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1.
Arch Pharm Res ; 45(2): 105-113, 2022 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-35201589

RESUMO

Phenalenone derivatives sourced from fungi are polyketides that have attracted significant interest because of their diverse chemical structures and potential bioactivities. As part of our ongoing quest to discover novel natural products with biological properties from diverse natural resources, three unreported phenalenone derivatives (1-3), named ent-12-methoxyisoherqueinone (1), (-)-scleroamide (2), and (+)-scleroamide (3), together with four known phenalenone derivatives, ent-atrovenetinone (4), isoherqueinone (5), herqueinone (6), and ent-peniciherquinone (7) were isolated from the Hawaiian soil fungus Penicillium herquei FT729, collected on the Big Island, Hawaii. Compounds 2 and 3 were enantiomers, which were separated using a chiral-phase HPLC column, which provided optically pure compounds 2 and 3. The structures of the novel compounds were established by extensive spectroscopic analyses, including 1D and 2D NMR and high-resolution ESIMS. Their absolute configurations were determined using quantum chemical electronic circular dichroism (ECD) calculations. The inhibitory activity of the isolated compounds (1-7) against indoleamine 2,3-dioxygenase 1 (IDO1) was assessed. Compounds 1, 5-7 inhibited IDO1, with IC50 values of 32.59, 36.86, 19.05, and 24.18 µM, respectively. These findings demonstrated that the phenalenone derivatives 1 and 5-7, as IDO1 inhibitors, are promising anticancer immunotherapeutic agents.


Assuntos
Antineoplásicos/farmacologia , Indolamina-Pirrol 2,3,-Dioxigenase/antagonistas & inibidores , Penicillium , Fenalenos/farmacologia , Microbiologia do Solo , Antineoplásicos/química , Hawaii , Humanos , Indolamina-Pirrol 2,3,-Dioxigenase/efeitos dos fármacos , Concentração Inibidora 50 , Fenalenos/química , Relação Estrutura-Atividade
2.
Molecules ; 27(3)2022 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-35164334

RESUMO

Thiohydantoin and quinolone derivatives have attracted researchers' attention because of a broad spectrum of their medical applications. The aim of our research was to synthesize and analyze the antimicrobial properties of novel 2-thiohydantoin and 2-quinolone derivatives. For this purpose, two series of hybrid compounds were synthesized. Both series consisted of 2-thiohydantoin core and 2-quinolone derivative ring, however one of them was enriched with an acetic acid group at N3 atom in 2-thiohydantoin core. Antibacterial properties of these compounds were examined against bacteria: Staphylococcus aureus, Bacillus subtilis, Enterococcus faecalis, Escherichia coli, Pseudomonas aeruginosa, and Klebsiella pneumoniae. The antimicrobial assay was carried out using a serial dilution method to obtain the MIC. The influence of blue light irradiation on the tested compounds was investigated. The relative yield of singlet oxygen (1O2*, 1Δg) generation upon excitation with 420 nm was determined by a comparative method, employing perinaphthenone (PN) as a standard. Antimicrobial properties were also investigated after blue light irradiation of the suspensions of the hybrids and bacteria placed in microtitrate plates. Preliminary results confirmed that some of the hybrid compounds showed bacteriostatic activity to the reference Gram-positive bacterial strains and a few of them were bacteriostatic towards Gram-negative bacteria, as well. Blue light activation enhanced bacteriostatic effect of the tested compounds.


Assuntos
Antibacterianos/síntese química , Bactérias Gram-Negativas/efeitos dos fármacos , Bactérias Gram-Positivas/efeitos dos fármacos , Quinolonas/química , Tioidantoínas/química , Antibacterianos/química , Antibacterianos/farmacologia , Antifúngicos , Luz , Testes de Sensibilidade Microbiana , Estrutura Molecular , Fenalenos/farmacologia , Pseudomonas aeruginosa , Relação Estrutura-Atividade
3.
J Mater Chem B ; 9(48): 9946-9950, 2021 12 15.
Artigo em Inglês | MEDLINE | ID: mdl-34852032

RESUMO

Fluorescence imaging agents have recently received huge attention due to their important role in disease diagnostics. However, the intrinsic problems of these probes, such as complex synthetic routes and high molecular weight, remain challenging. Here, we developed novel phenaleno isoquinolinium-based fluorescent agents, Medical Fluorophores 37-41 (MF37-41), applicable to the quantitative and sensitive detection of sentinel lymph nodes (SLNs). These imaging agents showed no adverse effects on the proliferation of immune and normal cells and did not induce in vivo toxicity. In vivo fluorescence lifetime imaging demonstrated the accumulation of phenaleno isoquinolinium salts in the SLNs of nude mice within 15 min postinjection, consistent with our biodistribution findings. These results suggest that phenaleno isoquinolinium salts are feasible fluorescence imaging agents that can be used as potential lymphatic tracers.


