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1.
Org Lett ; 2020 Mar 18.
Artigo em Inglês | MEDLINE | ID: mdl-32186890

RESUMO

A novel 6/6/5/6 tetracyclic polyketide named chartspiroton (1) was isolated from a medicinal plant endophytic Streptomyces in Dendrobium officinale. The complete structure assignment with absolute stereochemistry was elucidated through spectroscopic data, computational calculations, and single-crystal X-ray diffraction. Chartspiroton features an unprecedented naphthoquinone derivative spiro-fused with a benzofuran lactone moiety. A plausible polyketide biosynthetic pathway for 1 suggested intriguing oxidative rearrangement steps to form the five-membered lactone ring.

2.
J Agric Food Chem ; 68(6): 1588-1595, 2020 Feb 12.
Artigo em Inglês | MEDLINE | ID: mdl-31994388

RESUMO

The discovery of new, safe, and effective pesticides is one of the main means for modern crop protection and parasitic disease control. During the search for new insecticidal secondary metabolites from endophytes in Stemona sessilifolia (a traditional Chinese medicine with a long history as an insecticide), 10 new insecticidal endostemonines A-J (1-10) were identified from an endophytic Streptomyces sp. BS-1. Their structures were determined by comprehensive spectroscopic analysis. Endostemonines A-J represent the first reported naturally occurring pyrrole-2-carboxylic ester derivatives, which consisted of different fatty acid chains at the C-2 of pyrrole ring were produced by traditional Chinese medicine endophytic microbes. All new tested compounds exhibited strong lethal activity against Aphis gossypii (LC50 value range of 3.55-32.00 mg/L after 72 h). This research highlighted the discovery of pesticide natural products from insecticidal medicinal plant endophytes for the first time, paving a new pathway for the development of pest control.


Assuntos
Endófitos/química , Compostos Heterocíclicos com 3 Anéis/metabolismo , Inseticidas/metabolismo , Stemonaceae/microbiologia , Streptomyces/química , Streptomyces/metabolismo , Animais , Afídeos/efeitos dos fármacos , Endófitos/metabolismo , Compostos Heterocíclicos com 3 Anéis/química , Compostos Heterocíclicos com 3 Anéis/toxicidade , Inseticidas/química , Inseticidas/toxicidade , Metabolismo Secundário
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.
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.

5.
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
6.
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
7.
Eur J Med Chem ; 152: 307-317, 2018 May 25.
Artigo em Inglês | MEDLINE | ID: mdl-29733999

RESUMO

Type 2 diabetes mellitus (T2DM) is a chronic, complex and multifactorial metabolic disorder, and targeting gluconeogenesis inhibition is a promising strategy for anti-diabetic drug discovery. This study discovered a new class of thieno[2,3-b]pyridine derivatives as hepatic gluconeogenesis inhibitors. First, a hit compound (DMT: IC50 = 33.8 µM) characterized by a thienopyridine core was identified in a cell-based screening of our privileged small molecule library. Structure activity relationships (SARs) study showed that replaced the CF3 in the thienopyridine core could improve the potency and led to the discovery of 8e (IC50 = 16.8 µM) and 9d (IC50 = 12.3 µM) with potent inhibition of hepatic glucose production and good drug-like properties. Furthermore, the mechanism of 8e for the inhibition of hepatic glucose production was also identified, which could be effective through the reductive expression of the mRNA transcription level of gluconeogenic genes, including glucose-6-phosphatase (G6Pase) and hepatic phosphoenolpyruvate carboxykinase (PEPCK). Additionally, 8e could also reduce the fasting blood glucose and improve the oral glucose tolerance and pyruvate tolerance in db/db mice. The optimization of this class of derivatives had provided us a start point to develop new anti-hepatic gluconeogenesis agents.


Assuntos
Descoberta de Drogas , Gluconeogênese/efeitos dos fármacos , Glucose/antagonistas & inibidores , Hipoglicemiantes/farmacologia , Fígado/efeitos dos fármacos , Piridinas/farmacologia , Animais , Relação Dose-Resposta a Droga , Gluconeogênese/genética , Glucose/biossíntese , Teste de Tolerância a Glucose , Hipoglicemiantes/síntese química , Hipoglicemiantes/química , Fígado/metabolismo , Camundongos , Camundongos Obesos , Estrutura Molecular , Piridinas/síntese química , Piridinas/química , Relação Estrutura-Atividade
8.
J Org Chem ; 83(13): 7239-7249, 2018 07 06.
Artigo em Inglês | MEDLINE | ID: mdl-29768920

