Polyketide Derivatives Research Articles

Polyketides from the Mangrove-derived fungal endophyte Pestalotiopsis clavispora

Six new polyketide derivatives, including pestalpolyol I (1), pestapyrones A (2) and B (3), (R)-periplanetin D (6), pestaxanthone (7), norpestaphthalide A (8), and an isolation artifact pestapyrone C (4), were obtained from extracts of the endophytic fungus Pestalotiopsis clavispora isolated from the Mangrove plant Rhizophora harrisonii. In addition, seven known metabolites, including similanpyrone B (5), (R,S)-5,7-dihydroxy-3-(1-hydroxyethyl)phthalide (9), for which we propose the trivial name norpestaphthalide B, pestaphthalides A (10) and B (11), 2-epi-herbarumin II (12), and pestalotiollides A (13) and B (14) were isolated. The structures of the new compounds were unambiguously elucidated on the basis of one- and two-dimensional NMR spectroscopy, as well as by high-resolution mass spectrometry. All compounds were tested for their cytotoxicity against the mouse lymphoma cell line L5178Y. Compound 1 exhibited strong activity with an IC50 value of 4.10μM. All other compounds (2–14) proved to be inactive (IC50>10μM) in this assay.

A Novel Aldo-Keto Reductase, HdRed, from the Pacific Abalone Haliotis discus hannai, Which Reduces Alginate-derived 4-Deoxy-l-erythro-5-hexoseulose Uronic Acid to 2-Keto-3-deoxy-d-gluconate

Abalone feeds on brown seaweeds and digests seaweeds' alginate with alginate lyases (EC 4.2.2.3). However, it has been unclear whether the end product of alginate lyases (i.e. unsaturated monouronate-derived 4-deoxy-L-erythro-5-hexoseulose uronic acid (DEH)) is assimilated by abalone itself, because DEH cannot be metabolized via the Embden-Meyerhof pathway of animals. Under these circumstances, we recently noticed the occurrence of an NADPH-dependent reductase, which reduced DEH to 2-keto-3-deoxy-D-gluconate, in hepatopancreas extract of the pacific abalone Haliotis discus hannai. In the present study, we characterized this enzyme to some extent. The DEH reductase, named HdRed in the present study, could be purified from the acetone-dried powder of hepatopancreas by ammonium sulfate fractionation followed by conventional column chromatographies. HdRed showed a single band of ∼ 40 kDa on SDS-PAGE and reduced DEH to 2-keto-3-deoxy-D-gluconate with an optimal temperature and pH at around 50 °C and 7.0, respectively. HdRed exhibited no appreciable activity toward 28 authentic compounds, including aldehyde, aldose, ketose, α-keto-acid, uronic acid, deoxy sugar, sugar alcohol, carboxylic acid, ketone, and ester. The amino acid sequence of 371 residues of HdRed deduced from the cDNA showed 18-60% identities to those of aldo-keto reductase (AKR) superfamily enzymes, such as human aldose reductase, halophilic bacterium reductase, and sea hare norsolorinic acid (a polyketide derivative) reductase-like protein. Catalytic residues and cofactor binding residues known in AKR superfamily enzymes were fairly well conserved in HdRed. Phylogenetic analysis for HdRed and AKR superfamily enzymes indicated that HdRed is an AKR belonging to a novel family.

Preparation of conjugated dienoates with Bestmann ylide: Towards the synthesis of zampanolide and dactylolide using a facile linchpin approach.

Bestmann ylide [(triphenylphosphoranylidene)ketene] acts as a chemical linchpin that links nucleophilic entities, such as alcohols or amines, with carbonyl moieties to produce unsaturated esters and amides, respectively. In this work, the formation of α,β,γ,δ-unsaturated esters (dienoates) is achieved through the coupling of Bestmann ylide, an alcohol and an α,β-unsaturated aldehyde. Primary and secondary alcohols, including allylic alcohols, are suitable substrates; the newly formed alkene has an E-geometry. Strategically, this represents a highly efficient route to unsaturated polyketide derivatives. A linchpin approach to the synthesis of a major fragment of the natural products zampanolide and dactylolide is investigated using Bestmann ylide to link the C16–C20 alcohol with the C3–C8 aldehyde fragment.