Assuntos
Materiais Biocompatíveis/química , Descoberta de Drogas , Corantes Fluorescentes/química , Isoquinolinas/química , Imagem Óptica , Fenalenos/química , Linfonodo Sentinela/diagnóstico por imagem , Animais , Materiais Biocompatíveis/administração & dosagem , Materiais Biocompatíveis/síntese química , Linhagem Celular , Cricetulus , Corantes Fluorescentes/administração & dosagem , Corantes Fluorescentes/síntese química , Injeções Intravenosas , Isoquinolinas/administração & dosagem , Teste de Materiais , Camundongos , Estrutura Molecular , Fenalenos/administração & dosagem
4.
J Nat Prod ; 84(11): 2832-2844, 2021 11 26.
Artigo em Inglês | MEDLINE | ID: mdl-34780692

RESUMO

Phytochemical profiling was undertaken on the crude extracts of the bulbs, stems, and the fruits of Haemodorum brevisepalum, to determine the nature of the chemical constituents present. This represents the first study to investigate the fruits of a species of Haemodorum. In total, 13 new and 17 previously reported compounds were isolated and identified. The new compounds were of the phenylphenalenone-type class, with a representative of a novel structural form, named tentatively "oxabenzochromenone" (1), a compound akin to an intermediate in a recently proposed phenylphenalenone metabolic network (2), seven new phenylphenalenones (4-10), four new phenylbenzoisochromenones (11-14), and a new phenylbenzoisochromenone derivative (18). The previously reported compounds identified were of the following structure classes: oxabenzochrysenone (3, 23-26), flavonol (15, 16), phenylbenzoisochromenone (17, 21, 22, 27-30), and phenylphenalenone (19, 20). Compounds 2-4, 6-9, 15-18, 21, 22, and 26 were subjected to antimicrobial evaluation with moderate activity observed against Staphylococcus aureus MRSA and slight activity against Pseudomonas aeruginosa and Candida albicans. Compounds 4, 6-9, 17, and 21 were also evaluated for anthelminthic activity against larvae of the blood-feeding parasitic nematode Haemonchus contortus.


Assuntos
Magnoliopsida/química , Fenalenos/isolamento & purificação , Compostos Fitoquímicos/análise , Anti-Infecciosos/farmacologia , Espectroscopia de Ressonância Magnética , Fenalenos/química , Fenalenos/farmacologia , Extratos Vegetais/análise
5.
Molecules ; 26(14)2021 Jul 10.
Artigo em Inglês | MEDLINE | ID: mdl-34299471

RESUMO

Phenylphenalenones, metabolites found in Schiekia timida (Haemodoraceae), are a class of specialized metabolites with many biological activities, being phytoalexins in banana plants. In the constant search to solve the problem of glyphosate and to avoid resistance to commercial herbicides, this work aimed to investigate the phytotoxic effect of the methanolic extract of S. timida seeds. The chemical composition of the seed extract was directly investigated by NMR and UPLC-QToF MS and the pre- and post-emergence phytotoxic effect on a eudicotyledonous model (Lactuca sativa) and a monocotyledonous model (Allium cepa) was evaluated through germination and seedling growth tests. Three concentrations of the extract (0.25, 0.50, and 1.00 mg/mL) were prepared, and four replicates for each of them were analyzed. Three major phenylphenalenones were identified by NMR spectroscopy: 4-hydroxy-anigorufone, methoxyanigorufone, and anigorufone, two of those reported for the first time in S. timida. The presence of seven other phenylphenalenones was suggested by the LC-MS analyses. The phenylphenalenone mixture did not affect the germination rate, but impaired radicle and hypocotyl growth on both models. The effect in the monocotyledonous model was statistically similar to glyphosate in the lowest concentration (0.25 mg/mL). Therefore, although more research on this topic is required to probe this first report, this investigation suggests for the first time that phenylphenalenone compounds may be post-emergence herbicides.


