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1.
J Nat Prod ; 85(3): 607-613, 2022 03 25.
Artigo em Inglês | MEDLINE | ID: mdl-35049297

RESUMO

Four new diphenyl ether derivatives, neopestolides A-D (2-5), were isolated from cultures of the plant endophytic fungus Neopestalotiopsis sp., along with the known metabolite pestalotiollide A (1); their structures were elucidated primarily by NMR experiments. The absolute configurations of 2 and 3-5 were deduced by electronic circular dichroism calculations and via Snatzke's method, respectively. Compounds 2-4 incorporate tetrahydrofuran moieties attached to the dibenzo[b,g][1,5]dioxocin-5(7H)-one skeleton via C-C linkages. Compounds 1 and 2 showed modest cytotoxicity against HepG2 cells.


Assuntos
Ascomicetos , Xylariales , Ascomicetos/química , Estrutura Molecular , Éteres Fenílicos/farmacologia , Plantas
2.
Small ; 18(9): e2105021, 2022 03.
Artigo em Inglês | MEDLINE | ID: mdl-35088527

RESUMO

Atherosclerosis (AS) is associated with high morbidity and mortality, thus imposing a growing burden on modern society. Herb-derived bicyclol (BIC) is a versatile bioactive compound that can be used to treat AS. However, its efficacy in AS is not yet described. Here, it is shown that BIC normalizes gut microflora dysbiosis induced by a high fat diet in Apoe(-/-) mice. Metagenome-wide association study analysis verifies that the modulation on carbohydrate-active enzymes and short-chain fatty acid generating genes in gut flora is among the mechanisms. The gut healthiness, especially the gut immunity and integrity, is restored by BIC intervention, leading to improved systemic immune cell dynamic and liver functions. Accordingly, the endothelial activation, macrophage infiltration, and cholesterol ester accumulation in the aortic arch are alleviated by BIC to lessen the plaque onset. Moreover, it is proved that the therapeutic effect of BIC on AS is transmissible by fecal microbiota transplantation. The current study, for the first time, demonstrates the antiatherosclerotic effects of BIC and shows that its therapeutic value can at least partially be attributed to its manipulation of gut microbiota.


Assuntos
Aterosclerose , Microbioma Gastrointestinal , Animais , Aterosclerose/tratamento farmacológico , Compostos de Bifenilo/farmacologia , Compostos de Bifenilo/uso terapêutico , Disbiose , Camundongos , Camundongos Endogâmicos C57BL
3.
Metab Eng ; 69: 198-208, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-34902590

RESUMO

Privileged ergot alkaloids (EAs) produced by the fungal genus Claviceps are used to treat a wide range of diseases. However, their use and research have been hampered by the challenging genetic engineering of Claviceps. Here we systematically refactored and rationally engineered the EA biosynthetic pathway in heterologous host Aspergillus nidulans by using a Fungal-Yeast-Shuttle-Vector protocol. The obtained strains allowed the production of diverse EAs and related intermediates, including prechanoclavine (PCC, 333.8 mg/L), chanoclavine (CC, 241.0 mg/L), agroclavine (AC, 78.7 mg/L), and festuclavine (FC, 99.2 mg/L), etc. This fungal platform also enabled the access to the methyl-oxidized EAs (MOEAs), including elymoclavine (EC), lysergic acid (LA), dihydroelysergol (DHLG), and dihydrolysergic acid (DHLA), by overexpressing a P450 enzyme CloA. Furthermore, by optimizing the P450 electron transfer (ET) pathway and using multi-copy of cloA, the titers of EC and DHLG have been improved by 17.3- and 9.4-fold, respectively. Beyond our demonstration of A. nidulans as a robust platform for EA overproduction, our study offers a proof of concept for engineering the eukaryotic P450s-contained biosynthetic pathways in a filamentous fungal host.