Varioxiranols A–G and 19-O-Methyl-22-methoxypre-shamixanthone, PKS and Hybrid PKS-Derived Metabolites from a Sponge-Associated Emericella variecolor Fungus

Chemical examination of a sponge (Cinachyrella sp.)-associated Emericella variecolor fungus resulted in the isolation of seven new polyketide derivatives, namely, varioxiranols A-G (1-7), and a new hybrid PKS-isoprenoid metabolite, 19-O-methyl-22-methoxypre-shamixanthone (8), together with nine known analogues. Their structures were elucidated on the basis of extensive spectroscopic analyses, including ECD effects, Mosher's method, X-ray diffraction, and chemical conversion for the determination of absolute configurations. Varioxiranols F and G were found for the first time to link a xanthone moiety with a benzyl alcohol via an ether bond, while the dioxolanone group of 5 is unusual in nature. A cell-based lipid-lowering assay revealed that pre-shamixanthone (12) exerted significant inhibition against lipid accumulation in HepG2 cells without cytotoxic effects, accompanying the potent reduction of total cholesterol and triglycerides. Real-time quantitative PCR indicated that pre-shamixanthone (12) mediated the reduction of lipid accumulation related to the down-regulation of the expression of the key lipogenic transcriptional factor SREBP-1c and its downstream genes encoding FAS and ACC.

A Convenient Access to Novel Amino-Hydroxy-Methyl Stereo­triads Containing an E-Trisubstituted Vinyl Iodide Unit

Conversion of α-amino aldehydes into protected amino-hydroxy-methyl stereotriads carrying an E-trisubstituted vinyl iodide unit was effected by means of a three-step protocol: a Marshall reaction of the α-amino aldehyde with a chiral propargylic mesylate, a silylcupration of the corresponding homopropargylic alcohol and an iododesilylation reaction of the resulting vinylsilane. This sequence delivered the expected compounds as their oxazolidinone derivatives, providing a convenient diastereoselective access to useful building blocks for polypropionate synthesis and polyketide derivatives.

Chemical Probes for the Functionalization of Polyketide Intermediates

AbstractA library of functionalized chemical probes capable of reacting with ketosynthase‐bound biosynthetic intermediates was prepared and utilized to explore in vivo polyketide diversification. Fermentation of ACP mutants of S. lasaliensis in the presence of the probes generated a range of unnatural polyketide derivatives, including novel putative lasalocid A derivatives characterized by variable aryl ketone moieties and linear polyketide chains (bearing alkyne/azide handles and fluorine) flanking the polyether scaffold. By providing direct information on microorganism tolerance and enzyme processing of unnatural malonyl‐ACP analogues, as well as on the amenability of unnatural polyketides to further structural modifications, the chemical probes constitute invaluable tools for the development of novel mutasynthesis and synthetic biology.

Chemical probes for the functionalization of polyketide intermediates.

A library of functionalized chemical probes capable of reacting with ketosynthase-bound biosynthetic intermediates was prepared and utilized to explore in vivo polyketide diversification. Fermentation of ACP mutants of S. lasaliensis in the presence of the probes generated a range of unnatural polyketide derivatives, including novel putative lasalocid A derivatives characterized by variable aryl ketone moieties and linear polyketide chains (bearing alkyne/azide handles and fluorine) flanking the polyether scaffold. By providing direct information on microorganism tolerance and enzyme processing of unnatural malonyl-ACP analogues, as well as on the amenability of unnatural polyketides to further structural modifications, the chemical probes constitute invaluable tools for the development of novel mutasynthesis and synthetic biology.

