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1.
J Am Chem Soc ; 142(20): 9389-9395, 2020 May 20.
Artigo em Inglês | MEDLINE | ID: mdl-32330028

RESUMO

An efficient divergent synthetic strategy that leverages the natural product spectinomycin to access uniquely functionalized monosaccharides is described. Stereoselective 2'- and 3'-reduction of key spectinomycin-derived intermediates enabled facile access to all eight possible 2,3-stereoisomers of 4,6-dideoxyhexoses as well as representative 3,4,6-trideoxysugars and 3,4,6-trideoxy-3-aminohexoses. In addition, the method was applied to the synthesis of two functionalized sugars commonly associated with macrolide antibiotics-the 3-O-alkyl-4,6-dideoxysugar d-chalcose and the 3-N-alkyl-3,4,6-trideoxysugar d-desosamine.

2.
Folia Microbiol (Praha) ; 65(2): 381-392, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31401763

RESUMO

Citrus black spot (CBS) and post-bloom fruit drop (PFD), caused by Phyllosticta citricarpa and Colletotrichum abscissum, respectively, are two important citrus diseases worldwide. CBS depreciates the market value and prevents exportation of citrus fruits to Europe. PFD under favorable climatic conditions can cause the abscission of flowers, thereby reducing citrus production by 80%. An ecofriendly alternative to control plant diseases is the use of endophytic microorganisms, or secondary metabolites produced by them. Strain LGMF1631, close related to Diaporthe cf. heveae 1, was isolated from the medicinal plant Stryphnodendron adstringens and showed significant antimicrobial activity, in a previous study. In view of the potential presented by strain LGMF1631, and the absence of chemical data for secondary metabolites produced by D. cf. heveae, we decided to characterize the compounds produced by strain LGMF1631. Based on ITS, TEF1, and TUB phylogenetic analysis, strain LGMF1631 was confirmed to belong to D. cf. heveae 1. Chemical assessment of the fungal strain LGMF1631 revealed one new seco-dihydroisocoumarin [cladosporin B (1)] along with six other related, already known dihydroisocoumarin derivatives and one monoterpene [(-)-(1S,2R,3S,4R)-p-menthane-1,2,3-triol (8)]. Among the isolated metabolites, compound 5 drastically reduced the growth of both phytopathogens in vitro and completely inhibited the development of CBS and PFD in citrus fruits and flowers. In addition, compound 5 did not show toxicity against human cancer cell lines or citrus leaves, at concentrations higher than used for the inhibition of the phytopathogens, suggesting the potential use of (-)-(3R,4R)-cis-4-hydroxy-5-methylmellein (5) to control citrus diseases.

3.
J Nat Prod ; 82(12): 3469-3476, 2019 Dec 27.
Artigo em Inglês | MEDLINE | ID: mdl-31833370

RESUMO

We report the isolation and characterization of three new nybomycins (nybomycins B-D, 1-3) and six known compounds (nybomycin, 4; deoxynyboquinone, 5; α-rubromycin, 6; ß-rubromycin, 7; γ-rubromycin, 8; and [2α(1E,3E),4ß]-2-(1,3-pentadienyl)-4-piperidinol, 9) from the Rock Creek (McCreary County, KY) underground coal mine acid reclamation site isolate Streptomyces sp. AD-3-6. Nybomycin D (3) and deoxynyboquinone (5) displayed moderate (3) to potent (5) cancer cell line cytotoxicity and displayed weak to moderate anti-Gram-(+) bacterial activity, whereas rubromycins 6-8 displayed little to no cancer cell line cytotoxicity but moderate to potent anti-Gram-(+) bacterial and antifungal activity. Assessment of the impact of 3 or 5 cancer cell line treatment on 4E-BP1 phosphorylation, a predictive marker of ROS-mediated control of cap-dependent translation, also revealed deoxynyboquinone (5)-mediated downstream inhibition of 4E-BP1p. Evaluation of 1-9 in a recently established axolotl embryo tail regeneration assay also highlighted the prototypical telomerase inhibitor γ-rubromycin (8) as a new inhibitor of tail regeneration. Cumulatively, this work highlights an alternative nybomycin production strain, a small set of new nybomycin metabolites, and previously unknown functions of rubromycins (antifungal activity and inhibition of tail regeneration) and also provides a basis for revision of the previously proposed nybomycin biosynthetic pathway.