Assuntos
Claviceps , Alcaloides de Claviceps , Vias Biossintéticas/genética , Claviceps/genética , Claviceps/metabolismo , Sistema Enzimático do Citocromo P-450/genética , Sistema Enzimático do Citocromo P-450/metabolismo , Alcaloides de Claviceps/genética , Alcaloides de Claviceps/metabolismo , Saccharomyces cerevisiae/metabolismo
4.
Signal Transduct Target Ther ; 6(1): 414, 2021 12 06.
Artigo em Inglês | MEDLINE | ID: mdl-34873151

RESUMO

Azvudine (FNC) is a nucleoside analog that inhibits HIV-1 RNA-dependent RNA polymerase (RdRp). Recently, we discovered FNC an agent against SARS-CoV-2, and have taken it into Phase III trial for COVID-19 patients. FNC monophosphate analog inhibited SARS-CoV-2 and HCoV-OC43 coronavirus with an EC50 between 1.2 and 4.3 µM, depending on viruses or cells, and selective index (SI) in 15-83 range. Oral administration of FNC in rats revealed a substantial thymus-homing feature, with FNC triphosphate (the active form) concentrated in the thymus and peripheral blood mononuclear cells (PBMC). Treating SARS-CoV-2 infected rhesus macaques with FNC (0.07 mg/kg, qd, orally) reduced viral load, recuperated the thymus, improved lymphocyte profiles, alleviated inflammation and organ damage, and lessened ground-glass opacities in chest X-ray. Single-cell sequencing suggested the promotion of thymus function by FNC. A randomized, single-arm clinical trial of FNC on compassionate use (n = 31) showed that oral FNC (5 mg, qd) cured all COVID-19 patients, with 100% viral ribonucleic acid negative conversion in 3.29 ± 2.22 days (range: 1-9 days) and 100% hospital discharge rate in 9.00 ± 4.93 days (range: 2-25 days). The side-effect of FNC is minor and transient dizziness and nausea in 16.12% (5/31) patients. Thus, FNC might cure COVID-19 through its anti-SARS-CoV-2 activity concentrated in the thymus, followed by promoted immunity.


Assuntos
Antivirais/administração & dosagem , Azidas/administração & dosagem , COVID-19/tratamento farmacológico , Desoxicitidina/análogos & derivados , SARS-CoV-2/metabolismo , Timo , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Coronavirus Humano OC43/metabolismo , Desoxicitidina/administração & dosagem , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Ratos , Timo/metabolismo , Timo/virologia
5.
Acta Pharm Sin B ; 11(9): 2850-2858, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-33723501

RESUMO

COVID-19 pandemic caused by SARS-CoV-2 infection severely threatens global health and economic development. No effective antiviral drug is currently available to treat COVID-19 and any other human coronavirus infections. We report herein that a macrolide antibiotic, carrimycin, potently inhibited the cytopathic effects (CPE) and reduced the levels of viral protein and RNA in multiple cell types infected by human coronavirus 229E, OC43, and SARS-CoV-2. Time-of-addition and pseudotype virus infection studies indicated that carrimycin inhibited one or multiple post-entry replication events of human coronavirus infection. In support of this notion, metabolic labelling studies showed that carrimycin significantly inhibited the synthesis of viral RNA. Our studies thus strongly suggest that carrimycin is an antiviral agent against a broad-spectrum of human coronaviruses and its therapeutic efficacy to COVID-19 is currently under clinical investigation.

6.
Artigo em Inglês | MEDLINE | ID: mdl-35309096

RESUMO

Many microorganisms have mechanisms that protect cells against attack from viruses. The fermentation components of Streptomyces sp. 1647 exhibit potent anti-influenza A virus (IAV) activity. This strain was isolated from soil in southern China in the 1970s, but the chemical nature of its antiviral substance(s) has remained unknown until now. We used an integrated multi-omics strategy to identify the antiviral agents from this streptomycete. The antibiotics and Secondary Metabolite Analysis Shell (antiSMASH) analysis of its genome sequence revealed 38 biosynthetic gene clusters (BGCs) for secondary metabolites, and the target BGCs possibly responsible for the production of antiviral components were narrowed down to three BGCs by bioactivity-guided comparative transcriptomics analysis. Through bioinformatics analysis and genetic manipulation of the regulators and a biosynthetic gene, cluster 36 was identified as the BGC responsible for the biosynthesis of the antiviral compounds. Bioactivity-based molecular networking analysis of mass spectrometric data from different recombinant strains illustrated that the antiviral compounds were a class of structural analogues. Finally, 18 pseudo-tetrapeptides with an internal ureido linkage, omicsynins A1-A6, B1-B6, and C1-C6, were identified and/or isolated from fermentation broth. Among them, 11 compounds (omicsynins A1, A2, A6, B1-B3, B5, B6, C1, C2, and C6) are new compounds. Omicsynins B1-B4 exhibited potent antiviral activity against IAV with the 50% inhibitory concentration (IC50) of approximately 1 µmol∙L-1 and a selectivity index (SI) ranging from 100 to 300. Omicsynins B1-B4 also showed significant antiviral activity against human coronavirus HCoV-229E. By integrating multi-omics data, we discovered a number of novel antiviral pseudo-tetrapeptides produced by Streptomyces sp. 1647, indicating that the secondary metabolites of microorganisms are a valuable source of novel antivirals.

