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On the basis of the one strain-many compounds (OSMAC) strategy, two new hygromycin A derivatives (3, 4), together with six known compounds were isolated from a medicinal plant inter rhizospheric Streptomyces in Pulsatilla chinensis. The structures of 3 and 4 were elucidated using NMR and HRESIMS analyses. A plausible biosynthetic pathway for these compounds was discussed. All the compounds were evaluated for their antimicrobial and cytotoxic activities. Compound 5 exhibited potent inhibitory activity against S. aureus and B. subtilis with the MICs of 16 and 8 μg ml

Two new prenylated flavonoids named sinoflavonoids NJ and NK (1–2), along with ten known compounds were isolated from the fruits of Podophyllum hexandrum Royle. The chemical structures were determined through NMR spectroscopic data and MS analysis. Sinoflavonoid NJ (1) with an unusual 5,11-dioxabenzo[b]fluoren-10-one skeleton was firstly reported from Berberidaceae. The isolated flavonoids were tested with LPS-induced RAW 264.7 mouse macrophages model for their anti-inflammatory activity. Sinoflavonoid NJ (1) showed the most potent inhibition on nitric oxide production with IC50 value as 0.06 μM.

Muraymycins are peptidyl nucleoside antibiotics that contain two Cβ-modified amino acids, (2S,3S)-capreomycidine and (2S,3S)-β-OH-Leu. The former is also a component of chymostatins, which are aldehyde-containing peptidic protease inhibitors that─like muraymycin─are derived from nonribosomal peptide synthetases (NRPSs). Using feeding experiments and in vitro characterization of 12 recombinant proteins, the biosynthetic mechanism for both nonproteinogenic amino acids is now defined. The formation of (2S,3S)-capreomycidine is shown to involve an FAD-dependent dehydrogenase:cyclase that requires an NRPS-bound pathway intermediate as a substrate. This cryptic dehydrogenation strategy is both temporally and mechanistically distinct in comparison to the biosynthesis of other capreomycidine diastereomers, which has previously been shown to proceed by Cβ-hydroxylation of free l-Arg catalyzed by a member of the nonheme Fe2+- and α-ketoglutarate (αKG)-dependent dioxygenase family and (eventually) a dehydration-mediated cyclization process catalyzed by a distinct enzyme(s). Contrary to our initial expectation, the sole nonheme Fe2+- and αKG-dependent dioxygenase candidate Mur15 encoded within the muraymycin gene cluster is instead demonstrated to catalyze specific Cβ hydroxylation of the Leu residue to generate (2S,3S)-β-OH-Leu that is found in most muraymycin congeners. Importantly, and in contrast to known l-Arg-Cβ-hydroxylases, the Mur15-catalyzed reaction occurs after the NRPS-mediated assembly of the peptide scaffold. This late-stage functionalization affords the opportunity to exploit Mur15 as a biocatalyst, proof of concept of which is provided.

Twelve guaianolide-type sesquiterpene oligomers with diverse structures were isolated from the whole plants of Ainsliaea fragrans, including a novel trimer (1) and two new dimers (2, 3). The chemical structures of the new compounds were elucidated through spectroscopic data interpretation and computational calculations. Ainsfragolide (1) is an unusual guaianolide sesquiterpene trimer generated with a novel C-C linkage at C2'-C15″, which may be biosynthesized prospectively through a further Michael addition. Cytotoxicity results showed that ainsfragolide (1) was the most potent compound against five cancer cell lines with IC50 values in the range of 0.4-8.3 μM.

Two new cadinane sesquiterpenes named myrrhterpenes A and B (1, 2), along with eighteen known analogs were isolated from the resin of Commiphora myrrha. Their structures were determined by various NMR and MS spectrometry analysis, as well as by comparison with related compounds. Anti-inflammatory activity with LPS-induced RAW 264.7 macrophages revealed that two new compounds displayed potent inhibition on nitric oxide production.