RESUMO

Muraymycins belong to a family of nucleoside antibiotics that have a distinctive disaccharide core consisting of 5-amino-5-deoxyribofuranose (ADR) attached to 6'- N-alkyl-5'- C-glycyluridine (GlyU). Here, we functionally assign and characterize six enzymes from the muraymycin biosynthetic pathway involved in the core assembly that starts from uridine monophosphate (UMP). The biosynthesis is initiated by Mur16, a nonheme Fe(II)- and α-ketoglutarate-dependent dioxygenase, followed by four transferase enzymes: Mur17, a pyridoxal-5'-phosphate (PLP)-dependent transaldolase; Mur20, an aminotransferase; Mur26, a pyrimidine phosphorylase; and Mur18, a nucleotidylyltransferase. The pathway culminates in glycosidic bond formation in a reaction catalyzed by an additional transferase enzyme, Mur19, a ribosyltransferase. Analysis of the biochemical properties revealed several noteworthy discoveries including that (i) Mur16 and downstream enzymes can also process 2'-deoxy-UMP to generate a 2-deoxy-ADR, which is consistent with the structure of some muraymycin congeners; (ii) Mur20 prefers l-Tyr as the amino donor source; (iii) Mur18 activity absolutely depends on the amine functionality of the ADR precursor consistent with the nucleotidyltransfer reaction occurring after the Mur20-catalyzed aminotransfer reaction; and (iv) the bona fide sugar acceptor for Mur19 is (5' S,6' S)-GlyU, suggesting that ribosyltransfer occurs prior to N-alkylation of GlyU. Finally, a one-pot, six-enzyme reaction was utilized to generate the ADR-GlyU disaccharide core starting from UMP.


Assuntos
Antibacterianos/metabolismo , Glicina/metabolismo , Peptídeos/metabolismo , Ribose/metabolismo , Uridina/metabolismo , Especificidade por Substrato
9.
Artigo em Inglês | MEDLINE | ID: mdl-29735559

RESUMO

Muraymycins are antibacterial natural products from Streptomyces spp. that inhibit translocase I (MraY), which is involved in cell wall biosynthesis. Structurally, muraymycins consist of a 5'-C-glycyluridine (GlyU) appended to a 5″-amino-5″-deoxyribose (ADR), forming a disaccharide core that is found in several peptidyl nucleoside inhibitors of MraY. For muraymycins, the GlyU-ADR disaccharide is further modified with an aminopropyl-linked peptide to generate the simplest structures, annotated as the muraymycin D series. Two enzymes encoded in the muraymycin biosynthetic gene cluster, Mur29 and Mur28, were functionally assigned in vitro as a Mg·ATP-dependent nucleotidyltransferase and a Mg·ATP-dependent phosphotransferase, respectively, both modifying the 3″-OH of the disaccharide. Biochemical characterization revealed that both enzymes can utilize several nucleotide donors as cosubstrates and the acceptor substrate muraymycin also behaves as an inhibitor. Single-substrate kinetic analyses revealed that Mur28 preferentially phosphorylates a synthetic GlyU-ADR disaccharide, a hypothetical biosynthetic precursor of muraymycins, while Mur29 preferentially adenylates the D series of muraymycins. The adenylated or phosphorylated products have significantly reduced (170-fold and 51-fold, respectively) MraY inhibitory activities and reduced antibacterial activities, compared with the respective unmodified muraymycins. The results are consistent with Mur29-catalyzed adenylation and Mur28-catalyzed phosphorylation serving as complementary self-resistance mechanisms, with a distinct temporal order during muraymycin biosynthesis.


Assuntos
Proteínas de Bactérias/antagonistas & inibidores , Nucleosídeos/biossíntese , Nucleosídeos/química , Nucleotidiltransferases/química , Peptídeos/química , Fosfotransferases/química , Streptomyces/metabolismo , Transferases/antagonistas & inibidores , Antibacterianos/biossíntese , Nucleotídeos/biossíntese , Nucleotidiltransferases/genética , Fosforilação , Fosfotransferases/genética
10.
J Nat Prod ; 81(4): 942-948, 2018 04 27.
Artigo em Inglês | MEDLINE | ID: mdl-29553733

