , Células Hep G2 , Humanos
3.
J Mol Model ; 28(9): 283, 2022 Aug 31.
Artigo em Inglês | MEDLINE | ID: mdl-36044079

RESUMO

The application of antineoplastic chemotherapeutic agents causes a common side effect known as chemotherapy-induced peripheral neuropathy (CIPN) that leads to reducing the quality of patient's life. This research involves the performance of molecular docking and molecular dynamic (MD) simulation studies to explore the impact of terpenoids of Ginkgo biloba on the targets (CB-1, TLR4, FAAH-1, COX-1, COX-2) that can significantly affect the controlling of CIPN's symptoms. According to the in-vitro and in-vivo investigations, terpenoids, particularly ginkgolides B, A, and bilobalide, can cause significant effects on neuropathic pain. The molecular docking results disclosed the tendency of our ligands to interact with mainly CB1 and FAAH-1, as well as partly with TLR4, throughout their interactions with targets. Terpene trilactone can exhibit a lower rate of binding energy than CB1's inhibitor (7dy), while being precisely located in the CB1's active site and capable of inducing stable interactions by forming hydrogen bonds. The analyses of MD simulation proved that ginkgolide B was a more suitable activator and inhibitor for CB1 and TLR4, respectively, when compared to bilobalide and ginkgolide A. Moreover, bilobalide is capable of inhibiting FAAH-1 more effectively than the two other ligands. According to the analyses of ADME, every three ligands followed the Lipinski's rule of five. Considering these facts, the exertion of three ligands is recommended for their anti-inflammatory, neuroprotective, and anti-nociception influences caused by primarily activating CB1 and inhibiting FAAH-1 and TLR4; in this regard, these compounds can stand as potential candidates for the control and treatment of CIPN's symptoms.


Assuntos
Bilobalídeos , Doenças do Sistema Nervoso Periférico , Ciclopentanos/química , Ciclopentanos/farmacologia , Furanos/farmacologia , Ginkgo biloba/química , Humanos , Lactonas/química , Simulação de Acoplamento Molecular , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Doenças do Sistema Nervoso Periférico/tratamento farmacológico , Doenças do Sistema Nervoso Periférico/prevenção & controle , Extratos Vegetais , Terpenos/farmacologia , Receptor 4 Toll-Like
4.
Eur J Med Chem ; 231: 114156, 2022 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-35131538

RESUMO

Neural precursor cell expressed developmentally downregulated protein-8 (NEDD8) is a ubiquitin-like protein, which activates an important post-translational modification process: neddylation, thereby regulating the stability and degradation of various proteins related to multiple physiological processes. And the abnormal activation of NEDD8 (overexpression or underexpression) is related to the occurrence of multiple cancers including gastric carcinoma. NEDD8 activating enzyme (NAE), a key enzyme for the activation of NEDD8, controls the initiation of the NEDD8 transfer cascade, which is an important target for anti-tumor drugs. With the disclosure of the anti-tumor mechanism, NAE modulators (inhibitors and agonists) have gradually become a research hotspot in the development of anti-tumor drugs. And the application of NAE modulators has also been further expanded, not only limited to certain hematological tumors, its therapeutic potential in multiple solid tumors, especially gastric carcinoma, has been gradually uncovered. This paper mainly explains the structural characteristics, catalytic sites, and mechanism of NAE. And the relationships between neddylation and tumors are also elaborated from the perspective of NAE regulating the downstream pathways. In addition, the NAE modulators reported in recent years were reviewed, mainly focusing on their discovery processes, structure-activity relationships, inhibitory efficacy, pharmacological mechanism, and clinical research. And we reasonably predict the application of NAE modulators in gastric carcinoma, according to its relationship with neddylation. We summarize the issues in NAE modulator development and discuss the possible development directions.