Acute toxicity of karlotoxins to mice

Karlotoxins, polyketide derivatives produced by the dinoflagellate Karlodinium veneficum, are associated with fish kills in temperate estuaries world-wide. In this study, the acute effects of 3 pure karlotoxin analogs (KmTx 1, KmTx 3 and KmTx 2) have been examined in mice. Transient lethargy and increased respiratory rates were observed soon after dosing with the karlotoxins by intraperitoneal injection, but no deaths were recorded in animals dosed with KmTx 2 at up to 500 μg/kg or with KmTx 1 or KmTx 3 at up to 4000 μg/kg. Animals dosed intraperitoneally with KmTx 1 and KmTx 3 at 4000 μg/kg showed a pronounced decrease in food and water intake, lasting 3–4 days after dosing, accompanied by a significant decrease in body weight. After this time, the lost body weight was regained and the behavior and appearance of the mice remained normal throughout the following 10-day observation period. No effects were seen in mice dosed orally with KmTx 1 or KmTx 3 at a dose of 4000 μg/kg. It is concluded that contamination of seafood if it were to occur with these karlotoxins is unlikely to pose a major risk of acute intoxication in consumers.

Polyketides from the mangrove-derived endophytic fungus Acremonium strictum

Five new polyketide derivatives, 6′-hydroxypestalotiopsone C (1), acropyrone (2), bicytosporone D (3), waol acid (4), and pestalotiopene C (5), together with seven known metabolites (6–12), were obtained from extracts of the endophytic fungus Acremonium strictum, isolated from the mangrove tree Rhizophora apiculata. The structures of the isolated compounds were elucidated on the basis of comprehensive NMR and MS analysis. Compounds 6, 7, and 9 showed moderate cytotoxic activity against human cisplatin-sensitive (IC50 values 27.1, 76.2, and 8.3μM, respectively) and resistant A2780 cell lines (IC50 values 12.6, 30.1, and 19.0μM, respectively), whereas only 9 exhibited antibacterial activity against Staphylococcus aureus (MIC value 14.3μM).

Psychrophilin E, a new cyclotripeptide, from co-fermentation of two marine alga-derived fungi of the genus Aspergillus

Chemical investigation of the mycelial extract of a mixed culture of two marine alga-derived fungal strains of the genus Aspergillus has yielded one new cyclotripeptide, psychrophilin E (1), the recently reported oxepin-containing alkaloids, protuboxepin A (2) and oxepinamide E (3), together with three other polyketide derivatives (4–6). The chemical structure and relative and absolute configurations of psychrophilin E (1) were unambiguously established based on HRMS, 1D, 2D NMR and chiral-phase HPLC analysis of its hydrolysate. All the isolated compounds were assessed for their anti-proliferative activity against four different human cancer cell lines and some of them revealed selective activities.

Polyketides with New Delhi Metallo-β-lactamase 1 Inhibitory Activity from Penicillium sp.

Three new polyketide compounds (1-3), a new quinolone alkaloid (4), and seven known polyketide derivatives were identified from the cultures of Penicillium sp. I09F 484, a strain isolated from the rhizosphere soil of the plant Picea asperata from Kanas Lake, Xinjiang, China. Their structures were elucidated by extensive spectroscopic data analysis. The absolute configurations of 1 and 4 were established by quantum chemical time-dependent density functional theory electronic circular dichroism calculation and Marfey's method, respectively. Compounds 1 and 2 displayed inhibitory activity against New Delhi metallo-β-lactamase 1 with IC₅₀ values of 94.9 and 87.9 μM, respectively.

N‐Bearing Furanone Derivatives from an Endophytic Fungus in Huperzia serrata

AbstractTwo new polyketide derivatives, huaspenones C and D (1 and 2, resp.), were isolated from the cultures of an endophytic fungus Peyronellaea sp. HS‐12, derived from the stems of Huperzia serrata. They share N‐bearing furan‐3(2H)‐one backbone, and 2 has an unprecedented furo[3,2‐c]pyridine skeleton. Their structures including the absolute configuration were elucidated by extensive spectroscopic analysis combined with quantum‐chemical calculations. (2E,4E)‐6‐hydroxy‐2‐methylocta‐2,4‐dienoic acid (3), a key intermediate of the biosynthesis of 1 and 2, was also obtained from the endophyte.