RESUMO

Muraymycins are nucleoside antibiotics isolated from Streptomyces sp. NRRL 30471 and several mutant strains thereof that were generated by random, chemical mutagenesis. Reinvestigation of two mutant strains using new media conditions led to the isolation of three new muraymycin congeners, named B8, B9, and C6 (1-3), as well as a known muraymycin, C1. Structures of the compounds were elucidated by HRMS and 1D and 2D NMR spectroscopic analyses. Complete 2D NMR assignments for the known muraymycin C1 are also provided for the first time. Compounds 1 and 2, which differ from other muraymycins by having an elongated, terminally branched fatty acid side chain, had picomolar IC50 values against Staphylococcus aureus and Aquifex aeolicus MraY and showed good antibacterial activity against S. aureus (MIC = 2 and 6 µg/mL, respectively) and Escherichia coli Δ tolC (MIC = 4 and 2 µg/mL, respectively). Compound 3, which is characterized by an N-acetyl modification of the primary amine of the dissacharide core that is shared among nearly all of the reported muraymycin congeners, greatly reduced its inhibitory and antibacterial activity compared to nonacylated muraymycin C1, which possibly indicates this modification is used for self-resistance.


Assuntos
Antibacterianos/química , Nucleosídeos/química , Streptomyces/química , Antibacterianos/farmacologia , Escherichia coli/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Nucleosídeos/farmacologia , Staphylococcus aureus/efeitos dos fármacos
11.
ChemMedChem ; 13(8): 779-784, 2018 04 23.
Artigo em Inglês | MEDLINE | ID: mdl-29438582

RESUMO

Muraymycins are a subclass of antimicrobially active uridine-derived natural products. Biological data on several muraymycin analogues have been reported, including some inhibitory in vitro activities toward their target protein, the bacterial membrane enzyme MraY. However, a structure-activity relationship (SAR) study on naturally occurring muraymycins based on such in vitro data has been missing so far. In this work, we report a detailed SAR investigation on representatives of the four muraymycin subgroups A-D using a fluorescence-based in vitro MraY assay. For some muraymycins, inhibition of MraY with IC50 values in the low-picomolar range was observed. These inhibitory potencies were compared with antibacterial activities and were correlated to modelling data derived from a previously reported X-ray crystal structure of MraY in complex with a muraymycin inhibitor. Overall, these results will pave the way for the development of muraymycin analogues with optimized properties as antibacterial drug candidates.


Assuntos
Antibacterianos/farmacologia , Escherichia coli/efeitos dos fármacos , Nucleosídeos/farmacologia , Peptídeos/farmacologia , Staphylococcus aureus/efeitos dos fármacos , Antibacterianos/química , Proteínas de Bactérias/antagonistas & inibidores , Proteínas de Bactérias/química , Proteínas de Bactérias/metabolismo , Cristalografia por Raios X , Escherichia coli/crescimento & desenvolvimento , Infecções por Escherichia coli/tratamento farmacológico , Infecções por Escherichia coli/microbiologia , Humanos , Simulação de Acoplamento Molecular , Nucleosídeos/química , Nucleotídeos/química , Nucleotídeos/farmacologia , Peptídeos/química , Infecções Estafilocócicas/tratamento farmacológico , Infecções Estafilocócicas/microbiologia , Staphylococcus aureus/crescimento & desenvolvimento , Relação Estrutura-Atividade , Transferases/antagonistas & inibidores , Transferases/química , Transferases/metabolismo , Ureia/química , Ureia/farmacologia
12.
Eur J Med Chem ; 145: 622-633, 2018 Feb 10.
Artigo em Inglês | MEDLINE | ID: mdl-29339255

RESUMO

A series of LX2343 derivatives were designed, synthesized and evaluated as neuroprotective agents for Alzheimer's disease (AD) in vitro. Most of the compounds displayed potent neuroprotective activities. Especially for compound A6, exhibited a remarkable EC50 value of 0.22 µM. Further investigation demonstrated that compound A6 can significantly reduce Aß production and increase Aß clearance, and alleviate Tau hyperphosphorylation. Most importantly, compound A6 could ameliorate learning and memory impairments in APP/PS1 transgenic mice. The present study evidently showed that compound A6 is a potent neuroprotective agent and might serve as a promising lead candidate for the treatment of Alzheimer's disease.


