Margaret A. Brimble

Pyranonaphthoquinone antibiotics—isolation, structure and biological activity

The aim of this review is to survey the chemical and biological literature relating to the isolation, characterisation and biological activity of the pyranonaphthoquinone family of antibiotics. Previous reviews1,2,3 on naphthoquinones have made reference to simple members of this family, however, to date no comprehensive review has been undertaken. In the present report an overview of monomeric, dimeric and carbohydrate derived pyranonaphthoquinones will be presented which includes several new compounds appearing in the literature between 1989 and the present time. The class of compounds known as the pyranonaphthoquinone antibiotics are isolated from various strains of bacteria and fungi, the majority being microbial in origin. The basic skeleton of these antibiotics is the naphtho[2,3-c]pyran-5,10-dione ring system 1. Some members of this group contain an additional glactone ring fused to the dihydropyran moiety 2, while others possess a carboxylic acid side chain 3 resulting from ring opening of the g-lactone.

Molecules derived from the extremes of life

In order to survive extremes of pH, temperature, salinity and pressure, organisms have been found to develop unique defences against their environment, leading to the biosynthesis of novel molecules ranging from simple osmolytes and lipids to complex secondary metabolites. This review highlights novel molecules isolated from microorganisms that either tolerate or favour extreme growth conditions.

Isolation, biological activity and synthesis of benzannulated spiroketal natural products.

Covering: up to late 2009 A review of the isolation, biological activity and synthesis of natural products containing a benzannulated spiroketal moiety is provided.

Effect of fungal metabolite peramine and analogs on feeding and development of argentine stem weevil (Listronotus bonariensis)

Peramine, a pyrrolopyrazine alkaloid produced by the fungal endophyte of perennial ryegrassAcremonium lolii, deterred the feeding of both adults and larvae of the graminacious herbivore, the Argentine stem weevil (Listronotus bonariensis), at 0.1 μg/g and 10 μg/g, respectively. In a no-choice test fewer stem weevil larvae fed and developed on diet containing as little as 2 μg/g peramine. The proportion of larvae which did not develop beyond the first instar was higher on diet containing peramine and appeared to be due to a higher proportion of larvae which did not feed. For larvae which fed on the peramine-containing diet, feeding scores and times to pupation were not significantly different from those of controls. A number of simple peramine analogues showed feeding-deterrent activity against adult weevils, indicating the importance of the pyrrolopyrazine ring system of peramine in determining feeding-deterrent activity.

A one-pot approach to neoglycopeptides using orthogonal native chemical ligation and click chemistry.

The powerful combination of native chemical ligation and click chemistry has been used to affect a one-pot synthesis of neoglycopeptides from propargyl-containing peptides using GalNAc-N(3) as the glycan component. A versatile chemical toolkit for the fully convergent synthesis of neoglycoproteins using click chemistry, native chemical ligation, and kinetically controlled ligation is thus demonstrated.

An Efficient Formal Synthesis of the Human Telomerase Inhibitor (±)-γ-Rubromycin†

(1, Scheme 1), the prototypical member of astructurally related family of antibiotics known as therubromycins, consists of a densely oxygenated naphthazarinring and an isocoumarin moiety linked through a uniquearomatic 5,6-spiroketal ring system (Scheme 1). The rubro-mycins exhibit a wide range of biological activity includingantimicrobialandanticancerproperties.

Spiroimine shellfish poisoning (SSP) and the spirolide family of shellfish toxins: Isolation, structure, biological activity and synthesis

Covering: 1995 up to May 2010 Spirolides are metabolites of the dinoflagellates Alexandrium ostenfeldii and Alexandrium peruvianum. Spirolides (A–D) were isolated from the digestive glands of contaminated mussels (Mytilus edulis), scallops (Placopecten magellanicus) and toxic plankton from the east coast of Nova Scotia in Canada. Fourteen members of the spirolide family of marine biotoxins have since been identified from around the world. The relative stereochemistry of these compounds was established via molecular modelling and NMR studies. Related marine toxins containing a spiroimine unit have been classified as fast-acting toxins and the spirolides also target muscarinic and nicotinic acetylcholine receptors and are weak activators of L-type transmembrane Ca2+ channels. The spirolides are macrocycles that are comprised of two parts: a bis-spiroacetal moiety and an unusual 6,7-bicyclic spiroimine.