Background: Pedunculoside (PE) is a triterpene saponin from the barks of Ilex rotunda, a Traditional Chinese Medicine called Jiubiying, which is used for the treatment of cold and fever, tonsillitis, sore throat, acute and chronic hepatitis, etc. Previous studies have confirmed that crude extract orally has a significant therapeutic effect on myocardial infarction. Methods: A simple, sensitive, and specific method by using UPLC-MS/MS to study the pharmacokinetics of PE in rats was developed and validated, with ilexsaponin A as an internal standard. Methanol was used as a protein precipitation reagent for blood sample extraction. A Waters Acquity C18 column (2.1 mm × 50 mm, 1.7 μm) was used for chromatographic separation with a gradient elution of CH3CN: 0.1% formic acid (0.3 mL·min-1). Negative ion electrospray ionization was used for detection in multiple reaction monitoring mode. Results: PE was linear within the concentration range of 0.14-1118.00 ng/mL. The LLOQ was 0.14 ng/mL for the plasma samples. The intra-day and inter-day precision were ranged from 1.18% to 10.48%, while the accuracy ranged from -1.32% to 1.68%, indicating satisfactory precision and accuracy of the assay. The extraction recoveries for PE and IS were ranged from 81.40% to 86.65%, with no significant variation among the three concentrations, respectively. PE remained stable at room temperature (25°C) for 3 h, in auto-sampler (4°C) for 24 h, after three freeze-thaw cycles, and in long-term storage at ‒20°C for 30 days. The PK results of PE indicated its poor oral bioavailability (3.37%). Conclusion: Non-compartmental pharmacokinetics parameters indicated that PE was rapidly distributed to the tissues and metabolized. The pharmacokinetic data of this paper highlighted the first-time report of PE oral bioavailability with two different administration manners, which will help to better understand how PE metabolized in rats and exert its pharmacological effect in vivo.

A novel octahydroindolizine alkaloid, named dendrocrepidamine (1) with an unusual 18,19,19'-cyclopropanone-dendrocrepine skeleton, was isolated from the ethanol extract of the roots of Dendrobium crepidatum, along with six known compounds (2-7). The structure of 1 was elucidated through HR-ESIMS, NMR spectroscopic data and computational calculations. All compounds were examined for their inhibitory effects on nitric oxide (NO) production induced by lipopolysaccharide (LPS) in RAW264.7 cells with IC50 values in the range of 3.04-54.89 µM. In vivo, crepidatin (6) (80, 40 and 10 mg/kg) showed a significant protective effect against LPS-induced acute lung injury (ALI) in mice.

Natural products and natural product-derived compounds have been widely used for pharmaceuticals for many years, and the search for new natural products that may have interesting activity is ongoing. Abyssomicins are natural product molecules that have antibiotic activity via inhibition of the folate synthesis pathway in microbiota. These compounds also appear to undergo a required [4 + 2] cycloaddition in their biosynthetic pathway. Here we report the structure of an flavin adenine dinucleotide-dependent reductase, AbsH3, from the biosynthetic gene cluster of novel abyssomicins found in Streptomyces sp. LC-6-2.

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.

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.

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; β-rubromycin, 7; γ-rubromycin, 8; and [2α(1E,3E),4β]-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.

Muraymycins are peptidyl nucleoside antibiotics that contain two C(β)-modified amino acids, (2S,3S)-capreomycidine and (2S,3S)-β-OH-Leu. The former is also a component of chymostatins, which are aldehyde-containing peptidic protease inhibitors that—like muraymycin—are derived from nonribosomal peptide synthetases (NRPSs). Using feeding experiments and in vitro characterization of twelve recombinant proteins, the biosynthetic mechanism for both nonproteinogenic amino acids is now defined. The formation of (2S,3S)-capreomycidine is shown to involve an FAD-dependent dehydrogenase:cyclase that requires an NRPS-bound pathway intermediate as a substrate. This cryptic dehydrogenation strategy is both temporally and mechanistically distinct in comparison to the biosynthesis of other capreomycidine diastereomers, which has previously been shown to proceed by C(β)-hydroxylation of free l-Arg catalyzed by a member of the non-heme Fe(2+)- and α-ketoglutarate (αKG)-dependent dioxygenase family and (eventually) a dehydration-mediated cyclization process catalyzed by a distinct enzyme(s). Contrary to our initial expectation, the sole non-heme Fe(2+)- and αKG-dependent dioxygenase candidate Mur15 encoded within the muraymycin gene cluster is instead demonstrated to catalyze specific C(β) hydroxylation of the Leu residue to generate (2S,3S)-β-OH-Leu that is found in most muraymycin congeners. Importantly, and in contrast to known l-Arg-C(β)-hydroxylases, the Mur15-catalyzed reaction occurs after the NRPS-mediated assembly of the peptide scaffold. This late-stage functionalization affords the opportunity to exploit Mur15 as a biocatalyst, proof of concept of which is provided.