Assuntos
Alface/crescimento & desenvolvimento , Musa/química , Cebolas/crescimento & desenvolvimento , Fenalenos/toxicidade , Extratos Vegetais/toxicidade , Sementes/química , Germinação , Alface/efeitos dos fármacos , Cebolas/efeitos dos fármacos , Toxinas Biológicas/toxicidade
6.
Int J Mol Sci ; 22(8)2021 Apr 12.
Artigo em Inglês | MEDLINE | ID: mdl-33921452

RESUMO

The three complexes [Fe(opo)3], [Cu(opo)2], and [Zn(opo)2] containing the non-innocent anionic ligand opo- (opo- = 9-oxido-phenalenone, Hopo = 9-hydroxyphenalonone) were synthesised from the corresponding acetylacetonates. [Zn(opo)2] was characterised using 1H nuclear magnetic resonance (NMR) spectroscopy, the paramagnetic [Fe(opo)3] and [Cu(opo)2] by electron paramagnetic resonance (EPR) spectroscopy. While the EPR spectra of [Cu(opo)2] and [Cu(acac)2] in dimethylformamide (DMF) solution are very similar, a rather narrow spectrum was observed for [Fe(opo)3] in tetrahydrofuran (THF) solution in contrast to the very broad spectrum of [Fe(acac)3] in THF (Hacac = acetylacetone, 2,4-pentanedione; acac- = acetylacetonate). The narrow, completely isotropic signal of [Fe(opo)3] disagrees with a metal-centred S = 5/2 spin system that is observed in the solid state. We assume spin-delocalisation to the opo ligand in the sense of an opo- to FeIII electron transfer. All compounds show several electrochemical opo-centred reduction waves in the range of -1 to -3 V vs. the ferrocene/ferrocenium couple. However, for CuII and FeIII the very first one-electron reductions are metal-centred. Electronic absorption in the UV to vis range are due to π-π* transitions in the opo core, giving Hopo and [Zn(opo)2] a yellow to orange colour. The structured bands ranging from 400 to 500 for all compounds are assigned to the lowest energy π-π* transitions. They show markedly higher intensities and slight shifts for the CuII (brown) and FeIII (red) complexes and we assume admixing metal contributions (MLCT for CuII, LMCT for FeIII). For both complexes long-wavelength absorptions assignable to d-d transitions were detected. Detailed spectroelectrochemical experiments confirm both the electrochemical and the optical assignments. Hopo and the complexes [Cu(opo)2], [Zn(opo)2], and [Fe(opo)3] show antiproliferative activities against HT-29 (colon cancer) and MCF-7 (breast cancer) cell lines in the range of a few µM, comparable to cisplatin under the same conditions.


Assuntos
Proliferação de Células/efeitos dos fármacos , Complexos de Coordenação/química , Neoplasias/tratamento farmacológico , Pentanonas/química , Cisplatino/farmacologia , Complexos de Coordenação/síntese química , Complexos de Coordenação/farmacologia , Cobre/química , Eletroquímica , Células HT29 , Humanos , Ferro/química , Ligantes , Células MCF-7 , Neoplasias/patologia , Pentanonas/síntese química , Pentanonas/farmacologia , Fenalenos/química , Análise Espectral , Zinco/química
7.
Adv Clin Exp Med ; 30(4): 431-439, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33915038

