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.

Label-free SERS for natural product provenance

Introduction Natural product provenance is important in the food, beverage and pharmaceutical industries, for consumer confidence and with health implications. Raman spectroscopy has powerful molecular fingerprint abilities. Surface Enhanced Raman Spectroscopy’s (SERS) sharp peaks allow distinction between minimally different molecules, so it should be suitable for this purpose. Methods Naturally caffeinated beverages with Guarana extract, coffee and Red Bull energy drink as a synthetic caffeinated beverage for comparison (20 µL ea.) were reacted 1:1 with Gold nanoparticles functionalised with anti-caffeine antibody (ab15221) (10 minutes), air dried and analysed in a micro-Raman instrument. The spectral data was processed using Principle Component Analysis (PCA). Results The PCA showed Guarana sourced caffeine varied significantly from synthetic caffeine (Red Bull) on component 1 (containing 76.4% of the variance in the data). See figure 1. The coffee containing beverages, and in particular Robert Timms (instant coffee) were very similar on component 1, but the barista espresso showed minor variance on component 1. Both coffee sourced caffeine samples varied with red Bull on component 2, (20% of variance). ************************************************************ Figure 1 PCA comparing a naturally caffeinated beverage containing Guarana with coffee. ************************************************************ Discussion PCA is an unsupervised multivariate statistical method that determines patterns within data. Figure 1 shows Caffeine in Guarana is notably different to synthetic caffeine. Other researchers have revealed that caffeine in Guarana plants is complexed with tannins. Naturally sourced/ lightly processed caffeine (Monster Energy, Espresso) are more inherently different than synthetic (Red Bull) /highly processed (Robert Timms) caffeine, in figure 1, which is consistent with this finding and demonstrates this technique’s applicability. Guarana provenance is important because it is still largely hand produced and its demand is escalating with recognition of its benefits. This could be a powerful technique for Guarana provenance, and may extend to other industries where provenance / authentication are required, e.g. the wine or natural pharmaceuticals industries.

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.

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.

Synthetic studies towards the phloroglucin natural product hyperforin: construction of the fully prenylated bicyclic core

An approach towards the highly functionalized bicyclo[3.3.1]nonan-9-one core of the complex PPAP-based natural product hyperforin, with the full complement of prenyl substituents in required stereo-disposition, is delineated.

A concise synthesis of the bioactive meroterpenoid natural product (+/-)-liphagal, a potent PI3K inhibitor

A short, diversity-oriented synthesis that follows a biomimetic route to the marine natural product liphagal, from a commercially available building block, is delineated.

A total synthesis of the epoxyquinone based antifungal natural product (±)-ambuic acid

A total synthesis of the recently isolated polyketide natural product (+/-)-ambuic acid has been accomplished from the readily available Diels-Alder adduct of cyclopentadiene and 2-allyl-p-benzoquinone through a simple sequence with sound stereocontrol. (c) 2005 Elsevier Ltd. All rights reserved.

Assessment of In-House Natural Product and Synthetic Compound Libraries Based on In vitro Inhibition of Cholinesterases