Three new polyketide dimers named huoshanmycins A‒C (

Twelve guaianolide-type sesquiterpene oligomers with diverse structures were isolated from the whole plants of

A new diterpenoid named jatrophacine (

Iridin, one of the main bioactive components isolated from Belamcanda chinensis (L.) DC, exerts various pharmacological activities, such as anti-inflammation, antioxidant, and antitumor. However, the metabolism and pharmacokinetics of iridin are still unknown. After 100 mg/kg administration of iridin orally, the plasma, urine, and fecal bio-samples from Sprague–Dawley (SD) rats were collected and detected by ultrahigh-performance liquid chromatography–tandem mass spectrometry (UHPLC-MS/MS). The pharmacokinetics of the major metabolite irigenin (aglycon of iridin) and a total of thirteen metabolites of iridin were identified, including five metabolites in plasma, ten metabolites in urine, and six metabolites in feces. The most principal metabolic pathway of iridin was glucuronidation after demethylation and was mediated by UDP-glucuronosyltransferases (UGTs) 1A7, 1A8, 1A9 and 1A10. This study highlights the first-time investigation of the metabolism of iridin in vivo, and the pharmacokinetics of irigenin (the major metabolite of iridin) in rats. These results provide robust evidence for further research and clinical application of iridin.

Two new terragine analogs (

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.

An efficient and convenient method for the synthesis of oxazole derivatives from enamides has been established via a ruthenium-catalyzed C–O cyclization. This protocol allows for a wide functional group compatibility, broad substrate scope and ease of operation. This catalytic method is also applicable to other 5-membered O-containing and S-containing heterocyclic systems involving thiazole and furan scaffolds, thus this strategy can be broadly applied to organic synthesis and medicinal chemistry.

Two new terragine analogs (1‒2) with special succinimide and aminopentane moieties were isolated from the fermentation broth of Bacillus sp. SH-1.2-ROOT-18, an endophyte previously discovered from the root of Dendrobium officinale. The structures were elucidated base on comprehensive 1 D/2D NMR and MS data analysis. Complete NMR assignments for the first reported naturally occurring metabolite 3 was also provided.

Gypenosides, extracts of Gynostemma yixingense, have been traditionally prescribed to improve metabolic syndrome in Asian folk and local traditional medicine hospitals. However, the mechanism of its action remains unclarified. In this work, our results indicated that chronic administration of 2α-OH-protopanoxadiol (GP2), a metabolite of gypenosides in vivo, protected mice from high-fat diet-induced obesity and improved glucose tolerance by improving intestinal L-cell function. Mechanistically, GP2 treatment inhibited the enzymatic activity of bile salt hydrolase and modulated the proportions of the gut microbiota, which led to an increase in the accumulation of tauro-β-muricholic acid (TβMCA) in the intestine. TβMCA induced GLP-1 production and secretion by reducing the transcriptional activity of nuclear receptor farnesoid X receptor (FXR). Transplantation of GP2-remodelled fecal microbiota into antibiotic-treated mice also increased the intestinal TβMCA content and improved intestinal L-cell function. These findings demonstrate that GP2 ameliorates metabolic syndrome at least partly through the intestinal FXR/GLP-1 axis via gut microbiota remodelling and also suggest that GP2 may serve as a promising oral therapeutic agent for metabolic syndrome.

Natural products and natural product-derived compounds have been widely used for pharmaceuticals for many years, and the search for new natural products that may have interesting activity is ongoing. Abyssomicins are natural product molecules that have antibiotic activity via inhibition of the folate synthesis pathway in microbiota. These compounds also appear to undergo a required [4 + 2] cycloaddition in their biosynthetic pathway. Here we report the structure of an flavin adenine dinucleotide-dependent reductase, AbsH3, from the biosynthetic gene cluster of novel abyssomicins found in Streptomyces sp. LC-6-2.