Assuntos
Antineoplásicos , Carcinoma , Neoplasias Gástricas , Antineoplásicos/química , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Carcinoma/tratamento farmacológico , Ciclopentanos/química , Humanos , Neoplasias Gástricas/tratamento farmacológico , Relação Estrutura-Atividade , Ubiquitinas/metabolismo
5.
Sci Rep ; 11(1): 24176, 2021 12 17.
Artigo em Inglês | MEDLINE | ID: mdl-34921216

RESUMO

Apigenin is one of the most studied flavonoids and is widely distributed in the plant kingdom. Apigenin exerts important antioxidant, antibacterial, antifungal, antitumor activities, and anti-inflammatory effects in neurological or cardiovascular disease. Chalcone isomerase A (chiA) is an important enzyme of the flavonoid biosynthesis pathway. In order to enhance the apigenin production, the petunia chi A gene was transformed for Astragalus trigonus. Bialaphos survived plants were screened by PCR, dot blot hybridization and RT-PCR analysis. Also, jasmonic acid, salicylic acid, chitosan and yeast extract were tested to evaluate their capacity to work as elicitors for apigenin. Results showed that yeast extract was the best elicitor for induction of apigenin with an increase of 3.458 and 3.9 fold of the control for calli and cell suspension culture, respectively. Transformed cell suspension showed high apigenin content with a 20.17 fold increase compared to the control and 6.88 fold more than the yeast extract treatment. While, transformed T1 calli derived expressing chiA gene produced apigenin 4.2 fold more than the yeast extract treatment. It can be concluded that the highest accumulation of apigenin was obtained with chiA transgenic cell suspension system and it can be utilized to enhancement apigenin production in Astragalus trigonus.


Assuntos
Apigenina/metabolismo , Astrágalo/enzimologia , Liases Intramoleculares/genética , Técnicas de Cultura de Células , Extratos Celulares/química , Quitosana/química , Ciclopentanos/química , Flavonoides/biossíntese , Oxilipinas/química , Ácido Salicílico/química , Leveduras/química
6.
Chem Biodivers ; 18(12): e2100594, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34704347

RESUMO

Terrein is a small-molecule polyketide compound with a simple structure mainly isolated from fungi. Since its discovery in 1935, many scholars have conducted a series of research on its structure identification, isolation source, production increase, synthesis and biological activity. Studies have shown that terrein has a variety of biological activities, not only can inhibit melanin production and epidermal hyperplasia, but also has anti-cancer, anti-inflammatory, anti-angiopoietic secretion, antibacterial, insecticidal activities, and so on. It has potential application prospects in beauty, medicine, agriculture and other fields. This article reviews the process of structural identification of terrein since 1935, and summarizes the latest advances in its isolation, source, production increase, synthesis, and biological activity evaluation, with a view to providing a reference and helping for the in-depth research of terrein.


Assuntos
Antibacterianos/farmacologia , Antineoplásicos/farmacologia , Ciclopentanos/farmacologia , Fusarium/efeitos dos fármacos , Inseticidas/farmacologia , Schistosoma mansoni/efeitos dos fármacos , Animais , Antibacterianos/química , Antibacterianos/isolamento & purificação , Antineoplásicos/química , Antineoplásicos/isolamento & purificação , Aspergillus/química , Proliferação de Células/efeitos dos fármacos , Ciclopentanos/química , Ciclopentanos/isolamento & purificação , Humanos , Inseticidas/química , Inseticidas/isolamento & purificação , Estrutura Molecular
7.
J Photochem Photobiol B ; 223: 112287, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34454316

RESUMO

The rise in the antibiotic resistance rate of Helicobacter pylori has led to an increasing eradication failure of this carcinogenic bacterial pathogen worldwide. This underlines the need for alternative antibacterial strategies against H. pylori infection. Antimicrobial photodynamic therapy (aPDT) is a promising non-pharmacological antibacterial technology. In this study, the selective killing activities of three benzylidene cyclopentanone (BCP) photosensitizers (Y1, P1 and P3) towards H. pylori over normal human gastric epithelial GES-1 cells were evaluated and the ex vivo photodynamic inactivation effect was preliminarily assessed on twelve H. Pylor-infected mice. Results showed that under the irradiation of 24 J/cm2 532 nm laser, Y1, P1 and P3 at 2.5 µM induced a 3-log10 reduction of H. pylori CFU (99.9% killing). Confocal images showed that P3, unlike Y1 and P1, could not be uptaken by GES-1 cells. P3 at 2.5 to 20 µM showed not significant (p > 0.05) phototoxicity to GES-1 cells, nevertheless, Y1 and P1 under the same concentrations exhibited remarkable phototoxicity to GES-1 cells. In the co-culture of H. pylori and GES-1 cells, P3 at 2.5 µM led to a complete eradication of H. pylori under the irradiation of 24 J/cm2 532 nm laser. While for the GES-1 cells, no significant (p > 0.05) phototoxicity was observed under the same aPDT dosage. The ex vivo experiments showed that P3 mediated aPDT resulted in 82.4% to 100% reduction of H. pylori CFU without damaging the gastric mucosa. To sum up, P3 is a promising anti-H. pylori photosensitizer with the ability to selectively photo-inactivate H. pylori while sparing normal gastric tissues.


