A review of the synthesis of α-carbolines.

Since the first reported synthesis of an α-carboline almost a century ago, there has been a steady interest in the development of strategies towards this unique heterocyclic motif. This interest can mainly be attributed to a range of biological activity displayed by the α-carboline natural products including cytotoxicity, anticancer properties or CNS activity. Numerous studies have led to the development of a number of alternative methods to prepare simple α-carbolines as well as a range of synthetic α-carboline derived compounds.

Chemical synthesis of a pore-forming antimicrobial protein, caenopore-5, by using native chemical ligation at a glu-cys site.

The 2014 report from the World Health Organization (WHO) on antimicrobial resistance revealed an alarming rise in antibiotic resistance all around the world. Unlike classical antibiotics, with the exception of a few species, no acquired resistance towards antimicrobial peptides (AMPs) has been reported. Therefore, AMPs represent leads for the development of novel antibiotics.

Total synthesis of the macrocyclic N-Methyl enamides palmyrolide A and 2S-sanctolide A.

Full details of the total syntheses of the initially reported and revised structures of the neuroprotective agent palmyrolide A are reported. The key macrocyclization step was achieved using a sequential ring-closing metathesis/olefin isomerization reaction. Furthermore, the total synthesis of the related macrolide (2S)-sanctolide A is reported.

Synthesis and evaluation of 9-deoxy analogues of (-)-thysanone, an inhibitor of HRV 3C protease.

9-Deoxy analogues of the HRV 3C protease inhibitor (-)-thysanone display better inhibitory properties than the natural product, inferring the C9-OH hinders binding to the enzyme.

Protecting-group-free one-pot synthesis of glycoconjugates directly from reducing sugars.

The conversion of sugars into glycomimetics typically involves multiple protecting-group manipulations. The development of methodology allowing the direct aqueous conversion of free sugars into glycosides, and mimics of oligosaccharides and glycoconjugates in a high-yielding and stereoselective process is highly desirable. The combined use of 2-azido-1,3-dimethylimidazolinium hexafluorophosphate and the Cu-catalyzed Huisgen cycloaddition allowed the synthesis of a range of glycoconjugates in a one-step reaction directly from reducing sugars under aqueous conditions.

Recent developments in transition metal-catalysed spiroketalisation.

The spiroketal motif occurs in a wide range of biologically active natural products and represents a valuable target in medicinal chemistry and total synthesis. In recent years, innovative new synthetic methods have substantially expanded the range of potential precursors, cyclisation modes and opportunities for asymmetric catalysis and tandem processes. This Perspective aims to highlight recent rapid advances in the use of transition metal catalysis for spiroketal formation, in the context of our own investigations into gold-catalysed asymmetric spiroketalisation.

Convergent chemoenzymatic synthesis of a library of glycosylated analogues of pramlintide: structure-activity relationships for amylin receptor agonism.

Pramlintide (Symlin®), a synthetic analogue of the naturally occurring pancreatic hormone amylin, is currently used with insulin in adjunctive therapy for type 1 and type 2 diabetes mellitus. Herein we report a systematic study into the effect that N-glycosylation of pramlintide has on activation of amylin receptors. A highly efficient convergent synthetic route, involving a combination of solid phase peptide synthesis and enzymatic glycosylation, delivered a library of N-glycosylated variants of pramlintide bearing either GlcNAc, the core N-glycan pentasaccharide [Man3(GlcNAc)2] or a complex biantennary glycan [(NeuAcGalGlcNAcMan)2Man(GlcNAc)2] at each of its six asparagine residues.

Toward an asymmetric synthesis of the dimeric pyranonaphthoquinone antibiotic crisamicin A.

A full account of our efforts toward an asymmetric synthesis of crisamicin A are presented. The key steps include a Hauser-Kraus annulation of a cyanophthalide with a chiral enone-lactone, a stereoselective cyclization-reduction to install the pyran unit, and a Suzuki homocoupling to forge the key biaryl bond. This work has culminated in the asymmetric synthesis of a dimer bearing the complete carbon skeleton of the dimeric pyranonaphthoquinone natural product crisamicin A.