RESUMO

BACKGROUND: Keloid is a unique refractory syndrome characterized by a proliferation disorder of the fibroblasts. Recently, photodynamic therapy (PDT) has become a promising technique to modulate fibroblasts. However, use of the photosensitizer Phenalen-1-one (Ph1) in PDT for keloid remains to be explored. OBJECTIVES: This study investigated the efficacy of Ph1-PDT in the in vitro and in vivo models of keloid. MATERIAL AND METHODS: Cell viability was assessed with a Cell Counting Kit-8 (CCK-8) analysis in keloid fibroblasts. The migrated and invaded keloid fibroblasts after Ph1-PDT were detected using scratch and matrigel invasion assays in vitro. Flow cytometry measured the apoptosis changes. The protein concentrations and the mRNA expression of inflammatory modulators (interleukin 8 (IL-8) and IL-1ß) were determined using enzyme-linked immunosorbent assay (ELISA) and real-time quantitative polymerase chain reaction (RT-qPCR) methods, respectively. Nude mice were used to perform the transplantation of keloid grafts. Western blot analysis measured the protein expression of CD31, CD34, tumor growth factor ß1 (TGF-ß1), and collagen 1 in keloid fibroblasts and grafts. RESULTS: Our results revealed that Ph1-PDT significantly suppressed cell viability, migration and invasion, and enhanced the rate of cell apoptosis and caspase-3 expression in keloid fibroblasts. Moreover, in the nude mice model, Ph1-PDT decreased the volume of the graft and attenuated the vessel density by inhibiting the expression of vessel density biomarkers (CD31 and CD34) in keloid grafts. Furthermore, Ph1-PDT significantly inactivated the inflammatory mediators in keloid grafts. In addition, Ph1-PDT considerably attenuated the development of keloids by inhibiting TGF-ß1 and collagen 1 proteins in keloid fibroblasts and grafts. CONCLUSIONS: Ph1-PDT may suppress keloid progression by reducing vessel formation and inflammation, and promoting fibroblast apoptosis, suggesting a potential therapy method for keloid.


Assuntos
Queloide , Fotoquimioterapia , Animais , Apoptose , Proliferação de Células , Células Cultivadas , Fibroblastos/patologia , Queloide/tratamento farmacológico , Queloide/patologia , Camundongos , Camundongos Nus , Fenalenos , Fator de Crescimento Transformador beta1
8.
Gene ; 778: 145472, 2021 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-33549715

RESUMO

Plant type III polyketide synthases (PKSs) are associated with various functions in plant growth, development and defense by providing a multitude of polyketide scaffolds for diverse specialized metabolic pathways (SMPs). To decipher banana PKSs involved in specialized metabolism, genome-wide comparative analyses were conducted with A (Musa acuminata) and B (Musa balbisiana) genomes of banana. Both genomes retained eight chalcone synthases (CHSs), seven curcumin synthases (CURSs), three diketidyl-CoA synthases (DCSs) and one anther specific CHS (ASC). Segmental (42%) and tandem (37%) duplication events majorly flourished the banana PKS family. Six of 19 PKSs of A genome (designated as MaPKSs) showed relatively a higher expression in the root, corm, sheath, leaf and embryogenic cell suspension (ECS) of banana. To determine the defense response of MaPKSs and to highlight their candidacy in various SMPs, expression profiling was conducted by qPCR in ECSs treated with 100/200 µM of jasmonic acid (JA) and salicylic acid (SA) at 24/48 h. Maximum and subordinate expression induction of MaPKSs was apparent respectively against JA and SA treatments. Notably, most MaPKSs achieved their peak expression within 24 h of JA and the total flavonoid content was reached maximum within 24 h of JA/SA elicitations. Considering the homology, phylogeny, and expression levels in each analyzed sample (n = 13), three CHSs, three DCSs along with three CURSs and one ASC were selected as most promising candidates respectively for flavonoids, phenylphenalenones and sporopollenin biosynthesis in banana. Our findings provide a first-line resource to disclose the functions of banana PKSs involved in distinct SMPs.


Assuntos
Perfilação da Expressão Gênica/métodos , Musa/classificação , Policetídeo Sintases/genética , Sequenciamento Completo do Genoma/métodos , Biopolímeros/biossíntese , Carotenoides , Ciclopentanos/farmacologia , Flavonoides/biossíntese , Regulação da Expressão Gênica de Plantas/efeitos dos fármacos , Genoma de Planta , Redes e Vias Metabólicas/efeitos dos fármacos , Musa/genética , Oxilipinas/farmacologia , Fenalenos/metabolismo , Filogenia , Proteínas de Plantas/genética , Ácido Salicílico/farmacologia
10.
Bioorg Chem ; 106: 104477, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33279250