8.
J Nat Prod ; 83(3): 601-609, 2020 03 27.
Artigo em Inglês | MEDLINE | ID: mdl-31944123

RESUMO

Gliocladicillin C (3) is a cytotoxic epipolythiodioxopiperazine (ETP) isolated from the Ophiocordyceps-associated fungus Clonostachys rogersoniana. Although the disulfides/polysulfides in ETPs are believed to account for their cytotoxicity, and 11'-deoxyverticillin A was demonstrated to induce apoptosis and autophagy, how they mediate apoptosis and autophagy remained unknown. Here, we revealed that 3 activated caspase-dependent apoptosis and autophagy in human tumor cells, while the prepared disulfide-cleavage product failed to induce reactive oxygen species production and PARP cleavage, but further enhanced the autophagic flux compared to 3. Gliocladicillin C and its derivative also increased the phosphorylation of AMP-activated protein kinase and stimulated autophagy by affecting the glycolytic pathway. These results demonstrated that the disulfides played an essential role in inducing apoptosis, but not autophagy.


Assuntos
Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Produtos Biológicos/farmacologia , Piperazinas/farmacologia , Proteínas Quinases Ativadas por AMP/metabolismo , Antineoplásicos/química , Produtos Biológicos/química , Caspase 3 , Linhagem Celular Tumoral , Dissulfetos , Humanos , Hypocreales/química , Estrutura Molecular , Fosforilação , Piperazinas/química
9.
RSC Adv ; 10(26): 15622-15628, 2020 Apr 16.
Artigo em Inglês | MEDLINE | ID: mdl-35495431

RESUMO

Three new highly oxygenated pimarane diterpenoids, sarcosenones A-C (1-3), and the known 9α-hydroxy-1,8(14),15-isopimaratrien-3,7,11-trione (4), were isolated from cultures of an endolichenic fungus Sarcosomataceae sp. Their structures were elucidated based on NMR spectroscopic data and electronic circular dichroism (ECD) calculations. Compound 1 showed moderate cytotoxicity against a small panel of four human tumor cell lines, with IC50 values of 7.5-26.4 µM.

10.
J Am Chem Soc ; 141(36): 14052-14056, 2019 09 11.
Artigo em Inglês | MEDLINE | ID: mdl-31461283

RESUMO

Diels-Alder reactions are among the most powerful synthetic transformations to construct complex natural products. Despite that increasing of enzymatic intramolecular Diels-Alder reactions have been discovered, natural intermolecular Diels-Alderases are rarely described. Here, we report an intermolecular hetero-Diels-Alder reaction in the biosynthesis of tropolonic sesquiterpenes and functionally characterize EupfF as the first fungal intermolecular hetero-Diels-Alderase. We demonstrate that EupfF catalyzed the dehydration of a hydroxymethyl-containing tropolone (5) to generate a reactive tropolone o-quinone methide (6) and might further stereoselectively control the subsequent intermolecular hetero-Diels-Alder reaction with (1E,4E,8Z)-humulenol (8) to produce enantiomerically pure neosetophomone B (1). Our results reveal the biosynthetic pathway of 1 and expand the repertoire of activities of Diels-Alder cyclases.


Assuntos
Proteínas Fúngicas/metabolismo , Metiltransferases/metabolismo , Sesquiterpenos/metabolismo , Reação de Cicloadição , Proteínas Fúngicas/química , Metiltransferases/química , Conformação Molecular , Sesquiterpenos/química
11.
Cell Death Dis ; 10(8): 546, 2019 07 18.
Artigo em Inglês | MEDLINE | ID: mdl-31320611