BACKGROUND: Endophyte has now become a potential source for the discovery of novel natural products, as they participate in biochemical pathways of their hosts and produce analogous or novel bioactive compounds. As an epiphytic plant, Dendrobium officinale is one of precious Chinese medicines with various activities. It is well known for containing diverse endophytes, but so far not much is known about their secondary metabolites. METHODS: the plant tissues were cut and cultured on agar plates to isolate and purify the endophytic bacteria from Dendrobium officinale. Taxonomical identification of strains was performed by 16s rRNA. At the same time, the crude extracts of the strains were tested for antibacterial and cytotoxic activities to screen out one endophyte, Streptomyces sp. SH-1.2-R-15 for further study. After scale-up fermentation, isolation, purification and structure elucidation by using MS, 1D/2D-NMR spectroscopic method, secondary metabolites were identified and submitted for biological activity test. RESULTS: Fifty-eight endophytic strains representing 9 genera were obtained, with 50% of strains were Streptomyces. One of the most active strain, Streptomyces sp. 1.2-R-15, was selected for bioassay-guided isolation, which led to the discovery of two new peptide-type compounds 1 and 2, as well as a bioactive chartreusin, and four other known natural products. Their structures were determined by comprehensive spectroscopic techniques. Chartreusin showed potent cytotoxicity against Hep3B2.1-7 (IC(50) =18.19 µM) and H1299 (IC(50) =19.74 µM) cancer cell lines, and antibacterial activity against S. aureus (IC(50) =23.25 µM). CONCLUSIONS: This study highlights the endophytic bacteria from medical plant D. officinale have potential bioactivity and natural product diversity, thus implicates them as a valuable source for new anticancer and antibiotics agents.

A novel 6/6/5/6 tetracyclic polyketide named chartspiroton (

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

Several nucleoside antibiotics are structurally characterized by a 5″-amino-5″-deoxyribose (ADR) appended via a glycosidic bond to a high-carbon sugar nucleoside (5′S,6′S)-5′-C-glycyluridine (GlyU). GlyU is further modified with an N-alkylamine linker, the biosynthetic origin of which has yet to be established. By using a combination of feeding experiments with isotopically labeled precursors and characterization of recombinant proteins from multiple pathways, the biosynthetic mechanism for N-alkylamine installation for ADR–GlyU-containing nucleoside antibiotics has been uncovered. The data reveal S-adenosyl-l-methionine (AdoMet) as the direct precursor of the N-alkylamine, but, unlike conventional AdoMet- or decarboxylated AdoMet-dependent alkyltransferases, the reaction is catalyzed by a pyridoxal-5′-phosphate-dependent aminobutyryltransferase (ABTase) using a stepwise γ-replacement mechanism that couples γ-elimination of AdoMet with aza-γ-addition onto the disaccharide alkyl acceptor. In addition to using a conceptually different strategy for AdoMet-dependent alkylation, the newly discovered ABTases require a phosphorylated disaccharide alkyl acceptor, revealing a cryptic intermediate in the biosynthetic pathway. Rather than a typical S-adenosylmethionine-dependent alkyltransferase, the installation of the N-alkylamine linker in several nucleoside antibiotics is catalyzed via γ-replacement by a pyridoxal-5′-phosphate-dependent aminobutyryltransferase.

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.

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.

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.

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.

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.

A new diterpenoid named jatrophacine (1), with an unusual 4,5-seco- rhamnofolane skeleton, was isolated from the roots of Jatropha curcas, together with eleven known diterpenoids. The structure of the new compound was elucidated through a detailed analysis of its 1 D- and 2 D-NMR spectra. The X-ray structure of jatrophol (2) is also presented. Anti-inflammatory activity with LPS-induced RAW 264.7 macrophages revealed that compound 1 strongly inhibited the production of nitric oxide (IC50 = 0.53 μM).

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.

Six pairs of octahydroindolizine-type alkaloid enantiomers (1–6) including three new compounds [(−)-1/(+)-1, 2] were isolated from the stems of Dendrobium crepidatum. Their structures including the absolute configurations were elucidated by extensive spectroscopic analyses and comparison between the experimental and calculated electronic circular dichroism (ECD). All compounds were examined for their inhibitory effects on nitric oxide (NO) production induced by lipopolysaccharide (LPS) in RAW264.7 cells. It was found that compounds (+)-1, 2 and (+)-6 exhibited pronounced inhibition on NO production with IC50 values in the range of 3.62–16.11 µM, being more active than the positive control, dexamethasone (IC50 = 47.04 µM). In vivo, compound 6 (100, 50 and 10 mg/kg) showed protective effects against LPS-induced acute lung injury (ALI) in mice.

Summary 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.

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.