4.
Chem Sci ; 10(32): 7641-7648, 2019 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-31583069

RESUMO

A divergent modular strategy for the enantioselective total synthesis of 12 naturally-occurring griseusin type pyranonaphthoquinones and 8 structurally-similar analogues is described. Key synthetic highlights include Cu-catalyzed enantioselective boration-hydroxylation and hydroxyl-directed C-H olefination to afford the central pharmacophore followed by epoxidation-cyclization and maturation via diastereoselective reduction and regioselective acetylation. Structural revision of griseusin D and absolute structural assignment of 2a,8a-epoxy-epi-4'-deacetyl griseusin B are also reported. Subsequent mechanistic studies establish, for the first time, griseusins as potent inhibitors of peroxiredoxin 1 (Prx1) and glutaredoxin 3 (Grx3). Biological evaluation, including comparative cancer cell line cytotoxicity and axolotl embryo tail inhibition studies, highlights the potential of griseusins as potent molecular probes and/or early stage leads in cancer and regenerative biology.

5.
Chembiochem ; 2019 Oct 17.
Artigo em Inglês | MEDLINE | ID: mdl-31621997

RESUMO

Herein we describe the ability of the permissive glycosyltransferase (GT) OleD Loki to convert a diverse set of >15 histone deacetylase (HDAC) inhibitors (HDACis) into their corresponding hydroxamate glycosyl esters. Representative glycosyl esters were subsequently evaluated in assays for cancer cell line cytotoxicity, chemical and enzymatic stability, and axolotl embryo tail regeneration. Computational substrate docking models were predictive of enzyme-catalyzed turnover and suggest certain HDACis may form unproductive, potentially inhibitory, complexes with GTs.

6.
Fitoterapia ; 138: 104273, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31344395

RESUMO

Endophytic fungi have been considered a rich source for bioactive secondary metabolites with novel chemical structures. A high diverse group of endophytes, isolated from different medicinal plants, belongs to the genus Diaporthe. In a previously study performed by our group the crude extract of strain LGMF1583 showed considerable antibacterial activity mainly against Gram-negative bacteria. Based on ITS phylogeny analysis, strain LGMF1583 was identified as belonging to Diaporthe genus and may represent a new species. In the present study, we described the new species Diporthe vochysiae based on multilocus phylogeny analysis and morphological characteristics. The species name refers to the host, from which strain LGMF1583 was isolated, the medicinal plant Vochysia divergens. In view of the biotechnological potential of strain LGMF1583, we have also characterized the secondary metabolites produced by D. vochysiae. Chemical assessment of the D. vochysiae LGMF1583 revealed two new carboxamides, vochysiamides A (1) and B (2), in addition to the known metabolite, 2,5-dihydroxybenzyl alcohol (3). In the biological activity analysis, vochysiamide B (2) displayed considerable antibacterial activity against the Gram-negative bacterium Klebsiella pneumoniae (KPC), a producer of carbapenemases, MIC of 80 µg/mL. Carbapenemases are considered a major antimicrobial resistance threat, and infections caused by KPC have been considered a public health problem worldwide, and new compounds with activity against this bacterium are nowadays even more required.


Assuntos
Amidas/farmacologia , Antibacterianos/farmacologia , Ascomicetos/química , Myrtales/microbiologia , Plantas Medicinais/microbiologia , Amidas/isolamento & purificação , Antibacterianos/isolamento & purificação , Ascomicetos/classificação , Brasil , Linhagem Celular Tumoral , Endófitos/química , Humanos , Klebsiella pneumoniae/efeitos dos fármacos , Estrutura Molecular , Filogenia
7.
Sci Rep ; 9(1): 6751, 2019 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-31043677

RESUMO

Tissue regeneration is associated with complex changes in gene expression and post-translational modifications of proteins, including transcription factors and histones that comprise chromatin. We tested 172 compounds designed to target epigenetic mechanisms in an axolotl (Ambystoma mexicanum) embryo tail regeneration assay. A relatively large number of compounds (N = 55) inhibited tail regeneration, including 18 histone deacetylase inhibitors (HDACi). In particular, romidepsin, an FDA-approved anticancer drug, potently inhibited tail regeneration when embryos were treated continuously for 7 days. Additional experiments revealed that romidepsin acted within a very narrow, post-injury window. Romidepsin treatment for only 1-minute post amputation inhibited regeneration through the first 7 days, however after this time, regeneration commenced with variable outgrowth of tailfin tissue and abnormal patterning. Microarray analysis showed that romidepsin altered early, transcriptional responses at 3 and 6-hour post-amputation, especially targeting genes that are implicated in tumor cell death, as well as genes that function in the regulation of transcription, cell differentiation, cell proliferation, pattern specification, and tissue morphogenesis. Our results show that HDAC activity is required at the time of tail amputation to regulate the initial transcriptional response to injury and regeneration.