RESUMO

Eight phenalenone derivatives, including four new compounds, aceneoherqueinones A and B (1 and 2), (+)-aceatrovenetinone A (3a), and (+)-aceatrovenetinone B (3d), along with four known congeners, (-)-aceatrovenetinone A (3b), (-)-aceatrovenetinone B (3c), (-)-scleroderolide (4a), and (+)-scleroderolide (4b), were characterized from the marine mangrove-derived fungus Penicillium herquei MA-370. Among them, compounds 1 and 2 are rare phenalenone derivatives featuring cyclic ether unit between C-5 and C-2'. All of these compounds were subjected to chiral HPLC analysis, and the unstable stereoisomers 3a-3d, containing configurationally labile chirality centers, were characterized by online HPLC-ECD measurements supported with TDDFT-ECD calculations. The structures of these compounds were elucidated by detailed analysis of their NMR and mass spectroscopic data, and the absolute configuration of compound 1 was confirmed by X-ray diffraction analysis, while those of compounds 2 and 3a-3d were determined by TDDFT-ECD calculations of their ECD spectra. All of the isolated compounds were tested for the inhibitory activity against angiotensin-I-converting enzyme (ACE), and compounds 1 and 2 displayed activity with IC50 values 3.10 and 11.28 µM, respectively. The intermolecular interaction and potential binding sites of 1 and 2 with ACE were elaborated by molecular docking, showing that compound 1 bound well with ACE via hydrogen interactions with residues Ala261, Gln618, Trp621, and Asn624, while compound 2 interacted with residues Asp358 and Tyr360.


Assuntos
Inibidores da Enzima Conversora de Angiotensina/farmacologia , Penicillium/química , Peptidil Dipeptidase A/metabolismo , Fenalenos/farmacologia , Inibidores da Enzima Conversora de Angiotensina/química , Inibidores da Enzima Conversora de Angiotensina/isolamento & purificação , Teoria da Densidade Funcional , Relação Dose-Resposta a Droga , Estrutura Molecular , Fenalenos/química , Fenalenos/isolamento & purificação , Estereoisomerismo , Relação Estrutura-Atividade
11.
Bioorg Chem ; 105: 104397, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-33130348

RESUMO

The study of a Hawaiian volcanic soil-associated fungal strain Penicillium herquei FT729 led to the isolation of one unprecedented benzoquinone-chromanone, herqueilenone A (1) and two phenalenone derivatives (2 and 3). Their structures were determined through extensive analysis of NMR spectroscopic data and gauge-including atomic orbital (GIAO) NMR chemical shifts and ECD calculations. Herqueilenone A (1) contains a chroman-4-one core flanked by a tetrahydrofuran and a benzoquinone with an acetophenone moiety. Plausible pathways for the biosynthesis of 1-3 are proposed. Compounds 2 and 3 inhibited IDO1 activity with IC50 values of 14.38 and 13.69 µM, respectively. Compounds 2 and 3 also demonstrated a protective effect against acetaldehyde-induced damage in PC-12 cells.


Assuntos
Inibidores Enzimáticos/farmacologia , Indolamina-Pirrol 2,3,-Dioxigenase/antagonistas & inibidores , Penicillium/química , Fenalenos/farmacologia , Acetaldeído/antagonistas & inibidores , Acetaldeído/farmacologia , Animais , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/química , Inibidores Enzimáticos/isolamento & purificação , Humanos , Indolamina-Pirrol 2,3,-Dioxigenase/metabolismo , Testes de Sensibilidade Microbiana , Estrutura Molecular , Células PC12 , Fenalenos/química , Fenalenos/isolamento & purificação , Ratos , Relação Estrutura-Atividade
12.
Biomed Pharmacother ; 132: 110814, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33086179

RESUMO

The in vitro activity against Leishmania spp. of five novel designed compounds, phenalenone derivatives, is described in this study. Previous works have shown that some phenalenones present leishmanicidal activity, some of which could induce programmed cell death events in L. amazonensis parasites. In this research, we focused on the determination of the programmed cell death evidence by detecting the characteristic features of the apoptosis-like process, such as phosphatidylserine exposure and mitochondrial membrane potential, among others. The results showed that the new derivatives have comparable or better activity and selectivity than the commonly prescribed anti-leishmanial drug. This result was obtained by inducing stronger mitochondrial depolarization or more intense phosphatidylserine exposure than miltefosine, highlighting compound 8 with moreover 9-times better selectivity index. In addition, the new five molecules activated the apoptosis-like process in the parasite. All the signals observed were indicative of the death process that the parasites were undergoing.