Assuntos
Ciclopentanos/química , Helicobacter pylori/efeitos dos fármacos , Lasers , Fármacos Fotossensibilizantes/farmacologia , Animais , Compostos de Benzilideno/química , Cátions/química , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos da radiação , Ciclopentanos/metabolismo , Ciclopentanos/farmacologia , Ciclopentanos/uso terapêutico , Modelos Animais de Doenças , Mucosa Gástrica/efeitos dos fármacos , Mucosa Gástrica/microbiologia , Mucosa Gástrica/patologia , Mucosa Gástrica/efeitos da radiação , Infecções por Helicobacter/tratamento farmacológico , Infecções por Helicobacter/patologia , Helicobacter pylori/efeitos da radiação , Helicobacter pylori/ultraestrutura , Humanos , Camundongos , Fármacos Fotossensibilizantes/química , Fármacos Fotossensibilizantes/metabolismo , Fármacos Fotossensibilizantes/uso terapêutico
8.
Molecules ; 26(10)2021 May 13.
Artigo em Inglês | MEDLINE | ID: mdl-34068337

RESUMO

Cancer is a serious problem in modern medicine, mainly due to the insufficient effectiveness of currently available therapies. There is a particular interest in compounds of natural origin, which can be used in the prophylaxis, as well as in the treatment and support of cancer treatment. One such compound is jasmonic acid (3-oxo-2-(pent-2'-enyl)cyclopentane acetic acid; isolated active form: trans-(-)-(3R,7R)- and cis-(+)-(3R,7S)-jasmonic acid) and its derivatives, which, due to their wide range of biological activities, are also proposed as potential therapeutic agents. Therefore, a review of literature data on the biological activity of jasmonates was prepared, with particular emphasis on the mechanisms of jasmonate action in neoplastic diseases. The anti-tumor activity of jasmonate compounds is based on altered cellular ATP levels; induction of re-differentiation through the action of Mitogen Activated Protein Kinases (MAPKs); the induction of the apoptosis by reactive oxygen species. Jasmonates can be used in anti-cancer therapy in combination with other known drugs, such as cisplatin, paclitaxel or doxorubicin, showing a synergistic effect. The structure-activity relationship of novel jasmonate derivatives with anti-tumor, anti-inflammatory and anti-aging effects is also shown.


Assuntos
Ciclopentanos/farmacologia , Processos Neoplásicos , Oxilipinas/farmacologia , Animais , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Ciclopentanos/química , Metabolismo Energético , Humanos , Oxilipinas/química , Espécies Reativas de Oxigênio/metabolismo
9.
ChemMedChem ; 16(18): 2781-2785, 2021 09 16.
Artigo em Inglês | MEDLINE | ID: mdl-34115919

RESUMO

Several naturally occurring cyclopentenones, such as palmenones and nigrosporiones, exhibit antimicrobial activity. Herein we describe the antimicrobial activity of cyclopentenones and derivatives that can be easily accessed from biomass derivatives furfural and 5-hydroxymethylfurfural. Upon screening a range of functionalized trans-diamino-cyclopentenones (DCPs) and δ-lactone-fused cyclopentenones (LCPs), an oxime ether derivative of DCP was identified that exhibited remarkable antimicrobial activity against Gram-positive bacteria, including resistant strains such as methicillin-resistant S. aureus (MRSA) and vancomycin-resistant E. faecalis (VRE) strains.