8.
J Nat Prod ; 82(6): 1686-1693, 2019 06 28.
Artigo em Inglês | MEDLINE | ID: mdl-31117525

RESUMO

The structures and bioactivities of three unprecedented fused 5-hydroxyquinoxaline/alpha-keto acid amino acid metabolites (baraphenazines A-C, 1-3), two unique diastaphenazine-type metabolites (baraphenazines D and E, 4 and 5) and two new phenazinolin-type (baraphenazines F and G, 6 and 7) metabolites from the Himalayan isolate Streptomyces sp. PU-10A are reported. This study highlights the first reported bacterial strain capable of producing diastaphenazine-type, phenazinolin-type, and izumiphenazine A-type metabolites and presents a unique opportunity for the future biosynthetic interrogation of late-stage phenazine-based metabolite maturation.

9.
J Antibiot (Tokyo) ; 72(5): 306-310, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30792517

RESUMO

The isolation and structure elucidation of one new fungal metabolite, phenguignardic acid butyl ester (1a), and four previously reported metabolites (1b, 2a, 3-4) from the citrus phytopathogen Phyllosticta citricarpa LGMF06 are described. The new dioxolanone phenguignardic acid butyl ester (1a) had low phytotoxic activity in citrus leaves and fruits (at dose of 100 µg), and its importance as virulence factor in citrus black spot disease needs to be further addressed. Beside the phytotoxic analysis, we also evaluated the antibacterial (against methicillin sensitive and resistant Staphylococcus aureus) and cytotoxic (A549 non-small cell lung cancer, PC3 prostate cancer and HEL 299 normal epithelial lung) activities of the isolated compounds, which revealed that compounds 1a, 1b and 2a were responsible for the antibacterial activity of this strain.


Assuntos
Antibacterianos/isolamento & purificação , Antibacterianos/farmacologia , Ascomicetos/química , Produtos Biológicos/isolamento & purificação , Produtos Biológicos/farmacologia , Staphylococcus aureus/efeitos dos fármacos , Antibacterianos/química , Antineoplásicos/química , Antineoplásicos/isolamento & purificação , Antineoplásicos/farmacologia , Produtos Biológicos/química , Produtos Biológicos/toxicidade , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Citrus/microbiologia , Humanos , Estrutura Molecular , Doenças das Plantas/microbiologia
10.
Cell Chem Biol ; 26(3): 366-377.e12, 2019 03 21.
Artigo em Inglês | MEDLINE | ID: mdl-30661989

RESUMO

Peroxiredoxin 1 (Prx1) and glutaredoxin 3 (Grx3) are two major antioxidant proteins that play a critical role in maintaining redox homeostasis for tumor progression. Here, we identify the prototypical pyranonaphthoquinone natural product frenolicin B (FB) as a selective inhibitor of Prx1 and Grx3 through covalent modification of active-site cysteines. FB-targeted inhibition of Prx1 and Grx3 results in a decrease in cellular glutathione levels, an increase of reactive oxygen species (ROS), and concomitant inhibition of cancer cell growth, largely by activating the peroxisome-bound tuberous sclerosis complex to inhibit mTORC1/4E-BP1 signaling axis. FB structure-activity relationship studies reveal a positive correlation between inhibition of 4E-BP1 phosphorylation, ROS-mediated cancer cell cytotoxicity, and suppression of tumor growth in vivo. These findings establish FB as the most potent Prx1/Grx3 inhibitor reported to date and also notably highlight 4E-BP1 phosphorylation status as a potential predictive marker in response to ROS-based therapies in cancer.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Antineoplásicos/química , Proteínas de Ciclo Celular/metabolismo , Glutarredoxinas/metabolismo , Peroxirredoxinas/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/antagonistas & inibidores , Proteínas Adaptadoras de Transdução de Sinal/genética , Animais , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Proteínas de Ciclo Celular/antagonistas & inibidores , Proteínas de Ciclo Celular/genética , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Glutarredoxinas/antagonistas & inibidores , Humanos , Masculino , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Camundongos , Camundongos Nus , Naftoquinonas/química , Naftoquinonas/farmacologia , Naftoquinonas/uso terapêutico , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Peroxirredoxinas/antagonistas & inibidores , Fosforilação/efeitos dos fármacos , Interferência de RNA , RNA Interferente Pequeno/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transplante Heterólogo
11.
J Nat Prod ; 81(11): 2560-2566, 2018 11 26.
Artigo em Inglês | MEDLINE | ID: mdl-30418763