Assuntos
Antiprotozoários/farmacologia , Leishmania/efeitos dos fármacos , Fenalenos/farmacologia , Antiprotozoários/química , Apoptose/efeitos dos fármacos , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Fenalenos/química , Fosforilcolina/análogos & derivados , Fosforilcolina/farmacologia
13.
Bioorg Chem ; 101: 103893, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32492551

RESUMO

A critical biological event that contributes to the appearance and progress of cancer and diabetes is the reversible phosphorylation of proteins, a process controlled by protein tyrosine-kinases (PTKs) and protein tyrosine-phosphatases (PTPs). Within the PTPs, PTP1B has gained significant interest since it is a validated target in drug discovery. Indeed, several PTP1B inhibitors have been developed, from both, synthesis and natural products. However, none have been approved by the FDA, due to their poor selectivity and/or pharmacokinetic properties. One of the most significant challenges to the discovery of PTP1B inhibitors (in vitro or in silico) is the use of truncated structures (PTP1B1-300), missing valuable information about the mechanisms of inhibition, and selectivity of ligands. The present study describes the biochemical characterization of a full-length PTP1B (hPTP1B1-400), as well as the description of phenalenones 1-4 and ursolic acid (5) as allosteric modulators. Compounds 1-5 showed inhibitory potential on hPTP1B1-400, with IC50 values ranging from 12.7 to 82.1 µM. Kinetic studies showed that 1 and 5 behave as mixed and non-competitive inhibitors, respectively. Circular dichroism experiments confirmed that 1 and 5 induced conformational changes to hPTP1B1-400. Further insights into the structure of hPTP1B1-400 were obtained from a homology model, which pointed out that the C-terminus (residues 301-400) is highly disordered. Molecular docking with the homologated model suggested that compounds 1 and 3-5 bind to the C-terminal domain, likely inducing conformational changes on the protein. Docking positions of compounds 1, 4, and 5 were refined with molecular dynamics simulations. Importantly, these simulations confirmed the high flexibility of the C-terminus of hPTP1B1-400, as well as the changes to its rigidity when bound to 1, 4, and 5.


Assuntos
Fenalenos/farmacologia , Proteína Tirosina Fosfatase não Receptora Tipo 1/antagonistas & inibidores , Talaromyces/química , Simulação por Computador , Dimerização , Humanos , Técnicas In Vitro , Cinética , Simulação de Acoplamento Molecular , Fenalenos/química
14.
J Nat Prod ; 83(4): 1051-1060, 2020 04 24.
Artigo em Inglês | MEDLINE | ID: mdl-32119543

RESUMO

Cultivation and extraction of the fungus Talaromyces stipitatus led to the isolation of five new oxyphenalenone-amino acid hybrids, which were named talauxins E, Q, V, L, and I based on the corresponding one-letter amino acid codes, along with their putative biosynthetic precursor, duclauxin. The rapid reaction of duclauxin with amino acids to produce talauxins was demonstrated in vitro and exploited to generate a small library of natural and unnatural talauxins. Talauxin V was shown to undergo spontaneous elimination of methyl acetate to yield the corresponding neoclauxin scaffold. This process was modeled using density functional theory calculations, revealing a dramatic change in conformation resulting from the syn elimination of methyl acetate.


Assuntos
Fenalenos/química , Talaromyces/química , Cromonas/química , Cromonas/isolamento & purificação , Cromonas/farmacologia , Conformação Molecular , Estrutura Molecular , Ressonância Magnética Nuclear Biomolecular
15.
Arch Pharm (Weinheim) ; 353(5): e2000005, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32175625

RESUMO

Based on our previously reported Bcl-2/Mcl-1 dual inhibitor 4-thiomorpholinyl-2-cyano-3-amidinophenalenone (A1) that simultaneously occupies the p2 and p4 hydrophobic pockets of Bcl-2 and Mcl-1, we optimized molecules with different bond angles of the groups extending to the p4 pocket and bulky hydrophobic groups to explore p2. Research on structure-activity relationship resulted in a new derivative B4 that is capable of occupying both the p2 and p4 more deeply and completely than A1, with Ki values determined by fluorescence polarization assay (FPAs) improving to 0.31 µM for Bcl-2 and 0.16 µM for Mcl-1. Furthermore, B4 exhibited selective lethality on cancer cells over normal cells. It showed stronger apoptosis induction than (-)-gossypol on a Bcl-2/Mcl-1-dependent cancer cell line and killed an Mcl-1-dependent cell line which is resistant to ABT-199 treatment.