Assuntos
Antibacterianos/farmacologia , Ciclopentanos/farmacologia , Enterococcus faecalis/efeitos dos fármacos , Éter/farmacologia , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Oximas/farmacologia , Antibacterianos/síntese química , Antibacterianos/química , Ciclopentanos/síntese química , Ciclopentanos/química , Relação Dose-Resposta a Droga , Éter/síntese química , Éter/química , Testes de Sensibilidade Microbiana , Estrutura Molecular , Oximas/síntese química , Oximas/química , Relação Estrutura-Atividade , Resistência a Vancomicina/efeitos dos fármacos
10.
Biomolecules ; 11(3)2021 03 23.
Artigo em Inglês | MEDLINE | ID: mdl-33807046

RESUMO

Neddylation is a post-translational modification that is essential for a variety of cellular processes and is linked to many human diseases including cancer, neurodegeneration, and autoimmune disorders. Neddylation involves the conjugation of the ubiquitin-like modifier neural precursor cell expressed developmentally downregulated protein 8 (NEDD8) to target proteins, and has been studied extensively in various eukaryotes including fungi, plants, and metazoans. Here, we examine the biological processes influenced by neddylation in the social amoeba, Dictyostelium discoideum, using a well-established inhibitor of neddylation, MLN4924 (pevonedistat). NEDD8, and the target of MLN4924 inhibition, NEDD8-activating enzyme E1 (NAE1), are highly conserved in D. discoideum (Nedd8 and Nae1, respectively). Treatment of D. discoideum cells with MLN4924 increased the amount of free Nedd8, suggesting that MLN4924 inhibited neddylation. During growth, MLN4924 suppressed cell proliferation and folic acid-mediated chemotaxis. During multicellular development, MLN4924 inhibited cyclic adenosine monophosphate (cAMP)-mediated chemotaxis, delayed aggregation, and suppressed fruiting body formation. Together, these findings indicate that neddylation plays an important role in regulating cellular and developmental events during the D. discoideum life cycle and that this organism can be used as a model system to better understand the essential roles of neddylation in eukaryotes, and consequently, its involvement in human disease.


Assuntos
Ciclopentanos/química , Ciclopentanos/farmacologia , Dictyostelium/efeitos dos fármacos , Proteína NEDD8/metabolismo , Pirimidinas/química , Pirimidinas/farmacologia , Quimiotaxia/efeitos dos fármacos , Processamento de Proteína Pós-Traducional
11.
ChemMedChem ; 16(11): 1804-1812, 2021 06 07.
Artigo em Inglês | MEDLINE | ID: mdl-33635596

RESUMO

Cytotoxic complexes containing molybdenum are widely studied as a potential substitution for commercially used drugs that often suffer from pronounced side effects and cellular resistance. Compounds of the type [(η5 -Cp')Mo(CO)2 (N,N L)][BF4 ], where Cp is cyclopentadienyl and N,N L is a bidentate ligand, are well known for their strong anticancer activity. It is a generally accepted paradigm that the nature of the coordinated N,N L ligand has a major impact on the cytotoxicity. In this study, a series of new functionalised Cp complexes of molybdenum was synthesised from derivatised fulvenes as π-ligand precursors. Indeed, the coordination sphere's modulation by various N,N-chelating ligands afforded species active toward leukemic cell line MOLT-4 with IC50 values depending on the character of the N,N-chelator used. However, following study clearly showed that functionalisation of the Cp ring with an amine moiety considerably improved cytotoxicity. These results are of crucial importance for the future design of highly active cytotoxic drugs, as modification of cyclopentadienyl is believed to have a minor effect on biological activity.


Assuntos
Antineoplásicos/farmacologia , Complexos de Coordenação/farmacologia , Ciclopentanos/farmacologia , Molibdênio/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Complexos de Coordenação/síntese química , Complexos de Coordenação/química , Ciclopentanos/química , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Ligantes , Estrutura Molecular , Molibdênio/química
12.
Chempluschem ; 86(4): 533-539, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33540490

RESUMO

The conformational preferences of oligomers of δ-amino acid (δAc5 a) with a cyclopentyl constraint in the Cß -Cγ bond of the backbone were investigated by using DFT methods in the gas phase and in solution. The folded structures with C10 H-bonded pseudocycles were most preferred for dimer and tetramer of δAc5 a residues both in chloroform and water. However, for the hexameric Ac-(δAc5 a)6 -NHMe, the mixed H16/14 helical structure was found to be most preferred in chloroform (populated at 68 %), whereas the H14 helical structure was the most dominant conformation in water (populated at 60 %). The stability of the former was ascribed to the intrinsic conformational energy, whereas the solvation free energy was crucial to stabilize the latter. Pyrrolidine-substituted analogues of the hexameric Ac-(δAc5 a)6 -NHMe, with adjacent amine diads that are almost exactly one turn apart with two nitrogen atoms separated by ca. 5.5 Å, adopted helical structures. They are potential catalysts in nonpolar and polar solvents as they have similar structures to a helical 1 : 2 α:ß-heptapeptide that exhibited good catalytic performance in the crossed aldol condensation.


