Natural Products Chemistry Breaking News

Two new bromotyrosine alkaloids, pseudoceralidinone A (1) and aplysamine 7 (2), along with three known compounds were isolated from the Australian sponge Pseudoceratina verrucosa. Their structures were characterized by NMR and MS data and the synthetic route. Their cytotoxicity was evaluated against cancer cell lines (HeLa and PC3) and a noncancer cell line (NFF).

A new lipopeptide, ciliatamide D (1), was isolated from a marine sponge Stelletta sp., collected at Oshimashinsone, together with the known compound ciliatamide A (2). Ciliatamide D (1) is a congener of 2, in which N-Me-Phe is replaced by N-Me-Met(O). Marfey’s analysis of the acid hydrolysate of 1 demonstrated that the two constituent amino acids were both in the l-form. This result prompted us to carefully investigate the configuration of 2, resulting in the assignment of the l-form for both residues.

Yasufumi Imae, Kentaro Takada, Shigeru Okada, Yuji Ise, Hiroshi Yoshimura, Yasuhiro Morii, and Shigeki Matsunaga

J. Nat. Prod., Article ASAP

DOI: 10.1021/np300878b

Publication Date (Web): March 6, 2013

Discovering molecular components and their functionality is key to the development of hypotheses concerning the organization and regulation of metabolic networks. The iterative experimental testing of such hypotheses is the trajectory that can ultimately enable accurate computational modelling and prediction of metabolic outcomes. This information can be particularly important for understanding the biology of natural products, whose metabolism itself is often only poorly defined. Here, we describe factors that must be in place to optimize the use of metabolomics in predictive biology. A key to achieving this vision is a collection of accurate time-resolved and spatially defined metabolite abundance data and associated metadata. One formidable challenge associated with metabolite profiling is the complexity and analytical limits associated with comprehensively determining the metabolome of an organism. Further, for metabolomics data to be efficiently used by the research community, it must be curated in publicly available metabolomics databases. Such databases require clear, consistent formats, easy access to data and metadata, data download, and accessible computational tools to integrate genome system-scale datasets. Although transcriptomics and proteomics integrate the linear predictive power of the genome, the metabolome represents the nonlinear, final biochemical products of the genome, which results from the intricate system(s) that regulate genome expression. For example, the relationship of metabolomics data to the metabolic network is confounded by redundant connections between metabolites and gene-products. However, connections among metabolites are predictable through the rules of chemistry. Therefore, enhancing the ability to integrate the metabolome with anchor-points in the transcriptome and proteome will enhance the predictive power of genomics data. We detail a public database repository for metabolomics, tools and approaches for statistical analysis of metabolomics data, and methods for integrating these datasets with transcriptomic data to create hypotheses concerning specialized metabolisms that generate the diversity in natural product chemistry. We discuss the importance of close collaborations among biologists, chemists, computer scientists and statisticians throughout the development of such integrated metabolism-centric databases and software.

Manhoi Hur ,  Alexis Ann Campbell ,  Marcia Almeida-de-Macedo ,  Ling Li ,  Nick Ransom ,  Adarsh Jose ,  Matt Crispin ,  Basil J. Nikolau and Eve Syrkin Wurtele

Nat. Prod. Rep., 2013, Advance Article

DOI: 10.1039/C3NP20111B

Natural inspiration: Based on the biosynthesis of squalene-derived polyethers, a total synthesis of teurilene is described. The carbocation formation in the Nicholas reaction serves to control the initiation of a polyepoxide ring-opening cascade. The three furan rings present in teurilene were obtained in excellent yield in one step. Boc=tert-butoxycarbonyl, TMS=trimethylsilyl.

Julio Rodríguez-López, Dr. Fernando Pinacho Crisóstomo, Dr. Nuria Ortega, Prof. Matías López-Rodríguez, Prof. Víctor S. Martín, Dr. Tomás Martín

Article first published online: 21 FEB 2013

DOI: 10.1002/anie.201209159

The absolute configuration (AC) of the bioactive metabolites phyllostin (1) and scytolide (2), two hexahydro-1,4-benzodioxines produced by Phyllosticta cirsii, and oxysporone (3), a dihydrofuropyranone recently isolated from a strain of Diplodia africana, has been assigned by computational analysis of their optical rotatory dispersion (ORD), electronic circular dichroism (ECD), and vibrational circular dichroism (VCD) spectra. Computational prediction of ORD, ECD, and VCD allowed us to assign (3S,4aR,8S,8aR) AC to naturally occurring (−)-1, while (4aR,8S,8aR) AC was assigned to (−)-2 employing only ECD and VCD, because in this case ORD analysis turned out to be unsuitable for AC assignment. Theoretical prediction of both ORD and ECD spectra of 3 led to assignment of (4S,5R,6R) AC to (+)-3. In this case a satisfactory agreement between experimental and calculated VCD spectra was obtained only after taking into account solvent effects. This study shows that in the case of flexible and complex natural products only a concerted application of more than a single chiroptical technique permits unambiguous assignment of absolute configuration.