Assuntos
Antineoplásicos/farmacologia , Desenho de Fármacos , Proteína de Sequência 1 de Leucemia de Células Mieloides/antagonistas & inibidores , Fenalenos/farmacologia , Proteínas Proto-Oncogênicas c-bcl-2/antagonistas & inibidores , Antineoplásicos/síntese química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Células HEK293 , Humanos , Simulação de Acoplamento Molecular , Estrutura Molecular , Fenalenos/síntese química , Fenalenos/química , Relação Estrutura-Atividade
16.
Molecules ; 25(4)2020 Feb 20.
Artigo em Inglês | MEDLINE | ID: mdl-32093426

RESUMO

The alpha-glucosidase- and lipase-inhibitory activities of three phenalenones (1-3) and one phenylpropanoid (4) from the ethyl acetate extracts of a Pseudolophiosptoma sp. are described. They represent the first secondary metabolites reported from the genus Pseudolophiostoma. Scleroderolide (1) and sclerodione (2) exhibited potent α-glucosidase- and porcine-lipase-inhibitory activity during primary screening, with better IC50 values compared to the positive controls, N-deoxynojirimycin and orlistat. In silico techniques were employed to validate the probable biological targets and elucidate the mechanism of actions of phenalenones 1 and 2. Both compounds exhibited strong binding affinities to both alpha-glucosidase and porcine lipase through H-bonding and π-π interactions. Interestingly, favorable in silico ADME (absorption, distribution, metabolism, and excretion) properties such as gastrointestinal absorption were also predicted using software.


Assuntos
Ascomicetos/química , Inibidores de Glicosídeo Hidrolases , Lipase , Simulação de Acoplamento Molecular , Fenalenos , alfa-Glucosidases/química , Animais , Inibidores de Glicosídeo Hidrolases/química , Inibidores de Glicosídeo Hidrolases/isolamento & purificação , Lipase/antagonistas & inibidores , Lipase/química , Fenalenos/química , Fenalenos/isolamento & purificação , Suínos , Tailândia
17.
Nat Prod Res ; 34(23): 3320-3327, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30798639

RESUMO

The metabolites of the mycobiont culture of the lichen Trypethelium eluteriae were isolated by column chromatography and preparative TLC. Nine compounds (1-9) including two new trypethelones, 8-methoxytrypethelone (6) and 5'-hydroxy-8-ethoxytrypethelone (9), together with four known trypethelones (3-4, 7-8), and two known phenalenones (1-2) were characterized. It is the first report of 8-methoxytrypethelone methyl ether (5) purification as a racemic mixture in T. eluteriae. Earlier, 7-hydroxyl-8-methoxyltrypethelone (10) was reported as new compound with erroneous spectroscopic data. This compound was identified later as 8-hydroxytrypethelone methyl ether (4). X-ray crystallographic structures of compounds 5-7 were elucidated for the first time. Phenalenones (1-2) and trypethelones (5-6 and 9) were the additional compounds discovered in the cultured mycobiont of T. eluteriae. Six compounds (1-2, 5-8) were screened against Mycobacterium tuberculosis H37Rv and two compounds (7-8) against non-tuberculosis mycobacteria and other human pathogenic bacteria. Compound (7) inhibited M. tuberculosis H37Rv strain with an MIC of 12.5 µg/mL.


Assuntos
Antituberculosos/química , Antituberculosos/farmacologia , Ascomicetos/química , Mycobacterium tuberculosis/efeitos dos fármacos , Fenalenos/farmacologia , Policetídeos/farmacologia , Antibacterianos/química , Antibacterianos/farmacologia , Ascomicetos/metabolismo , Cristalografia por Raios X , Avaliação Pré-Clínica de Medicamentos , Líquens , Espectroscopia de Ressonância Magnética , Testes de Sensibilidade Microbiana , Estrutura Molecular , Micobactérias não Tuberculosas/efeitos dos fármacos , Fenalenos/química , Fenalenos/isolamento & purificação , Policetídeos/química , Policetídeos/isolamento & purificação
18.
Chemistry ; 26(12): 2713-2718, 2020 Feb 26.
Artigo em Inglês | MEDLINE | ID: mdl-31814180