Assuntos
Ciclopentanos/química , Peptídeos/química , Cristalografia por Raios X , Teoria da Densidade Funcional , Gases/química , Ligação de Hidrogênio , Peptídeos/metabolismo , Conformação Proteica , Pirrolidinas/química , Termodinâmica , Água/química
13.
Chem Biodivers ; 18(2): e2000956, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33533162

RESUMO

The marine fungus, Aspergillus flavipes (MTCC 5220), was isolated from the pneumatophore of a mangrove plant Acanthus ilicifolius found in Goa, India. The crude extract of A. flavipes was found to show anti-inflammatory activity. It blocked interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) production in lipopolysaccharide (LPS)-activated THP-1 cells with IC50 of 2.69±0.5 µM and 6.64±0.4 µM, respectively. The chemical investigation led to the isolation of optically inactive 4ß-[(1E)-propen-1-yl]cyclopentane-1ß,2ß-diol (1) along with a new optically active diastereoisomeric compound, 4ß-[(1E)-propen-1-yl]cyclopentane-1ß,2α-diol (2). In addition, the fungus also produced known compounds (+)-terrein (3), butyrolactone I (4) and butyrolactone II (5) in high yields. Among these, (+)-terrein (3) exhibited IL-6 and TNF-α inhibition activity with IC50 of 8.5±0.68 µM and 15.76±0.18 µM, respectively, while butyrolactone I (4) exhibited IC50 of 12.03±0.85 µM (IL-6) and 43.29±0.76 µM (TNF-α) inhibition activity with low toxicity to host cells in LPS stimulated THP-1 cells. This is the first report of the isolation and characterization of 4ß-[(1E)-propen-1-yl]cyclopentane-1ß,2α-diol (2). The structures of all the isolated compounds were elucidated on the basis of extensive detailed NMR spectroscopic data. Anti-inflammatory activity of the fungi A. flavipes is presented here for the first time, which was due to (+)-terrein and butyrolactone I, as the major constituents and they can be further explored in the therapeutic area.


Assuntos
Anti-Inflamatórios/química , Aspergillus/química , Produtos Biológicos/química , 4-Butirolactona/análogos & derivados , 4-Butirolactona/química , 4-Butirolactona/farmacologia , Anti-Inflamatórios/farmacologia , Produtos Biológicos/farmacologia , Ciclopentanos/química , Ciclopentanos/farmacologia , Humanos , Interleucina-6/antagonistas & inibidores , Interleucina-6/imunologia , Lipopolissacarídeos/imunologia , Células THP-1 , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Fator de Necrose Tumoral alfa/imunologia
14.
Eur J Med Chem ; 214: 113194, 2021 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-33548634

RESUMO

The discovery of natural specialized pro-resolving mediators and their corresponding receptors, such as formyl peptide receptor 2 (FPR2), indicated that resolution of inflammation (RoI) is an active process which could be harnessed for innovative approaches to tame pathologies with underlying chronic inflammation. In this work, homology modelling, molecular docking and pharmacophore studies were deployed to assist the rationalization of the structure-activity relationships of known FPR2 agonists. The developed pharmacophore hypothesis was then used in parallel with the homology model for the design of novel ligand structures and in virtual screening. In the first round of optimization compound 8, with a cyclopentane core, was chosen as the most promising agonist (ß-arrestin recruitment EC50 = 20 nM and calcium mobilization EC50 = 740 nM). In a human neutrophil static adhesion assay, compound 8 decreased the number of adherent neutrophils in a concentration dependent manner. Further investigation led to the more rigid cycloleucines (compound 22 and 24) with improved ADME profiles and maintaining FPR2 activity. Overall, we identified novel cyclopentane urea FPR2 agonists with promising ADMET profiles and the ability to suppress the inflammatory process by inhibiting the neutrophil adhesion cascade, which indicates their anti-inflammatory and pro-resolving properties.


Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Doenças Cardiovasculares/tratamento farmacológico , Ciclopentanos/farmacologia , Inflamação/tratamento farmacológico , Receptores de Formil Peptídeo/agonistas , Receptores de Lipoxinas/agonistas , Ureia/farmacologia , Anti-Inflamatórios não Esteroides/síntese química , Anti-Inflamatórios não Esteroides/química , Doenças Cardiovasculares/metabolismo , Adesão Celular/efeitos dos fármacos , Ciclopentanos/síntese química , Ciclopentanos/química , Relação Dose-Resposta a Droga , Células Hep G2 , Humanos , Inflamação/metabolismo , Modelos Moleculares , Estrutura Molecular , Neutrófilos/efeitos dos fármacos , Receptores de Formil Peptídeo/metabolismo , Receptores de Lipoxinas/metabolismo , Relação Estrutura-Atividade , Células Tumorais Cultivadas , Ureia/análogos & derivados , Ureia/química
15.
Eur J Pharmacol ; 894: 173853, 2021 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-33422507

RESUMO

Acute promyelocytic leukemia (APL) is associated with PML-RARα oncogene, which is treated using all-trans retinoic acid (ATRA)-based chemotherapy. However, chemoresistance is observed in 20-30% of treated patients and represents a clinical challenge, raising the importance of the development of new therapeutic options. In the present study, the effects of three synthetic cyclopenta[b]indoles on the leukemia phenotype were investigated using NB4 (ATRA-sensitive) and NB4-R2 (ATRA-resistant) cells. Among the tested synthetic cyclopenta[b]indoles, compound 2, which contains a heterocyclic nucleus, was the most active, presenting time-dependent cytotoxic activity in the µM range in APL cells, without cytotoxicity for normal leukocytes, and was selected for further characterization. Compound 2 significantly decreased clonogenicity, increased apoptosis, and caused cell cycle arrest at S and G2/M phases in a drug concentration-dependent manner. Morphological analyses indicated aberrant mitosis and diffuse tubulin staining upon compound 2 exposure, which corroborates cell cycle findings. In the molecular scenario, compound 2 reduced STMN1 expression and activity, and induced PARP1 cleavage and H2AX and CHK2 phosphorylation, and modulated CDKN1A, PMAIP1, GADD45A, and XRCC3 expressions, indicating reduction of cell proliferation, apoptosis, and DNA damage. Moreover, in the in vivo tubulin polymerization assay, NB4 and NB4-R2 cells showed a reduction in the levels of polymerized tubulin upon compound 2 exposure, which indicates tubulin as a target of the drug. Molecular docking supports this hypothesis. Taken together, these data indicated that compound 2 exhibits antileukemic effects through disrupting the microtubule dynamics, identifying a possible novel potential antineoplastic agent for the treatment of ATRA-resistant APL.


Assuntos
Antineoplásicos/farmacologia , Ciclopentanos/química , Indóis/farmacologia , Leucemia Promielocítica Aguda/tratamento farmacológico , Microtúbulos/metabolismo , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Dano ao DNA/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Humanos , Indóis/química , Microtúbulos/efeitos dos fármacos , Mitose/efeitos dos fármacos , Modelos Moleculares , Estatmina/biossíntese , Ensaio Tumoral de Célula-Tronco
16.
Int J Mol Sci ; 22(2)2021 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-33467778

RESUMO

In the methyl-D-erythritol-4-phosphate (MEP) pathway, 1-deoxy-D-xylose-5-phosphate synthase (DXS) is considered the key enzyme for the biosynthesis of terpenoids. In this study, PmDXS (MK970590) was isolated from Pinus massoniana. Bioinformatics analysis revealed homology of MK970590 with DXS proteins from other species. Relative expression analysis suggested that PmDXS expression was higher in roots than in other plant parts, and the treatment of P. massoniana seedlings with mechanical injury via 15% polyethylene glycol 6000, 10 mM H2O2, 50 µM ethephon (ETH), 10 mM methyl jasmonate (MeJA), and 1 mM salicylic acid (SA) resulted in an increased expression of PmDXS. pET28a-PmDXS was expressed in Escherichia coli TransB (DE3) cells, and stress analysis showed that the recombinant protein was involved in resistance to NaCl and drought stresses. The subcellular localization of PmDXS was in the chloroplast. We also cloned a full-length 1024 bp PmDXS promoter. GUS expression was observed in Nicotiana benthamiana roots, stems, and leaves. PmDXS overexpression significantly increased carotenoid, chlorophyll a, and chlorophyll b contents and DXS enzyme activity, suggesting that DXS is important in isoprenoid biosynthesis. This study provides a theoretical basis for molecular breeding for terpene synthesis regulation and resistance.


