Xanthones from fungi, lichens, and bacteria : the natural products and their synthesis

Many fungi, lichens, and bacteria produce xanthones (derivatives of 9H-xanthen-9-one, “xanthone” from the Greek “xanthos”, for “yellow”) as secondary metabolites. Xanthones are typically polysubstituted and occur as either fully aromatized, dihydro-, tetrahydro-, or, more rarely, hexahydro-derivatives. This family of compounds appeals to medicinal chemists because of their pronounced biological activity within a notably broad spectrum of disease states, a result of their interaction with a correspondingly diverse range of target biomolecules. This has led to the description of xanthones as “privileged structures”.(1) Historically, the total synthesis of the natural products has mostly been limited to fully aromatized targets. Syntheses of the more challenging partially saturated xanthones have less frequently been reported, although the development in recent times of novel and reliable methods for the construction of the (polysubstituted) unsaturated xanthone core holds promise for future endeavors. In particular, the fascinating structural and biological properties of xanthone dimers and heterodimers may excite the synthetic or natural product chemist.

Double trouble — the art of synthesis of chiral dimeric natural products

Double or nothing! Recently the total ynthesis of secalonic acids A and D was reported. This work and other natural product syntheses with a dimerization step as a common feature are featured in this highlight. The significant biological activity of the secalonic acids and the fact that their synthesis has fascinated synthetic chemists for the past forty years make this work a milestone in natural product synthesis.

Design, synthesis and spectroscopic characterisation of a focused library based on the polyandrocarpamine natural product scaffold

A focused library based on the marine natural products polyandrocarpamines A (1) and B (2) has been designed and synthesised using parallel solution-phase chemistry. In silico physicochemical property calculations were performed on synthetic candidates in order to optimise the library for drug discovery and chemical biology. A library of ten 2-aminoimidazolone products (3–12) was prepared by coupling glycocyamidine and a variety of aldehydes using a one-step stereoselective aldol condensation reaction under microwave conditions. All analogues were characterised by NMR, UV, IR and MS. The library was evaluated for cytotoxicity towards the prostate cancer cell lines, LNCaP, PC-3 and 22Rv1.

Design and synthesis of a screening library using the natural product scaffold 3-chloro-4-hydroxyphenylacetic acid

The fungal metabolite 3-chloro-4-hydroxyphenylacetic acid (1) was utilized in the generation of a unique drug-like screening library using parallel solution-phase synthesis. A 20-membered amide library (3–22) was generated by first converting 1 to methyl (3-chloro-4-hydroxyphenyl)acetate (2), then reacting this scaffold with a diverse series of primary amines via a solvent-free aminolysis procedure. The structures of the synthetic analogues (3–22) were elucidated by spectroscopic data analysis. The structures of compounds 8, 12, and 22 were confirmed by single X-ray crystallographic analysis. All compounds were evaluated for cytotoxicity against a human prostate cancer cell line (LNCaP) and for antiparasitic activity toward Trypanosoma brucei brucei and Plasmodium falciparum and showed no significant activity at 10 μM. The library was also tested for effects on the lipid content of LNCaP and PC-3 prostate cancer cells, and it was demonstrated that the fluorobenzyl analogues (12–14) significantly reduced cellular phospholipid and neutral lipid levels.

Tethering for Selective Synthesis of 2,2′-Biphenols : the Acetal Method

2,2'-Biphenols are a large and diverse group of compounds with exceptional properties both as ligands and bioactive agents. Traditional methods for their synthesis by oxidative dimerisation are often problematic and lead to mixtures of ortho- and para-connected regioisomers. To compound these issues, an intermolecular dimerisation strategy is often inappropriate for the synthesis of heterodimers. The ‘acetal method’ provides a solution for these problems: stepwise tethering of two monomeric phenols enables heterodimer synthesis, enforces ortho regioselectivity and allows relatively facile and selective intramolecular reactions to take place. The resulting dibenzo[1,3]dioxepines have been analysed by quantum chemical calculations to obtain information about the activation barrier for ring flip between the enantiomers. Hydrolytic removal of the dioxepine acetal unit revealed the 2,2′-biphenol target.

An efficient synthesis of (±)-frondosin B using a Stille–Heck reaction sequence

A concise, convergent synthesis of (±)-frondosin B has been developed based on the application of a Stille–Heck reaction sequence of 2-chloro-5-methoxybenzo[b]furan-3-yl triflate and 2-(3-butenyl)-3-(trimethylstannyl)cyclohex-2-enone giving the racemic natural product in a 34% overall yield.

The conversion of lignocellulosics to levulinic acid

Biomass represents an abundant and relatively low cost carbon resource that can be utilized to produce platform chemicals such as levulinic acid. Current processing technology limits the cost-effective production of levulinic acid in commercial quantities from biomass. The key to improving the yield and effi ciency of levulinic acid production from biomass lies in the ability to optimize and isolate the intermediate products at each step of the reaction pathway and reduce re-polymerization and side reactions. New technologies (including the use of microwave irradiation and ionic liquids) and the development of highly selective catalysts would provide the necessary step change for the optimization of key reactions. A processing environment that allows the use of biphasic systems and/or continuous extraction of products would increase reaction rates, yields and product quality. This review outlines the chemistry of levulinic acid synthesis and discusses current and potential technologies for producing levulinic acid from lignocellulosics.

The acetal concept : regioselective access toortho,ortho-diphenols via dibenzo-1,3-dioxepines

Traditional methods are ill-suited for the synthesis of ortho,ortho-biphenols, a structural motif found in many polyphenolic natural products, as well as synthetically useful compounds such as the chiral ligands binol, vapol, and vanol. The new route consists of a radical-based reaction of an acetal-tethered biphenyl ether substrate and subsequent hydrolytic cleavage of the dibenzo-1,3-dioxepine intermediate.