RESUMO

The isolation and structure elucidation of four new naturally occurring amino-nucleoside [puromycins B-E (1-4)] metabolites from a Himalayan isolate ( Streptomyces sp. PU-14-G, isolated from the Bara Gali region of northern Pakistan) is reported. Consistent with prior reports, comparative antimicrobial assays revealed the need for the free 2″-amine for anti-Gram-positive bacteria and antimycobacterial activity. Similarly, comparative cancer cell line cytotoxicity assays highlighted the importance of the puromycin-free 2″-amine and the impact of 3'-nucleoside substitution. These studies extend the repertoire of known naturally occurring puromycins and their corresponding SAR. Notably, 1 represents the first reported naturally occurring bacterial puromycin-related metabolite with a 3'- N-amino acid substitution that differs from the 3'- N-tyrosinyl of classical puromycin-type natural products. This discovery suggests the biosynthesis of 1 in Streptomyces sp. PU-14G may invoke a uniquely permissive amino-nucleoside synthetase and/or multiple synthetases and sets the stage for further studies to elucidate, and potentially exploit, new biocatalysts for puromycin chemoenzymatic diversification.


Assuntos
Nucleosídeos/metabolismo , Puromicina/química , Puromicina/isolamento & purificação , Streptomyces/metabolismo , Bactérias Gram-Positivas/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Estrutura Molecular , Mycobacterium/efeitos dos fármacos , Paquistão , Puromicina/biossíntese , Puromicina/farmacologia
12.
Sci Rep ; 8(1): 3122, 2018 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-29449610

RESUMO

Microorganisms associated with plants are highly diverse and can produce a large number of secondary metabolites, with antimicrobial, anti-parasitic and cytotoxic activities. We are particularly interested in exploring endophytes from medicinal plants found in the Pantanal, a unique and widely unexplored wetland in Brazil. In a bio-prospecting study, strains LGMF1213 and LGMF1215 were isolated as endophytes from Vochysia divergens, and by morphological and molecular phylogenetic analyses were characterized as Phaeophleospora vochysiae sp. nov. The chemical assessment of this species reveals three major compounds with high biological activity, cercoscosporin (1), isocercosporin (2) and the new compound 3-(sec-butyl)-6-ethyl-4,5-dihydroxy-2-methoxy-6-methylcyclohex-2-enone (3). Besides the isolation of P. vochysiae as endophyte, the production of cercosporin compounds suggest that under specific conditions this species causes leaf spots, and may turn into a pathogen, since leaf spots are commonly caused by species of Cercospora that produce related compounds. In addition, the new compound 3-(sec-butyl)-6-ethyl-4,5-dihydroxy-2-methoxy-6-methylcyclohex-2-enone showed considerable antimicrobial activity and low cytotoxicity, which needs further exploration.


Assuntos
Bactérias/isolamento & purificação , Myrtales/metabolismo , Myrtales/microbiologia , Antibacterianos/metabolismo , Anti-Infecciosos/metabolismo , Ascomicetos/metabolismo , Bactérias/metabolismo , Brasil , Endófitos/metabolismo , Magnoliopsida/metabolismo , Magnoliopsida/microbiologia , Testes de Sensibilidade Microbiana , Perileno/análogos & derivados , Filogenia , Plantas Medicinais/metabolismo
13.
J Nat Prod ; 80(4): 1141-1149, 2017 04 28.
Artigo em Inglês | MEDLINE | ID: mdl-28358212

RESUMO

The structures of 12 new "enantiomeric"-like abyssomicin metabolites (abyssomicins M-X) from Streptomyces sp. LC-6-2 are reported. Of this set, the abyssomicin W (11) contains an unprecedented 8/6/6/6 tetracyclic core, while the bicyclic abyssomicin X (12) represents the first reported naturally occurring linear spirotetronate. Metabolite structures were determined based on spectroscopic data and X-ray crystallography, and Streptomyces sp. LC-6-2 genome sequencing also revealed the corresponding putative biosynthetic gene cluster.