Assuntos
Pentosefosfatos/química , Pinus/enzimologia , Terpenos/química , Transferases/metabolismo , Acetatos/química , Clorofila/química , Clorofila A/química , Biologia Computacional , Ciclopentanos/química , Escherichia coli/metabolismo , Perfilação da Expressão Gênica , Oxilipinas/química , Pigmentação , Folhas de Planta , Caules de Planta/enzimologia , Regiões Promotoras Genéticas , Proteínas Recombinantes/metabolismo , Ácido Salicílico/química , Nicotiana/metabolismo , Transferases/genética , Xilose
17.
Bioorg Med Chem ; 29: 115887, 2021 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-33310545

RESUMO

A series of methoxy naphthyl substituted cyclopenta[d]pyrimidine compounds, 4-10, were designed and synthesized to study the influence of the 3-D conformation on microtubule depolymerizing and antiproliferative activities. NOESY studies with the N,2-dimethyl-N-(6'-methoxynaphthyl-1'-amino)-cyclopenta[d]pyrimidin-4-amine (4) showed hindered rotation of the naphthyl ring around the cyclopenta[d]pyrimidine scaffold. In contrast, NOESY studies with N,2-dimethyl-N-(5'-methoxynaphthyl-2'-amino)-cyclopenta[d]pyrimidin-4-amine (5) showed free rotation of the naphthyl ring around the cyclopenta[d]pyrimidine scaffold. The rotational flexibility and conformational dissimilarity between 4 and 5 led to a significant difference in biological activities. Compound 4 is inactive while 5 is the most potent in this series with potent microtubule depolymerizing effects and low nanomolar IC50 values in vitro against a variety of cancer cell lines. The ability of 5 to inhibit tumor growth in vivo was investigated in a U251 glioma xenograft model. The results show that 5 had better antitumor effects than the positive control temozolomide and have identified 5 as a potential preclinical candidate for further studies. The influence of conformation on the microtubule depolymerizing and antitumor activity forms the basis for the development of conformation-activity relationships for the cyclopenta[d]pyrimidine class of microtubule targeting agents.


Assuntos
Antineoplásicos/farmacologia , Neoplasias Encefálicas/tratamento farmacológico , Ciclopentanos/farmacologia , Glioma/tratamento farmacológico , Microtúbulos/efeitos dos fármacos , Pirimidinas/farmacologia , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Neoplasias Encefálicas/patologia , Proliferação de Células/efeitos dos fármacos , Ciclopentanos/síntese química , Ciclopentanos/química , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Glioma/patologia , Humanos , Masculino , Camundongos , Camundongos Nus , Modelos Moleculares , Conformação Molecular , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/patologia , Pirimidinas/síntese química , Pirimidinas/química , Relação Estrutura-Atividade , Células Tumorais Cultivadas
18.
Bioorg Med Chem Lett ; 31: 127672, 2021 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-33161126

RESUMO

The G-protein coupled receptor - GPR120 has recently been implicated as a novel target for colorectal cancer (CRC) and other cancer managements. In this study, a homology model of GPR120S (short isoform) was generated to identify potential anti-cancer compounds targeting the GPR120 receptor using a combined in silico docking-based virtual screening (DBVS), structure-activity relationships (SAR) and in vitro screening approach. SPECS database of synthetic chemical compounds (~350,000) was screened using the developed GPR120S model to identify molecules binding to the orthosteric binding pocket followed by an AutoDock SMINA rigid-flexible docking protocol. The best 13 hit molecules were then tested in vitro to evaluate their cytotoxic activity against SW480 - human CRC cell line expressing GPR120. The test compound 1 (3-​(4-​methylphenyl)​-​2-​[(2-​oxo-​2-​phenylethyl)​sulfanyl]​-​5,6-​dihydrospiro(benzo[h]​quinazoline-​5,1'-​cyclopentane)​-​4(3H)​-​one) showed ~ 90% inhibitory effects on cell growth with micromolar affinities (IC50 = 23.21-26.69 µM). Finally, SAR analysis of compound 1 led to the identification of a more active compound from the SPECS database showing better efficacy during cell-based cytotoxicity assay -5 (IC50 = 5.89-6.715 µM), while a significant reduction in cytotoxic effects of 5 was observed in GPR120-siRNA pre-treated SW480 cells. The GPR120S homology model generated, and SAR analysis conducted by this work discovered a potential chemical scaffold, dihydrospiro(benzo[h]quinazoline-5,1'-cyclopentane)-4(3H)-one, which will aid future research on anti-cancer drug development for CRC management.