Two N-containing polyketide derivatives from Peperomia dindygulensis

Two unprecedented N-containing polyketide derivatives, dindygulerinone A and B, together with three known polyketides, have been isolated from the whole plant of Peperomia dindygulensis. The new structures were elucidated as (–)-(4S)-2-[(Z)-1'-aminooctadec-11'-enylidene]-4-hydroxycyclohexane-1,3-dione (1) and 2-[(Z)-1'-aminooctadec-11'-enylidene]-cyclohexane-1,3-dione (2), respectively, by comparing with literature data and extensive spectroscopic methods, including 2D NMR and CD spectroscopic analysis.

New long-chain aliphatic compounds from Peperomia dindygulensis

Three long-chain aliphatic compounds, including one new polyketide derivative, dindygulerione C (1), one new octaketide derivative, dindygulerione D (2) and one new acylresorcinol derivative dindyguleranone (3) were isolated from the whole plant of the Chinese anticancer folk medicine Peperomia dindygulensis Miq. (Piperaceae). Dindygulerione C is an unprecedented example of a N-containing polyketide. The chemical structures and configurations of 1–3 were elucidated as (−)-(4S)-2-[(Z)-1′-(6″,7″-dihydroxyphenethyl-amino)octadec-11′-enylidene]-4-hydroxycyclohexane-1,3-dione (1), (+)-2-heptadecyl-4-hydroxy-3,4,7,8-tetrahydro-2H-chromen-5(6H)-one (2) and 2-(1,3-dihydroxyphenyl)-octacosan-1′-one (3), respectively, by comparing with the literature data and extensive spectroscopic methods, including 2-D NMR and circular dichroism spectroscopic analysis. The cytotoxicity of 1–3 was evaluated against Hep3B and HepG2 liver cancer cell lines.

ChemInform Abstract: Organocatalytic Asymmetric Vinylogous Aldol Reactions

AbstractReview: about 50 refs.

Organocatalytic Asymmetric Vinylogous Aldol Reactions

The aldol reaction is one of the most predominantly used reactions for the formation of C–C bonds in synthetic organic chemistry. The vinylogous extension of this fundamental C–C bond-forming reaction to nucleophilic components, such as the vinylogous aldol reaction is significant because it provides rapid access to polyketide derivatives such as δ-hydroxy-β-keto esters and α,β-unsaturated δ-hydroxy carbonyl compounds. Further transformation of these compounds can be accomplished with good diastereoselectivity and leads the way to polyol units, a motif common to many pharmaceutically important natural products. Details of recent advances in the organocatalytic vinylogous aldol reaction and its applications are discussed in this review.

Evolutionary Origins of the Fumonisin Secondary Metabolite Gene Cluster in Fusarium verticillioides and Aspergillus niger.

The secondary metabolite gene clusters of euascomycete fungi are among the largest known clusters of functionally related genes in eukaryotes. Most of these clusters are species specific or genus specific, and little is known about how they are formed during evolution. We used a comparative genomics approach to study the evolutionary origins of a secondary metabolite cluster that synthesizes a polyketide derivative, namely, the fumonisin (FUM) cluster of Fusarium verticillioides, and that of Aspergillus niger another fumonisin (fumonisin B) producing species. We identified homologs in other euascomycetes of the Fusarium verticillioides FUM genes and their flanking genes. We discuss four models for the origin of the FUM cluster in Fusarium verticillioides and argue that two of these are plausible: (i) assembly by relocation of initially scattered genes in a recent Fusarium verticillioides; or (ii) horizontal transfer of the FUM cluster from a distantly related Sordariomycete species. We also propose that the FUM cluster was horizontally transferred into Aspergillus niger, most probably from a Sordariomycete species.