Assuntos
Compostos Bicíclicos Heterocíclicos com Pontes/isolamento & purificação , Compostos de Espiro/isolamento & purificação , Streptomyces/química , Compostos Bicíclicos Heterocíclicos com Pontes/química , Carvão Mineral , Cristalografia por Raios X , Conformação Molecular , Estrutura Molecular , Família Multigênica , Ressonância Magnética Nuclear Biomolecular , Compostos de Espiro/química , Streptomyces/genética
14.
Nat Chem Biol ; 13(4): 366-368, 2017 04.
Artigo em Inglês | MEDLINE | ID: mdl-28166207

RESUMO

This study highlights the biochemical and structural characterization of the L-tryptophan C6 C-prenyltransferase (C-PT) PriB from Streptomyces sp. RM-5-8. PriB was found to be uniquely permissive to a diverse array of prenyl donors and acceptors including daptomycin. Two additional PTs also produced novel prenylated daptomycins with improved antibacterial activities over the parent drug.


Assuntos
Dimetilaliltranstransferase/química , Dimetilaliltranstransferase/metabolismo , Streptomyces/enzimologia , Modelos Moleculares , Estrutura Molecular , Especificidade por Substrato
15.
Angew Chem Int Ed Engl ; 56(11): 2994-2998, 2017 03 06.
Artigo em Inglês | MEDLINE | ID: mdl-28140487

RESUMO

Four cyclopentenone-containing ansamycin polyketides (mccrearamycins A-D), and six new geldanamycins (Gdms B-G, including new linear and mycothiol conjugates), were characterized as metabolites of Streptomyces sp. AD-23-14 isolated from the Rock Creek underground coal mine acid drainage site. Biomimetic chemical conversion studies using both simple synthetic models and Gdm D confirmed that the mccrearamycin cyclopentenone derives from benzilic acid rearrangement of 19-hydroxy Gdm, and thereby provides a new synthetic derivatization strategy and implicates a potential unique biocatalyst in mccrearamycin cyclopentenone formation. In addition to standard Hsp90α binding and cell line cytotoxicity assays, this study also highlights the first assessment of Hsp90α modulators in a new axolotl embryo tail regeneration (ETR) assay as a potential new whole animal assay for Hsp90 modulator discovery.


Assuntos
Carvão Mineral/microbiologia , Ciclopentanos/farmacologia , Proteínas de Choque Térmico HSP90/antagonistas & inibidores , Lactamas Macrocíclicas/farmacologia , Streptomyces/química , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Ciclopentanos/química , Ciclopentanos/isolamento & purificação , Proteínas de Choque Térmico HSP90/metabolismo , Humanos , Kentucky , Lactamas Macrocíclicas/química , Lactamas Macrocíclicas/isolamento & purificação , Conformação Molecular , Estereoisomerismo , Streptomyces/metabolismo
16.
J Nat Prod ; 80(1): 2-11, 2017 01 27.
Artigo em Inglês | MEDLINE | ID: mdl-28029795

RESUMO

The isolation and structure elucidation of six new bacterial metabolites [spoxazomicin D (2), oxachelins B and C (4, 5), and carboxamides 6-8] and 11 previously reported bacterial metabolites (1, 3, 9-12a, and 14-18) from Streptomyces sp. RM-14-6 is reported. Structures were elucidated on the basis of comprehensive 1D and 2D NMR and mass spectrometry data analysis, along with direct comparison to synthetic standards for 2, 11, and 12a,b. Complete 2D NMR assignments for the known metabolites lenoremycin (9) and lenoremycin sodium salt (10) were also provided for the first time. Comparative analysis also provided the basis for structural revision of several previously reported putative aziridine-containing compounds [exemplified by madurastatins A1, B1, C1 (also known as MBJ-0034), and MBJ-0035] as phenol-dihydrooxazoles. Bioactivity analysis [including antibacterial, antifungal, cancer cell line cytotoxicity, unfolded protein response (UPR) modulation, and EtOH damage neuroprotection] revealed 2 and 5 as potent neuroprotectives and lenoremycin (9) and its sodium salt (10) as potent UPR modulators, highlighting new functions for phenol-oxazolines/salicylates and polyether pharmacophores.