Giuseppe Mazzeo, Ernesto Santoro, Anna Andolfi, Alessio Cimmino, Pavle Troselj, Ana G. Petrovic, Stefano Superchi, Antonio Evidente, and Nina Berova

J. Nat. Prod., Article ASAP

DOI: 10.1021/np300770s

Publication Date (Web): February 21, 2013

Circular dichroism (CD) spectroscopy is one of the most useful techniques for the stereochemical analysis of chiral biopolymers and fine chemicals. It has become invaluable for the assignment of the absolute configuration, the study of conformational isomers, and the determination of racemization kinetics of CD active chiral compounds. Molecular interactions between a nonracemic chiral substrate and a chromophoric, CD-silent probe that is achiral or exists as a racemic mixture of rapidly interconverting enantiomeric conformations or configurations can induce a strong, characteristic chiroptical readout. A covalent or noncovalent binding event that coincides with a well-defined asymmetric induction process can effectively imprint the chiral information of the substrate on the stereodynamic sensor and thus generate intense Cotton effects in the UV region of the latter. The probe can thus function as a stereochemical reporter unit and analysis of the CD spectrum often provides accurate information about the absolute configuration and enantiomeric composition of the substrate used. In this review, recent developments in circular dichroism analysis of chiral compounds with stereodynamic probes are described and particular emphasis is given to sensor design, chiral induction processes and applications scope.

DOI: 10.1039/C3CS35498A

Six unprecedented bisindole alkaloids, trigolutesins A and B (1–2) with a unique polycyclic skeleton and trigolutes A–D (3–6) with another polycyclic skeleton, were isolated from the twigs of Trigonostemon lutescens. Their structures and relative configurations were elucidated by spectroscopic data and single-crystal X-ray diffraction crystallography. Trigolutesin A (1) showed weak AChE inhibitory activity.

Shan-Shan Ma†‡, Wen-Li Mei*†, Zhi-Kai Guo†, Shou-Bai Liu†, You-Xing Zhao†, De-Lan Yang†, Yan-Bo Zeng†, Bei Jiang‡, and Hao-Fu Dai

Org. Lett., Article ASAP

DOI: 10.1021/ol4002619

Publication Date (Web): March 12, 2013

A new pyrroloiminoquinone alkaloid, named atkamine, with an unusual scaffold was discovered from a cold, deep water Alaskan sponge Latrunculia sp. collected from the Aleutian Islands. Olefin metathesis was utilized to determine the location of the double bond in the hydrocarbon chain. The absolute configuration was determined by using computational approaches combing with the ECD (electronic circular dichroism) spectroscopy.

Yike Zou and Mark T. Hamann

Org. Lett., Article ASAP

DOI: 10.1021/ol400294v

Publication Date (Web): March 8, 2013

(+)-Laburnamine (1), a rare alkaloid extracted from Laburnum anagyroides seeds (4 mg from 1 kg), was shown to bind with high affinity (Ki, 293 nM) to the α4β2 nicotinic receptor subtype, which is, respectively, 126 and 136 times higher than to the α3β4 (Ki 37 μM) and α7 subtypes (Ki 40 μM). When its ability to release [3H]-dopamine from striatal slices was tested in a functional assay, compound 1 behaved as a partial agonist with an EC50 of 5.8 μM and an Emax that was 43% that of nicotine. When incubated with nicotine in the same assay, 1 prevented a maximal effect from being reached.

Bruno Tasso*†, Federica Novelli†, Fabio Sparatore†, Francesca Fasoli‡, and Cecilia Gotti‡

J. Nat. Prod., Article ASAP

DOI: 10.1021/np3007028

Publication Date (Web): March 5, 2013

Where once there was the genome, now there are thousands of ’omes. Nature goes in search of the ones that matter.