RESUMO

Human NAD(P)H: Quinone Oxidoreductase 1 (hNQO1) is an attractive enzyme for cancer therapeutics due to its significant overexpression in tumors compared to healthy tissues. Its unique catalytic mechanism involving the two-electron reduction of quinone-based compounds has made it a useful target to exploit in the design of hNQO1 fluorescent chemosensors and hNQO1-activatable-prodrugs. In this work, hNQO1 is exploited for an optical therapeutic. The probe uses the photosensitizer, phenalenone, which is initially quenched via photo-induced electron transfer by the attached quinone. Native phenalenone is liberated in the presence of hNQO1 resulting in the production of cytotoxic singlet oxygen upon irradiation. hNQO1-mediated activation in A549 lung cancer cells containing high levels of hNQO1 induces a dose-dependent photo-cytotoxic response after irradiation. In contrast, no photo-cytotoxicity was observed in the normal lung cell line, MRC9. By targeting hNQO1, this scaffold can be used to enhance the cancer selectivity of photodynamic therapy.


Assuntos
Antineoplásicos/química , NAD(P)H Desidrogenase (Quinona)/química , NAD/metabolismo , Fenalenos/química , Fármacos Fotossensibilizantes/química , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Humanos , NAD(P)H Desidrogenase (Quinona)/farmacologia , Fenalenos/farmacologia , Fotoquimioterapia , Fármacos Fotossensibilizantes/farmacologia , Quinonas/metabolismo , Oxigênio Singlete/química
19.
Parasit Vectors ; 12(1): 601, 2019 Dec 23.
Artigo em Inglês | MEDLINE | ID: mdl-31870406

RESUMO

BACKGROUND: The in vitro activity against Leishmania spp. of a novel group of compounds, phenalenone derivatives, is described in this study. Previous studies have shown that some phenalenones present leishmanicidal activity, and induce a decrease in the mitochondrial membrane potential in L. amazonensis parasites, so in order to elucidate the evidence of programmed cell death occurring inside the promastigote stage, different assays were performed in two different species of Leishmania. METHODS: We focused on the determination of the programmed cell death evidence by detecting the characteristic features of the apoptosis-like process, such as phosphatidylserine exposure, mitochondrial membrane potential, and chromatin condensation among others. RESULTS: The results showed that four molecules activated the apoptosis-like process in the parasite. All the signals observed were indicative of the death process that the parasites were undergoing. CONCLUSIONS: The present results highlight the potential use of phenalenone derivatives against Leishmania species and further studies should be undertaken to establish them as novel leishmanicidal therapeutic agents.


Assuntos
Antiprotozoários/química , Antiprotozoários/farmacologia , Apoptose/efeitos dos fármacos , Leishmania/efeitos dos fármacos , Fenalenos/química , Fenalenos/farmacologia , Humanos , Leishmania/citologia , Leishmania/crescimento & desenvolvimento , Leishmaniose/parasitologia , Estágios do Ciclo de Vida/efeitos dos fármacos , Estrutura Molecular
20.
Mar Drugs ; 17(12)2019 Nov 30.
Artigo em Inglês | MEDLINE | ID: mdl-31801271

RESUMO

The fungi Chrysosporium lobatum TM-237-S5 was isolated from the sponge Acanthella cavernosa, collected from the mesophotic coral ecosystem of the Red Sea. The strain was cultivated on a potato dextrose agar (PDA) medium, coupling solid-state fermentation and solid-state extraction (SSF/SSE) with a neutral macroreticular polymeric adsorbent XAD Amberlite resin (AMBERLITE XAD1600N). The SSF/SSE lead to high chemodiversity and productivity compared to classical submerged cultivation. Ten phenalenone related compounds were isolated and fully characterized by one-dimensional and two-dimensional NMR and HRMS. Among them, four were found to be new compounds corresponding to isoconiolactone, (-)-peniciphenalenin F, (+)-8-hydroxyscleroderodin, and (+)-8-hydroxysclerodin. It is concluded that SSF/SSE is a powerful strategy, opening a new era for the exploitation of microbial secondary metabolites.


Assuntos
Chrysosporium/metabolismo , Fenalenos/isolamento & purificação , Poríferos/microbiologia , Animais , Meios de Cultura , Ecossistema , Fermentação , Oceano Índico , Fenalenos/química , Metabolismo Secundário
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