Structural Basis for Receptor Activity-Modifying Protein-Dependent Selective Peptide Recognition by a G Protein-Coupled Receptor.

Summary Association of receptor activity-modifying proteins (RAMP1-3) with the G protein-coupled receptor (GPCR) calcitonin receptor-like receptor (CLR) enables selective recognition of the peptides calcitonin gene-related peptide (CGRP) and adrenomedullin (AM) that have diverse functions in the cardiovascular and lymphatic systems. How peptides selectively bind GPCR:RAMP complexes is unknown. We report crystal structures of CGRP analog-bound CLR:RAMP1 and AM-bound CLR:RAMP2 extracellular domain heterodimers at 2.5 and 1.8 Å resolutions, respectively. The peptides similarly occupy a shared binding site on CLR with conformations characterized by a β-turn structure near their C termini rather than the α-helical structure common to peptides that bind related GPCRs. The RAMPs augment the binding site with distinct contacts to the variable C-terminal peptide residues and elicit subtly different CLR conformations. The structures and accompanying pharmacology data reveal how a class of accessory membrane proteins modulate ligand binding of a GPCR and may inform drug development targeting CLR:RAMP complexes.

Synthesis and antifreeze activity of fish antifreeze glycoproteins and their analogues

Fishes from both Arctic and Antarctic waters produce antifreeze glycoproteins (AFGPs) that modify and inhibit the growth of ice crystals, allowing them to survive in extreme cold conditions. These glycoproteins exhibit thermal hysteresis activity, i.e. they work in a non-colligative manner, separating the melting and freezing points of a solution. Such compounds have many potential applications; unfortunately their development is hampered by the difficulty of obtaining pure material. The synthesis of AFGPs is therefore a challenge that numerous groups have been tackling. The AFGPs consist predominantly of a repetitive three amino acid unit (Ala-Ala-Thr)n with the disaccharide β-D-galactosyl-(1–3)-α-D-N-acetylgalactosamine attached to the hydroxyl oxygen of each threonine residue. A large number of analogues have also been synthesized in order to find compounds that exhibit the same activity but that are easier to prepare. Starting from the early years of the AFGP discovery and including the more recent research, this perspective summarizes the different routes used to synthesize native AFGPs and lists the most relevant analogues synthesized, along with some information on their synthesis and their antifreeze activity, if evaluated. In this perspective we have taken special care to differentiate compounds that induce thermal hysteresis, compounds that modify the normal growth habit of ice crystals, and compounds that exhibit recrystallization inhibition properties.

A review of neuroprotective agents.

The brain remains an area where little corrective surgery can be performed and the reversal of damage is almost impossible. Recently, reports of agents offering neuroprotection have begun to appear in the literature. The concept of neuroprotection is the administration of some agent, which should reverse some of the damage or prevent further damage. Some agents offer protection against cell degeneration to the neuronal cells. Still other agents specifically protect the dopamine neurons and the retina. The majority of neuroprotective agents are antioxidants. An immunosuppressive calcineurin inhibitor, NOS inhibitor, sigma-1 modulator, AMPA antagonist and Ca2+ channel blocker have all shown neuroprotective activity. An estrogen agonist and two glycoprotein IIb/IIIa antagonists also exhibit neuroprotective activity. Most of the synthetic compounds presented were not originally designed as neuroprotective agents but were found to possess neuroprotective activity in later studies. Many of these compounds are biologically active natural products, either plant extracts or endogenous peptides/proteins. This review will present the most recent reports on these agents.