The marine bacterium Pseudoalteromonas sp. S2B, isolated from the Gulf of Mexico after the Deepwater Horizon oil spill, was found to produce lystabactins A, B, and C (1–3), three new siderophores. The structures were elucidated through mass spectrometry, amino acid analysis, and NMR. The lystabactins are composed of serine (Ser), asparagine (Asn), two formylated/hydroxylated ornithines (FOHOrn), dihydroxy benzoic acid (Dhb), and a very unusual nonproteinogenic amino acid, 4,8-diamino-3-hydroxyoctanoic acid (LySta). The iron-binding properties of the compounds were investigated through a spectrophotometric competition.

Hannah K. Zane and Alison Butler*

J. Nat. Prod., Article ASAP

DOI: 10.1021/np3008655

Publication Date (Web): February 27, 2013

Natural product drug discovery programs often rely on the use of silica (Si) gel, reversed-phase media, or size-exclusion resins (e.g., RP-C18, Sephadex LH-20) for compound purification. The synthetic polymer-based sorbent Diaion HP20SS (cross-linked polystyrene matrix) is used as an alternative to prepare purified natural product libraries. To evaluate the impact of chromatographic media on the isolation of biologically active, yet chromatographically unstable natural products, Diaion HP20SS was evaluated side-by-side with normal-phase sorbents for irreversible binding of extract constituents and their effects on bioactivity. An array of chemically diverse natural product-rich extracts was selected as a test panel, and a cell-based reporter assay for hypoxia-inducible factor-1 (HIF-1) was employed to monitor potential change(s) in bioactivity. Silica gel caused significant irreversible binding of three out of 10 extracts. Curcuma longa, Saururus cernuus, and Citrus reticulata extracts showed decreased HIF-1 inhibitory activity after elution through Si gel. An additional nonpolar column wash of HP20SS with EtOAc retained considerable bioactivities of active extracts. In general, Si gel produced the greatest loss of bioactivity. However, HP20SS elution reduced significantly HIF-1 inhibitory activity of certain extracts (e.g., Asimina triloba).

Sandipan Datta†, Yu-Dong Zhou*†, and Dale G. Nagle*†§

†Department of Pharmacognosy and §Research Institute of Pharmaceutical Sciences, School of Pharmacy, University of Mississippi, University, Mississippi 38677, United States

J. Nat. Prod., Article ASAP

DOI: 10.1021/np300858c

Publication Date (Web): February 26, 2013 

Herqueiazole (1), herqueioxazole (2), and herqueidiketal (3), polyaromatic metabolites with a novel skeletal class, were isolated from the marine-derived fungus Penicillium sp. Based on the combined spectroscopic analyses, the structures of 1 and 2 were determined to be the first examples of pyrrole- and oxazole-containing phenalenone compounds, respectively, whereas 3 possessed a novel skeleton with a highly oxidized naphthoquinone moiety. Compound 3 exhibited moderate cytotoxicity and significant inhibitory activity against sortase A.

Elin Julianti†, Jung-Ho Lee†, Lijuan Liao†, Wanki Park‡, Sunghyouk Park†, Dong-Chan Oh†, Ki-Bong Oh*‡, and Jongheon Shin*†

Org. Lett., Article ASAP

DOI: 10.1021/ol4002174

Publication Date (Web): February 22, 2013

We report 12 cyanobactin cyclic peptides, the aestuaramides, from the cultivated cyanobacterium Lyngbya aestuarii. We show that aestuaramides are synthesized enzymatically as reverse O-prenylated tyrosine ethers that subsequently undergo a Claisen rearrangement to produce forward C-prenylated tyrosine. These results reveal that a nonenzymatic Claisen rearrangement dictates isoprene regiochemistry in a natural system. They also reveal one of the mechanisms that organisms use to generate structurally diverse compound libraries starting from simple ribosomal peptide pathways (RiPPs).

Chemistry is progressively unraveling the processes that underlie the evolution of matter towards states of higher complexity and the generation of novel features along the way by self-organization under the pressure of information. Chemistry has evolved from molecular to supramolecular to become adaptive chemistry by way of constitutional dynamics, which allow for adaptation, through component selection in an equilibrating set. Dynamic systems can be represented by weighted dynamic networks that define the agonistic and antagonistic relationships between the different constituents linked through component exchange. Such networks can be switched through amplification/up-regulation of the best adapted/fittest constituent(s) in a dynamic set. Accessing higher level functions such as training, learning, and decision making represent future lines of development for adaptive chemical systems.

Prof. Dr. Jean-Marie Lehn

Angewandte Chemie International Edition

Article first published online: 18 FEB 2013

DOI: 10.1002/anie.201208397