RESUMO

Growth factor receptor bound protein 2 (Grb2) is an adaptor protein critical for signal transduction and endocytosis, but its role in DNA damage response (DDR) remains unknown. Here, we report that either knockdown of Grb2 or overexpression of the mutated Grb2 promotes micronuclei formation in response to oxidative stress. Furthermore, Grb2 was demonstrated to interact with phosphatase and tensin homologue (PTEN; a tumor suppressor essential for nuclear stability), and the loss of Grb2 reduced the nuclear-localized PTEN, which was further decreased upon stimulation with hydrogen peroxide (H2O2). Overexpression of the T398A-mutated, nuclear-localized PTEN reduced micronuclei frequency in the cells deficient of functional Grb2 via rescuing the H2O2-dependent expression of Rad51, a protein essential for the homologous recombination (HR) repair process. Moreover, depletion of Grb2 markedly decreased the expression of Rad51 and its interaction with PTEN. Notably, Rad51 showed a preference to immunoprecipation with the T398A-PTEN mutant, and silencing of Rad51 alone accumulated micronuclei concurring with decreased expression of both Grb2 and PTEN. Our findings indicate that Grb2 interacts with PTEN and Rad51 to regulate genomic stability in DDR by mediating the nuclear translocation of PTEN to affect the expression of Rad51.


Assuntos
Núcleo Celular/metabolismo , Dano ao DNA/genética , Reparo do DNA/genética , Proteína Adaptadora GRB2/metabolismo , Micronúcleos com Defeito Cromossômico/efeitos dos fármacos , PTEN Fosfo-Hidrolase/metabolismo , Transporte Ativo do Núcleo Celular , Núcleo Celular/genética , Núcleo Celular/ultraestrutura , Dano ao DNA/efeitos dos fármacos , Proteína Adaptadora GRB2/genética , Instabilidade Genômica/efeitos dos fármacos , Células HEK293 , Células HeLa , Humanos , Peróxido de Hidrogênio/toxicidade , Mutação , Estresse Oxidativo , PTEN Fosfo-Hidrolase/genética , Ligação Proteica , Rad51 Recombinase/genética , Rad51 Recombinase/metabolismo , Transdução de Sinais/genética
12.
Org Biomol Chem ; 17(28): 6782-6785, 2019 07 17.
Artigo em Inglês | MEDLINE | ID: mdl-31276151

RESUMO

Gliocladiosin A (1) and B (2), two dipeptides conjugated with macrolides, were identified from a verM disruption mutant of the Cordycep-colonizing fungus Clonostachys rogersoniana. The structures and absolute configurations of 1 and 2 were determined on the basis of spectroscopic data analysis, including MS, NMR, CD and X-ray diffraction. A biogenetic pathway for 1 and 2 was proposed. These two compounds showed moderate antibacterial effects.


Assuntos
Antibacterianos/farmacologia , Bacillus subtilis/efeitos dos fármacos , Dipeptídeos/farmacologia , Hypocreales/química , Klebsiella pneumoniae/efeitos dos fármacos , Antibacterianos/biossíntese , Antibacterianos/química , Cristalografia por Raios X , Dipeptídeos/biossíntese , Dipeptídeos/química , Testes de Sensibilidade Microbiana , Modelos Moleculares , Conformação Molecular
13.
J Nat Prod ; 82(6): 1678-1685, 2019 06 28.
Artigo em Inglês | MEDLINE | ID: mdl-31120749

RESUMO

Phomanolides C-F (1-4), four new meroterpenoids, were isolated from a Phoma sp., together with the known phomanolides A (5) and B (6); their structures were elucidated primarily by NMR experiments. The absolute configurations of 1-3 were assigned by electronic circular dichroism calculations, and that of 4 was established by X-ray diffraction analysis using Cu Kα radiation. Compounds 1-3 incorporate an unprecedented trioxa[4.4.3]propellane subunit in their skeletons. Compounds 2 and 4 were weakly cytotoxic.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Ascomicetos/química , Fungos Mitospóricos/química , Terpenos/farmacologia , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/isolamento & purificação , Cristalografia por Raios X , Reação de Cicloadição , Ensaios de Seleção de Medicamentos Antitumorais , Estrutura Molecular , Estereoisomerismo , Terpenos/química , Terpenos/isolamento & purificação
14.
Fungal Genet Biol ; 129: 7-15, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-30980906