Assuntos
Antibacterianos/isolamento & purificação , Antibacterianos/farmacologia , Antifúngicos/isolamento & purificação , Antifúngicos/farmacologia , Éteres/química , Éteres/farmacologia , Fármacos Neuroprotetores/isolamento & purificação , Fármacos Neuroprotetores/farmacologia , Oligopeptídeos/isolamento & purificação , Oligopeptídeos/farmacologia , Oxazóis/isolamento & purificação , Oxazóis/farmacologia , Peptídeos/farmacologia , Fenóis/química , Fenóis/farmacologia , Streptomyces/química , Antibacterianos/química , Antifúngicos/química , Região dos Apalaches , Carvão Mineral , Éteres/isolamento & purificação , Humanos , Estrutura Molecular , Fármacos Neuroprotetores/química , Ressonância Magnética Nuclear Biomolecular , Oligopeptídeos/química , Oxazóis/química , Peptídeos/química , Fenóis/isolamento & purificação
17.
J Nat Prod ; 80(1): 12-18, 2017 01 27.
Artigo em Inglês | MEDLINE | ID: mdl-28029796

RESUMO

The assessment of glycosyl-scanning to expand the molecular and functional diversity of metabolites from the underground coal mine fire-associated Streptomyces sp. RM-14-6 is reported. Using the engineered glycosyltransferase OleD Loki and a 2-chloro-4-nitrophenylglycoside-based screen, six metabolites were identified as substrates of OleD Loki, from which 12 corresponding metabolite glycosides were produced and characterized. This study highlights the first application of the 2-chloro-4-nitrophenylglycoside-based screen toward an unbiased set of unique microbial natural products and the first reported application of the 2-chloro-4-nitrophenylglycoside-based transglycosylation reaction for the corresponding preparative synthesis of target glycosides. Bioactivity analysis (including antibacterial, antifungal, anticancer, and EtOH damage neuroprotection assays) revealed glycosylation to attenuate the neuroprotective potency of 4, while glycosylation of the structurally related inactive spoxazomicin C (3) remarkably invoked neuroprotective activity.


Assuntos
Antifúngicos/isolamento & purificação , Antifúngicos/farmacologia , Glicosídeos/química , Fármacos Neuroprotetores/isolamento & purificação , Fármacos Neuroprotetores/farmacologia , Oligopeptídeos/isolamento & purificação , Oligopeptídeos/farmacologia , Oxazóis/isolamento & purificação , Oxazóis/farmacologia , Streptomyces/química , Antifúngicos/química , Glicosilação , Estrutura Molecular , Fármacos Neuroprotetores/química , Oligopeptídeos/química , Oxazóis/química
18.
J Nat Prod ; 79(10): 2731-2739, 2016 10 28.
Artigo em Inglês | MEDLINE | ID: mdl-27736087

RESUMO

Four new Y-type actinomycin analogues named Y6-Y9 (1-4) were isolated and characterized from the scale-up fermentation of the Streptomyces sp. strain Gö-GS12, as well as actinomycin Zp (5), which was, for the first time, isolated as a natural product. Structures of the new compounds were elucidated by the cumulative analyses of NMR spectroscopy and HRMS. The 4-hydroxythreonine on the ß-ring of 1 uniquely undergoes both a rearrangement by a 2-fold acyl shift and an additional ring closure with the amino group of the phenoxazinone chromophore, and the α-rings of 4 and 5 contain a rare 5-methyl proline. Compounds 2-5 showed potent antibacterial activities against Gram-positive bacteria that correlated with cytotoxicity against representative human cell lines. The combination of a ß-ring rearrangement and additional ring closure in 1 rendered this actinomycin significantly less potent relative to the nonrearranged comparator actinomycin Y5 and other actinomycins.


Assuntos
Antibacterianos , Dactinomicina , Streptomyces/química , Antibacterianos/química , Antibacterianos/isolamento & purificação , Antibacterianos/farmacologia , Sobrevivência Celular , Dactinomicina/análogos & derivados , Dactinomicina/química , Dactinomicina/isolamento & purificação , Dactinomicina/farmacologia , Fermentação , Humanos , Estrutura Molecular , Ressonância Magnética Nuclear Biomolecular , Prolina/química , Treonina/análogos & derivados , Treonina/química
19.
ACS Med Chem Lett ; 6(10): 1053-8, 2015 Oct 08.
Artigo em Inglês | MEDLINE | ID: mdl-26487911

RESUMO

The synthesis of a set of digitoxigenin neogluco/xylosides and corresponding study of their anticancer SAR revealed sugar amine regiochemistry has a dramatic effect upon activity. Specifically, this study noted sugar 3-amino followed by 4-amino-substitution to be most advantageous where the solvent accessibility of the appended amine within neoglycoside-Na(+),K(+)-ATPase docked models correlated with increased anticancer potency. This study presents a preliminary model for potential further warhead optimization in the context of antibody-directed steroidal glycosides and extends the demonstrated compatibility of aminosugars in the context of neoglycosylation.

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