The first line medication for mild to moderate Alzheimer s disease (AD) is based on cholinesterase inhibitors which prolong the effect of the neurotransmitter acetylcholine in cholinergic nerve synapses which relieves the symptoms of the disease. Implications of cholinesterases involvement in disease modifying processes has increased interest in this research area. The drug discovery and development process is a long and expensive process that takes on average 13.5 years and costs approximately 0.9 billion US dollars. Drug attritions in the clinical phases are common due to several reasons, e.g., poor bioavailability of compounds leading to low efficacy or toxic effects. Thus, improvements in the early drug discovery process are needed to create highly potent non-toxic compounds with predicted drug-like properties. Nature has been a good source for the discovery of new medicines accounting for around half of the new drugs approved to market during the last three decades. These compounds are direct isolates from the nature, their synthetic derivatives or natural mimics. Synthetic chemistry is an alternative way to produce compounds for drug discovery purposes. Both sources have pros and cons. The screening of new bioactive compounds in vitro is based on assaying compound libraries against targets. Assay set-up has to be adapted and validated for each screen to produce high quality data. Depending on the size of the library, miniaturization and automation are often requirements to reduce solvent and compound amounts and fasten the process. In this contribution, natural extract, natural pure compound and synthetic compound libraries were assessed as sources for new bioactive compounds. The libraries were screened primarily for acetylcholinesterase inhibitory effect and secondarily for butyrylcholinesterase inhibitory effect. To be able to screen the libraries, two assays were evaluated as screening tools and adapted to be compatible with special features of each library. The assays were validated to create high quality data. Cholinesterase inhibitors with various potencies and selectivity were found in natural product and synthetic compound libraries which indicates that the two sources complement each other. It is acknowledged that natural compounds differ structurally from compounds in synthetic compound libraries which further support the view of complementation especially if a high diversity of structures is the criterion for selection of compounds in a library.

An Eventful Synthetic Approach Towards the Biologically Potent Natural Product Ottelione A: Enantio-, Regio- and Stereoselective Construction of the Bicyclic Core

A novel synthetic approach towards the recently reported anti-tumor and anti-tuberculor natural product ottelione A from the readily available Diels-Alder adduct of cyclopentadiene and p-benzoquinone is delineated. Our short strategy, besides being enantio-, regio- and stereoselective, charts an eventful course and is inherently well-suited for adaptation towards diverse synthetic analogues of this biologically potent natural product.

Enantioselective Synthesis of Possible Diastereomers of Heptadeca-1-ene-4,6-diyne-3,8,9,10-tetrol; Putative Structure of a Conjugated Diyne Natural Product Isolated from Hydrocotyle leucocephala

Enantioselective synthesis of possible diastereomers of heptadeca-1-ene-4,6-diyne-3,8,9,10-tetrol, a structure proposed for the natural product isolated from Hydrocotyle leucocephala is accomplished. The reported spectral data of the natural product did not match those of any of the isomers that were synthesized and established that the structure proposed for the natural product is not correct and requires revision.

The chemistry of a non-natural product: Troger's base

Troger's base was the first amine to be resolved where the chirality was solely due to very high inversion barrier around nitrogen atom(s). Though the molecule was known over a century, work done during the past one decade has shown that Troger's base and its analogues could be used as chiral solvating agents, DNA-binding ligands and for the construction of biomimetic molecular receptors and clathrate hosts, Asymmetric synthesis of Troger's base analogues has also been achieved recently, Because of the rigid, 'V'-shaped chiral nature of this molecule, there is a growing interest for use of this unit in the design of potential host systems, This review article focuses on the chemistry of Troger's base along with the possible future utilities.

Synthetic studies directed towards the potent cytotoxic natural product ottelione A: stereoselective construction of the complete framework

A stereoselective strategy for the rapid acquisition of the complete framework (dideoxyottelione A) of the promising cytotoxic agent ottelione A, with four contiguous stereogenic centres on a hydrindane skeleton and a sensitive 4-methylenecyclohex-2-enone functionality, from the readily available Diels-Alder adduct of 1,2,3,4-tetrachloro-5,5-dimethoxycyclopentadiene and norbornadiene, is delineated.

Hybrid systems through natural product leads: An approach towards new molecular entities

Hybrid systems are constructs of different molecular entities, natural or unnatural, to generate functional molecules in which the characteristics of various components are modulated, amplified or give rise to entirely new properties. These hybrids can be designed from carefully selected components either through domain intergration of key structural/functional features or via straightforward covalent linkages. Some of the recently reported hybrid systems based on steroid, carbohydrate, C-60-fullerene platforms, amongst others, mainly crafted with the object of enhancement of the therapeutical spectrum, will be discussed.