RESUMO

Eupenifeldin, a bistropolone meroterpenoid, was first discovered as an antitumor agent from the fungus Eupenicillium brefeldianum. We also isolated this compound and a new congener from a strain of Phoma sp. (CGMCC 10481), and evaluated their antitumor effects. Eupenifeldin showed potent in vitro anti-glioma activity. This tropolone-humulene-tropolone meroterpenoid could be originated from two units of tropolone orthoquinone methides and a 10-hydroxyhumulene moiety via hetero-Diels-Alder reactions. To explore the biosynthesis of this class of tropolonic sesquiterpenes, the genome of a eupenifeldin-producing Phoma sp. was sequenced and analyzed. The biosynthetic gene cluster of eupenifeldin (eup) was identified and partially validated by genomic analysis, gene disruption, and product analysis. A nonreducing polyketide synthase EupA, a FAD-dependent monooxygenase EupB, and a non-heme Fe (II)-dependent dioxygenase EupC, were identified as the enzymes responsible for tropolone formation. While the terpene cyclase EupE of an unknown family was characterized to catalyze humulene formation, and a cytochrome P450 enzyme EupD was responsible for hydroxylation of humulene. This study sheds light on the biosynthesis of eupenifeldin, and paves the way to further decipher its biosynthetic pathway.


Assuntos
Ascomicetos/enzimologia , Ascomicetos/genética , Família Multigênica , Tropolona/análogos & derivados , Vias Biossintéticas , Genoma Fúngico , Hidroxilação , Oxigenases de Função Mista/genética , Sesquiterpenos Monocíclicos/metabolismo , Policetídeo Sintases/genética , Análise de Sequência de DNA , Tropolona/metabolismo
15.
J Nat Prod ; 82(3): 462-468, 2019 03 22.
Artigo em Inglês | MEDLINE | ID: mdl-30576135

RESUMO

Rogersonins A (1) and B (2), two new indole alkaloid-polyketide hybrids, have been isolated from cultures of a verG disruption mutant of the Cordyceps-colonizing fungus Clonostachys rogersoniana; their structures were elucidated primarily by NMR experiments. The absolute configurations of 1 and 2 were assigned using the modified Mosher method and via electronic circular dichroism and NMR calculations. Compounds 1 and 2 incorporate an imidazolone N-oxide moiety that has not been reported in any natural products.


Assuntos
Genes Fúngicos , Hypocreales/química , Imidazóis/metabolismo , Alcaloides Indólicos/metabolismo , Mutação , Linhagem Celular Tumoral , Humanos , Hypocreales/genética , Estrutura Molecular , Óxidos/metabolismo , Análise Espectral/métodos
16.
RSC Adv ; 9(21): 12146-12152, 2019 Apr 12.
Artigo em Inglês | MEDLINE | ID: mdl-35517032

RESUMO

Four new heptaketides, pseudonectrins A-D (1-4), and four known compounds (5-8) were isolated from cultures of an endophytic fungus Nectria pseudotrichia. Their structures were elucidated primarily by NMR experiments. The absolute configurations of 1-3 and 4 were assigned by electronic circular dichroism calculations and the modified Mosher method, respectively. Compound 1-3 showed moderate cytotoxicity, with IC50 values of 11.6-41.2 µM.

17.
Front Microbiol ; 9: 1773, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30127776

RESUMO

Trichodermol, a fungal sesquiterpene derived from the farnesyl diphosphate pathway, is the biosynthetic precursor for trichodermin, a member of the trichothecene class of fungal toxins produced mainly by the genera of Trichoderma and Fusarium. Trichodermin is a promising candidate for the development of fungicides and antitumor agents due to its significant antifungal and cytotoxic effects. It can also serve as a scaffold to generate new congeners for structure-activity relationship (SAR) study. We reconstructed the biosynthetic pathway of trichodermol in Saccharomyces cerevisiae BY4741, and investigated the effect of produced trichodermol on the host by de novo RNA sequencing (RNA-Seq) and quantitative Real-time PCR analyses. Co-expression of pESC::FgTRI5 using plasmid pLLeu-tHMGR-UPC2.1 led to trichodiene production of 683 µg L-1, while integration of only the codon-optimized FgTRI5 into the chromosome of yeast improved the production to 6,535 µg L-1. Subsequent expression of the codon-optimized cytochrome P450 monooxygenase encoding genes, TaTRI4 and TaTRI11, resulted in trichodermol, with an estimated titer of 252 µg L-1 at shake flask level. RNA-Seq and qPCR analyses revealed that the produced trichodermol downregulated the expression of the genes involved in ergosterol biosynthesis, but significantly upregulated the expression of PDR5 related to membrane transport pathway in S. cerevisiae. Collectively, we achieved the first heterologous biosynthesis of trichodermol by reconstructing its biosynthetic pathway in yeast, and the reconstructed pathway will serve as a platform to generate trichodermin analogs as potential candidates for agrochemicals and anticancer agents through further optimizations.