Assuntos
Antineoplásicos/farmacologia , Ciclopentanos/farmacologia , Receptores Acoplados a Proteínas G/antagonistas & inibidores , Antineoplásicos/síntese química , Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , Ciclopentanos/síntese química , Ciclopentanos/química , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Simulação de Acoplamento Molecular , Estrutura Molecular , Receptores Acoplados a Proteínas G/genética , Receptores Acoplados a Proteínas G/metabolismo , Relação Estrutura-Atividade , Células Tumorais Cultivadas
19.
J Chem Ecol ; 46(11-12): 1105-1116, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33089352

RESUMO

Western flower thrips (WFT), Frankliniella occidentalis, is a serious insect pest of Chrysanthemum [Chrysanthemum × morifolium Ramat. (Asteraceae)]. Here we have investigated whether genotypic variation in constitutive and inducible resistance to WFT correlates with phenotypic differences in leaf trichome density and the activity of the defense-related enzyme polyphenol oxidase (PPO) in chrysanthemum. Non-glandular and glandular leaf trichome densities significantly varied among ninety-five chrysanthemum cultivars. Additional analyses in a subset of these cultivars, differing in leaf trichome density, revealed significant variation in PPO activities and resistance to WFT as well. Constitutive levels of trichome densities and PPO activity, however, did not correlate with chrysanthemum resistance to WFT. Further tests showed that exogenous application of the phytohormone jasmonic acid (JA) increased non-glandular trichome densities, PPO activity and chrysanthemum resistance to WFT, and that these effects were cultivar dependent. In addition, no tradeoff between constitutive and inducible resistance to WFT was observed. JA-mediated induction of WFT resistance, however, did not correlate with changes in leaf trichome densities nor PPO activity levels. Taken together, our results suggest that chrysanthemum can display both high levels of constitutive and inducible resistance to WFT, and that leaf trichome density and PPO activity may not play a relevant role in chrysanthemum defenses against WFT.


Assuntos
Chrysanthemum/química , Chrysanthemum/parasitologia , Tisanópteros/efeitos dos fármacos , Tricomas/metabolismo , Animais , Catecol Oxidase/metabolismo , Ciclopentanos/química , Ciclopentanos/metabolismo , Genótipo , Interações Hospedeiro-Parasita , Controle de Insetos , Repelentes de Insetos/química , Repelentes de Insetos/metabolismo , Oxilipinas/química , Oxilipinas/metabolismo , Extratos Vegetais/análise , Reguladores de Crescimento de Plantas
20.
Sci Rep ; 10(1): 16760, 2020 10 07.
Artigo em Inglês | MEDLINE | ID: mdl-33028915

RESUMO

The roles of ethylene, jasmonic acid, and salicylic acid and their interactions in frankincense resin production in Boswellia sacra trees growing in the drylands of Oman were studied. On March 18 (Experiment 1) and September 17 (Experiment 2), 2018, 32-year-old B. sacra trees with multiple trunks were selected at the Agricultural Experiment Station, Sultan Qaboos University, Oman. Various lanolin pastes containing Ethrel, an ethylene-releasing compound; methyl jasmonate; sodium salicylate; and combinations of these compounds were applied to debarked wounds 15 mm in diameter on the trunks. After a certain period, the frankincense resin secreted from each wound was harvested and weighed. The anatomical characteristics of the resin ducts were also studied in the bark tissue near the upper end of each wound. The combination of Ethrel and methyl jasmonate greatly enhanced frankincense resin production within 7 days in both seasons. The application of methyl jasmonate alone, sodium salicylate alone or a combination of both did not affect resin production. These findings suggest a high possibility of artificial enhancement of frankincense resin production by the combined application of Ethrel and methyl jasmonate to B. sacra trees.


Assuntos
Boswellia , Ciclopentanos/química , Etilenos/química , Franquincenso/química , Oxilipinas/química , Resinas Vegetais/química , Ácido Salicílico/química , Omã
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