The ascidian natural product eusynstyelamide B is a novel topoisomerase II poison that induces DNA damage and growth arrest in prostate and breast cancer cells

As part of an anti-cancer natural product drug discovery program, we recently identified eusynstyelamide B (EB), which displayed cytotoxicity against MDA-MB-231 breast cancer cells (IC50 = 5 μM) and induced apoptosis. Here, we investigated the mechanism of action of EB in cancer cell lines of the prostate (LNCaP) and breast (MDA-MB-231). EB inhibited cell growth (IC50 = 5 μM) and induced a G2 cell cycle arrest, as shown by a significant increase in the G2/M cell population in the absence of elevated levels of the mitotic marker phospho-histone H3. In contrast to MDA-MB-231 cells, EB did not induce cell death in LNCaP cells when treated for up to 10 days. Transcript profiling and Ingenuity Pathway Analysis suggested that EB activated DNA damage pathways in LNCaP cells. Consistent with this, CHK2 phosphorylation was increased, p21CIP1/WAF1 was up-regulated and CDC2 expression strongly reduced by EB. Importantly, EB caused DNA double-strand breaks, yet did not directly interact with DNA. Analysis of topoisomerase II-mediated decatenation discovered that EB is a novel topoisomerase II poison.

The undesirable acetylation of cellulose by the acetate ion of 1-ethyl-3-methylimidazolium acetate

The ionic liquid (IL) 1-ethyl-3-methylimidazolium acetate ([C2mim]OAc) is considered to be an inert solvent of cellulose and lignocellulosic biomass. Acetylation (1.7 % mol, or DS 0.017) of cellulose after dissolution in [C2mim]OAc (150 °C for 20 min), is demonstrated by compositional analysis, FTIR analysis and 13C NMR spectroscopy (in [C2min]OAc with 13C enriched acetate). This acetylation, in the absence of added acylating agents, has not been reported before and may limit [C2mim]OAc utility in industrial scale biomass processing, even at this low extent. For example, cellulose acetylation may contribute to IL loss in processes where the IL is recovered and reused and inhibit enzyme saccharification of cellulose in lignocellulosic biofuel production processes based on saccharification and fermentation.

A novel cyclization product from the polyphosphoric acid catalyzed addition of propanal to limonene

The polyphosphoric acid catalyzed addition of propanal to limonene yielded a novel bicyclic ether 2,2,6-trimethyl-4-ethyl-3-oxabicyclo[3.3.1]non-6-ene (I). The yield of (I) was significantly increased by carrying out the reaction under nitrogen rather than in air.

The Chemistry of Mycotoxins

Mycotoxins – from the Greek μύκης (mykes, mukos) “fungus” and the Latin (toxicum) “poison” – are a large and growing family of secondary metabolites and hence natural products produced by fungi, in particular by molds (1). It is estimated that well over 1,000 mycotoxins have been isolated and characterized so far, but this number will increase over the next few decades due the availability of more specialized analytical tools and the increasing number of fungi being isolated. However, the most important classes of fungi responsible for these compounds are Alternaria, Aspergillus (multiple forms), Penicillium, and Stachybotrys. The biological activity of mycotoxins ranges from weak and/or sometimes positive effects such as antibacterial activity (e.g. penicillin derivatives derived from Penicillium strains) to strong mutagenic (e.g. aflatoxins, patulin), carcinogenic (e.g. aflatoxins), teratogenic, neurotoxic (e.g. ochratoxins), nephrotoxic (e.g. fumonisins, citrinin), hepatotoxic, and immunotoxic (e.g. ochratoxins, diketopiperazines) activities (1, 2), which are discussed in detail in this volume.

Pteridine-, thymidine-, choline- and imidazole-derived alkaloids from the Australian ascidian, Leptoclinides durus

Four new acylated pteridine alkaloids, duramidines A-D, two new acylated thymidine alkaloids, leptoclinidines A and B, two new 1-acylglyceryl-3-(O- carboxyhydroxymethylcholine) alkaloids, durabetaines A and B, three new 1,3-dimethyl-5-methylsulfanylimidazole alkaloids, leptoclinidamines D-F, and the known alkaloids leptoclinidamines B and C and 6-bromo-1H-indolo-3-yl-oxoacetic acid methyl ester were isolated from the Australian ascidian Leptoclinides durus. The duramidines are the first pteridine alkaloids, possessing a three carbon side chain esterified at C-1′ with a 4-hydroxy-2′- methoxycinnamic acid, and are either hydroxylated or sulfated at C-2′. The leptoclinidines are the first 3′-indole-3-carboxylic acid ester derivatives of thymidine to be reported in the literature. The durabetaines are the first glyceryl-3-(O-carboxyhydroxymethylcholine) alkaloids to be reported from an animal source and are also the only known derivatives from this class to be acylated with aromatic carboxylic acids. MS and NMR data analysis established the structures of the new compounds. All compounds were shown to be inactive when tested for cytotoxic activity against prostate (LNCaP) and breast (MDA-MB-231) cancer cell lines and antimicrobial activity against Pseudomonas aeruginosa and Staphylococcus aureus.

Kingamide A, a new indole alkaloid from the ascidian Leptoclinides kingi

Chemical investigation of the CH2Cl2/MeOH extract from the Australian ascidian Leptoclinides kingi led to the isolation of a new brominated indole alkaloid, kingamide A (1). The planar structure of kingamide A was elucidated following the interpretation of 1D/2D NMR and MS data, and the absolute configuration was determined using Marfey's method. This is the first report of a natural product from L. kingi.