18.
J Nat Prod ; 81(8): 1752-1759, 2018 08 24.
Artigo em Inglês | MEDLINE | ID: mdl-30024750

RESUMO

Four new highly oxygenated p-terphenyls, hawaiienols A-D (1-4), have been isolated from cultures of Paraconiothyrium hawaiiense, a fungus associated with the Septobasidium-infected insect Diaspidiotus sp.; their structures were elucidated primarily by NMR experiments. The absolute configurations of 1 and 2-4 were assigned by single-crystal X-ray diffraction analysis using Cu Kα radiation and via electronic circular dichroism calculations, respectively. Compound 1 incorporated the first naturally occurring 4,7-dioxatricyclo[3.2.1.03,6]octane unit in its p-terphenyl skeleton and showed cytotoxicity toward six human tumor cell lines.


Assuntos
Antibióticos Antineoplásicos/química , Antibióticos Antineoplásicos/farmacologia , Ascomicetos/metabolismo , Insetos/microbiologia , Compostos de Terfenil/química , Compostos de Terfenil/farmacologia , Animais , Ascomicetos/química , Linhagem Celular Tumoral , Dicroísmo Circular , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Espectroscopia de Ressonância Magnética , Estrutura Molecular , Espectrometria de Massas por Ionização por Electrospray , Difração de Raios X
19.
Molecules ; 23(6)2018 May 25.
Artigo em Inglês | MEDLINE | ID: mdl-29799466

RESUMO

Sporulosol (1), a new ketal, together with four known compounds, has been isolated from the liquid fermentation cultures of a wetland-soil-derived fungus, Paraconiothyrium sporulosum. Its structure was elucidated primarily by NMR experiments, and was further confirmed by X-ray crystallography. Sporulosol was obtained as a racemic mixture and the resolved two enantiomers racemized immediately after chiral separation. Sporulosol appears to be the first ketal derived from a 6H-benzo[c]chromen-6-one and a benzofuranone unit. The compound showed modest cytotoxicity toward the human tumor cell line T24, with an IC50 value of 18.2 µM.


Assuntos
Acetais/isolamento & purificação , Antineoplásicos/isolamento & purificação , Ascomicetos/química , Microbiologia do Solo , Acetais/farmacologia , Antineoplásicos/farmacologia , Ascomicetos/metabolismo , Benzofuranos/química , Benzofuranos/metabolismo , Benzopiranos/química , Benzopiranos/metabolismo , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/patologia , Fermentação , Humanos , Estereoisomerismo
20.
ACS Chem Biol ; 13(3): 703-711, 2018 03 16.
Artigo em Inglês | MEDLINE | ID: mdl-29384350

RESUMO

Chloropupukeananin and chloropestolides are novel metabolites of the plant endophyte Pestalotiopsis fici, showing antimicrobial, antitumor, and anti-HIV activities. Their highly complex and unique skeletons were generated from the coisolated pestheic acid (1) and iso-A82775C (10) based on our previous studies. Here, we identified the biosynthetic gene cluster iac of 10 and characterized an iacE encoded prenyltransferase. Deletion of iacE abolished iso-A82775C production, accumulated the prenyl group-lacking siccayne (2), and generated four new chloropestolides (3-6). Compounds 5 and 6 showed antibacterial effects against Staphylococcus aureus and Bacillus subtilis, and 5 was also cytotoxic to human tumor cell lines HeLa, MCF-7, and SW480. These results provided the first genetic and biochemical insights into the biosynthesis of natural prenylepoxycyclohexanes and demonstrated the feasibility for generation of diversified congeners by manipulating the biosynthetic genes of 10.


Assuntos
Antibacterianos/isolamento & purificação , Dimetilaliltranstransferase/metabolismo , Extratos Vegetais/química , Compostos de Espiro , Xylariales/enzimologia , Antibacterianos/farmacologia , Bacillus subtilis/efeitos dos fármacos , Linhagem Celular Tumoral , Cicloexanos , Dimetilaliltranstransferase/genética , Humanos , Hidrocarbonetos Clorados/química , Hidrocarbonetos Clorados/isolamento & purificação , Éteres Fenílicos/química , Éteres Fenílicos/isolamento & purificação , Sesquiterpenos , Staphylococcus aureus/efeitos dos fármacos , Xylariales/química , Xylariales/metabolismo
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