4-Coumarate:CoA ligase family members from elicitor-treated Sorbus aucuparia cell cultures

Sorbus aucuparia cell cultures accumulate biphenyl and dibenzofuran phytoalexins in response to elicitor treatment. These polyketide derivatives arise from the starter substrate benzoyl-CoA, the biosynthesis of which is largely unresolved. Two CoA ligases involved are cinnamate:CoA ligase and benzoate:CoA ligase, which were assumed to be related in S. aucuparia to the ubiquitous 4-coumarate:CoA ligase (4CL). cDNAs encoding three distinct 4CLs from elicitor-treated S. aucuparia cell cultures were isolated using RT-PCR and RACE techniques and functionally expressed in Escherichia coli as His 6-tagged proteins (Sa4CL2 and Sa4CL3) or GST-fusion protein (Sa4CL1). All three isoenzymes preferred 4-coumaric acid over cinnamic acid in spectrophotometric assays and failed to utilize benzoic acid in radioisotopic assays. After elicitor treatment of S. aucuparia cell cultures, the transcript levels of all three Sa4CLs increased but were significantly lower than the maximum expression rates of the phenylalanine ammonia-lyase ( PAL) and biphenyl synthase 1 ( BIS1) genes. The substrate specificities and the expression profiles indicate that the three 4CL isoenzymes are not involved in benzoyl-CoA biosynthesis in S. aucuparia cell cultures. Sa4CL3 and PAL transcripts also accumulated in response to light treatment. Phylogenetically, Sa4CL1 and Sa4CL2 belong to the class I cluster and Sa4CL3 groups in the class II cluster. Sa4CL3 contains a 49-amino acid N-terminal extension, which includes a chloroplast sorting signal.

Secondary Metabolites from a Marine-Derived Endophytic Fungus Penicillium chrysogenum QEN-24S

Penicillium chrysogenum QEN-24S, an endophytic fungus isolated from an unidentified marine red algal species of the genus Laurencia, displayed inhibitory activity against the growth of pathogen Alternaria brassicae in dual culture test. Chemical investigation of this fungal strain resulted in the isolation of four new (1–3 and 5) and one known (4) secondary metabolites. Their structures were identified as two polyketide derivatives penicitides A and B (1 and 2), two glycerol derivatives 2-(2,4-dihydroxy-6-methylbenzoyl)-glycerol (3) and 1-(2,4-dihydroxy-6-methylbenzoyl)- glycerol (4), and one monoterpene derivative penicimonoterpene (5). Penicitides A and B (1 and 2) feature a unique 10-hydroxy- or 7,10-dihydroxy-5,7-dimethylundecyl moiety substituting at C-5 of the α-tetrahydropyrone ring, which is not reported previously among natural products. Compound 5 displayed potent activity against the pathogen A. brassicae, while compound 1 exhibited moderate cytotoxic activity against the human hepatocellular liver carcinoma cell line.

Polyketide derivatives of endophytic fungus Pestalotiopsis sp. isolated from the Chinese mangrove plant Rhizophora mucronata

A detailed chemical investigation of the minor metabolites produced by the endophytic fungus Pestalotiopsis sp. isolated from the Chinese mangrove Rhizophora mucronata afforded sixteen new compounds of polyketide origin, including pestalotiopyrones A–H (1–8), pestalotiopisorin A (10), pestalotiollides A–B (11–12), pestalotiopin A (13), and four amides pestalotiopamides A–D (14–17), along with three known compounds, nigrosporapyrone D (9), 2-anhydromevalonic acid (18), and p-hydroxy benzaldehyde (19). The structures of all compounds were unambiguously established from their spectroscopic data that included HR-ESIMS and 1- and 2-dimensional NMR spectroscopy, and by comparison with the literature.