Assuntos
Acetamidas/farmacologia , Doença de Alzheimer/tratamento farmacológico , Desenho de Drogas , Fármacos Neuroprotetores/farmacologia , Sulfonamidas/farmacologia , Acetamidas/síntese química , Acetamidas/química , Peptídeos beta-Amiloides/antagonistas & inibidores , Peptídeos beta-Amiloides/metabolismo , Animais , Relação Dose-Resposta a Droga , Células HEK293 , Humanos , Aprendizagem em Labirinto/efeitos dos fármacos , Transtornos da Memória/tratamento farmacológico , Camundongos , Camundongos Transgênicos , Estrutura Molecular , Fármacos Neuroprotetores/síntese química , Fármacos Neuroprotetores/química , Relação Estrutura-Atividade , Sulfonamidas/síntese química , Sulfonamidas/química , Células Tumorais Cultivadas
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.
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
15.
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
16.
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
18.
Angew Chem Int Ed Engl ; 54(38): 11219-22, 2015 Sep 14.
Artigo em Inglês | MEDLINE | ID: mdl-26230189

RESUMO

The first enantioselective total synthesis of griseusin A, griseusin C, 4'-deacetyl-griseusin A, and two non-native counterparts in 11-14 steps is reported. This strategy highlights a key hydroxy-directed CH olefination of 1-methylene isochroman with an α,ß-unsaturated ketone followed by subsequent stereoselective epoxidation and regioselective cyclization to afford the signature tetrahydro-spiropyran ring. Colorectal cancer cell cytotoxicities of the final products highlight the impact of the griseusin tetrahydro-spiropyran ring on bioactivity. As the first divergent enantioselective synthesis, the strategy put forth sets the stage for further griseusin mechanism-of-action and SAR studies.


Assuntos
Linhagem Celular Tumoral , Humanos , Espectroscopia de Ressonância Magnética , Naftoquinonas/síntese química , Naftoquinonas/química , Estereoisomerismo
19.
J Nat Prod ; 78(7): 1723-9, 2015 Jul 24.
Artigo em Inglês | MEDLINE | ID: mdl-26091285

RESUMO

Actinomadura melliaura ATCC 39691, a strain isolated from a soil sample collected in Bristol Cove, California, is a known producer of the disaccharide-substituted AT2433 indolocarbazoles (6-9). Reinvestigation of this strain using new media conditions led to >40-fold improvement in the production of previously reported AT2433 metabolites and the isolation and structure elucidation of the four new analogues, AT2433-A3, A4, A5, and B3 (1-4). The availability of this broader set of compounds enabled a subsequent small antibacterial/fungal/cancer SAR study that revealed disaccharyl substitution, N-6 methylation, and C-11 chlorination as key modulators of bioactivity. The slightly improved anticancer potency of the newly reported N-6-desmethyl 1 (compared to 6) contrasts extensive SAR of monoglycosylated rebeccamycin-type topoisomerase I inhibitors where N-6 alkylation has contributed to improved potency and ADME. Complete 2D NMR assignments for the known metabolite BMY-41219 (5) and (13)C NMR spectroscopic data for the known analogue AT2433-B1 (7) are also provided for the first time.


Assuntos
Actinomycetales/química , Antibióticos Antineoplásicos/isolamento & purificação , Carbazóis/isolamento & purificação , Carbazóis/farmacologia , Alcaloides Indólicos/isolamento & purificação , Alcaloides Indólicos/farmacologia , Inibidores da Topoisomerase I/isolamento & purificação , Inibidores da Topoisomerase I/farmacologia , Antibióticos Antineoplásicos/química , Antibióticos Antineoplásicos/farmacologia , California , Carbazóis/química , Humanos , Alcaloides Indólicos/química , Testes de Sensibilidade Microbiana , Micrococcus luteus/efeitos dos fármacos , Estrutura Molecular , Mycobacterium smegmatis/efeitos dos fármacos , Ressonância Magnética Nuclear Biomolecular , Saccharomyces cerevisiae/efeitos dos fármacos , Microbiologia do Solo , Staphylococcus aureus/efeitos dos fármacos , Inibidores da Topoisomerase I/química
20.
Org Lett ; 17(11): 2796-9, 2015 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-25961722

RESUMO

Terfestatins B (1) and C (2), new p-terphenyls bearing a novel unsaturated hexuronic acid (4-deoxy-α-L-threo-hex-4-enopyranuronate), a unique ß-D-glycosyl ester of 5-isoprenylindole-3-carboxylate (3) and the same rare sugar, and two new hygromycin precursors, were characterized as metabolites of the coal mine fire isolate Streptomyces sp. RM-5-8. EtOH damage neuroprotection assays using rat hippocampal-derived primary cell cultures with 1, 2, 3 and echoside B (a terfestatin C-3'-ß-D-glucuronide from Streptomyces sp. RM-5-8) revealed 1 as potently neuroprotective, highlighting a new potential application of the terfestatin scaffold.


Assuntos
Glucosídeos/química , Glucuronídeos/química , Glicosídeos/química , Ácidos Hexurônicos/química , Streptomyces/química , Compostos de Terfenil/química , Animais , Estrutura Molecular , Ratos
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