Synthesis of truncated analogues of preptin-(1–16), and investigation of their ability to stimulate osteoblast proliferation.

Preptin, a 34-amino acid residue peptide hormone is co-secreted with insulin from the β-pancreatic cells and is active in fuel metabolism. We have previously established that a shorter fragment of preptin, namely preptin-(1–16), stimulates bone growth by proliferation and increasing the survival rate of osteoblasts. This was demonstrated in both in vitro and in vivo models.

Structure and activity of Streptococcus pyogenes SipA: a signal peptidase-like protein essential for pilus polymerisation.

The pili expressed on the surface of the human pathogen Streptococcus pyogenes play an important role in host cell attachment, colonisation and pathogenesis. These pili are built from two or three components, an adhesin subunit at the tip, a major pilin that forms a polymeric shaft, and a basal pilin that is attached to the cell wall. Assembly is carried out by specific sortase (cysteine transpeptidase) enzyme.

Total synthesis of virgatolide B via exploitation of intramolecular hydrogen bonding.

A full account of the enantioselective total synthesis of virgatolide B is reported. Key features of the synthesis include an sp(3)-sp(2) Suzuki-Miyaura cross-coupling of a β-trifluoroboratoamide with an aryl bromide, regioselective intramolecular carboalkoxylation, and a 1,3-anti-selective Mukaiyama aldol reaction. Intramolecular hydrogen bonding governed the regioselectivity of the key spiroketalization step, affording the natural product as a single regioisomer.

An investigation of the role of the adiponectin variable domain on the stability of the collagen-like domain.

The chemical synthesis is described of a polypeptide construct possessing both the variable and the collagen-like domain of adiponectin, which can be used as a model system for probing the influence of the variable domain on multimerization of this important circulating hormone. Using a collagen domain repeat peptide unit derived from native adiponectin or a glutamic acid analogue was ineffective due to noncollagenous conformational properties in both cases. However, employing a collagen model peptide and linking this to the variable domain thioester peptide using native chemical ligation proved effective.

Glucose as an agent of post-translational modification in diabetes--New cardiac epigenetic insights.

Diabetes elicits cardiac metabolic stress involving impaired glucose uptake and metabolic substrate shifts. Diabetic cardiac pathology is well documented in human patients and experimental animal models to be characterized by diastolic dysfunction, but the underlying mechanisms are not well understood. Signaling disturbances involved in cardiac insulin resistance are linked to glucose handling abnormalities.

Preparation of truncated orf virus entry fusion complex proteins by chemical synthesis.

Members of the Chordopoxvirinae subfamily possess an unusual 11 protein entry-fusion complex (EFC) that is highly conserved and present in all species. The mode of action of this EFC is unknown, and the interactions of the constituent proteins are uncharacterised. Here, we present the chemical synthesis of membrane domain truncated linear constructs of two EFC proteins in orf virus, ORFV036 and 049.

Plant antimicrobial peptides snakin-1 and snakin-2: chemical synthesis and insights into the disulfide connectivity.

Antimicrobial peptides and proteins represent an important class of plant defensive compounds against pathogens and provide a rich source of lead compounds in the field of drug discovery. We describe the effective preparation of the cysteine-rich snakin-1 and -2 antimicrobial peptides by using a combination of solid-phase synthesis and native chemical ligation. A subsequent cysteine/cystine mediated oxidative folding to form the six internal disulfide bonds concurrently gave the folded proteins in 40-50 % yield.

Synthesis and methemoglobinemia-inducing properties of benzocaine isosteres designed as humane rodenticides.

A number of isosteres (oxadiazoles, thiadiazoles, tetrazoles and diazines) of benzocaine were prepared and evaluated for their capacity to induce methemoglobinemia-with a view to their possible application as humane pest control agents. It was found that an optimal lipophilicity for the formation of methemoglobin (metHb) in vitro existed within each series, with 1,2,4-oxadiazole 3 (metHb%=61.0±3.

Synthesis and cytotoxicity of pyranonaphthoquinone natural product analogues under bioreductive conditions.

Unlabelled: We have synthesised a focused library of derivatives of natural products containing the pyranonaphthoquinone moiety including the first report of such a scaffold with an appended tetrazole functionality. Examples include kalafungin derivatives as well as analogues of nanaomycin and eleutherin. These compounds were assessed for cytotoxic activation by breast cancer cell lines engineered to express the prototypic human one- and two-electron quinone bioreductive enzymes, NADPH: cytochrome P450 oxidoreductase (POR) and

Nad(p)h: quinoneoxidoreductase 1 (NQO1; DT-diaphorase), respectively.

An important side reaction using the thiol, 3,6-dioxa-1,8-octanedithiol (DODT), in 9-fluorenylmethoxycarbonyl-based solid phase peptide synthesis.

A considerable quantity of an alkylation by-product is observed when using 3,6-dioxa-1,8-octanedithiol as a scavenger during acidic release of peptides containing the thioether amino acid methionine from the solid support. Adjustment of the cleavage conditions by replacement of 3,6-dioxa-1,8-octanedithiol with ethane dithiol or by using methionine sulfoxide as an alternative to methionine resulted in no such impurity. The by-product was detectable by liquid chromatography and mass spectrometry and characterised by NMR spectroscopy of an isolated model peptide.

Total synthesis of heronapyrrole C.

A flexible total synthesis of the 2-nitropyrrole-derived marine natural product, (+)-heronapyrrole C, is reported. The approach is based on regioselective access to key building blocks containing the rare 4-substituted 2-nitropyrrole motif. Sharpless asymmetric epoxidation and dihydroxylation and a Shi epoxidation were used to introduce the five stereogenic centers of the bis-THF-diol side chain.

Synthesis of the 2-methylene analogue of the HRV 3C protease inhibitor thysanone (2-carbathysanone).

The Human Rhinovirus (HRV) is the major aetiological agent for the common cold, for which only symptomatic treatment is available. HRV maturation and replication is entirely dependent on the activity of a virally encoded 3C protease that represents an attractive target for the development of therapeutics to treat the common cold. Herein we report the synthesis and biological evaluation of the 2-methylene analogue of the HRV 3C protease inhibitor (-)-thysanone (1) namely 2-carbathysanone (2), in an attempt to decipher the structural features in the natural product that are responsible for the 3C protease activity.

Synthesis and methemoglobinemia-inducing properties of analogues of para-aminopropiophenone designed as humane rodenticides.

A number of structural analogues of the known toxicant para-aminopropiophenone (PAPP) have been prepared and evaluated for their capacity to induce methemoglobinemia--with a view to their possible application as humane pest control agents. It was found that an optimal lipophilicity for the formation of methemoglobin (metHb) in vitro existed for alkyl analogues of PAPP (aminophenones 1-20; compound 6 metHb% = 74.1 ± 2).

Synthesis of an azido precursor to (2S,5R)-5-hydroxylysine using an asymmetric organocatalytic chlorination/reduction sequence.

An efficient, robust, and scalable synthesis of an azido precursor to the modified amino acid (2S,5R)-5-hydroxylysine was developed on the basis of the use of a highly stereoselective organocatalytic α-chlorination-reduction protocol. The final Fmoc-protected (2S,5R)-6-azido-5-hydroxylysine derivative can be used in solid-phase peptide synthesis, providing access to proteins that contain large quantities of post-translationally modified lysine (e.g.

Structure-activity relationships of the N-terminus of calcitonin gene-related peptide: key roles of alanine-5 and threonine-6 in receptor activation.

Background And Purpose: The N-terminus of calcitonin gene-related peptide (CGRP) is important for receptor activation, especially the disulphide-bonded ring (residues 1-7). However, the roles of individual amino acids within this region have not been examined and so the molecular determinants of agonism are unknown. This study has examined the role of residues 1, 3-6 and 8-9, excluding Cys-2 and Cys-7.

Total synthesis of virgatolide B.

The first total synthesis of the benzannulated spiroketal virgatolide A is presented. Key features include sp(3)-sp(2) Suzuki coupling of an enantiomerically enriched β-trifluoroboratoamide and an aryl bromide, regioselective intramolecular carboalkoxylation, and a 1,3-anti-selective Mukaiyama aldol reaction followed by global deprotection/cyclization with regioselectivity governed by internal hydrogen bonding.