Organonitrogen Chemistry introduces a wealth of fascinating organic chemistry involving nitrogen. There are three main sections to the book, each being introduced by a summary of the underlying chemical principles. The main organonitrogen functional groups are covered systematically, each chapter concluding with a brief summary of the chemistry. Topics include amines, ammonium compounds, nitrogen bases, and synthesis of amines. The second part of the book covers amines, ammonium compounds, nitrogen bases, and synthesis of amines. Finally, the text looks at compounds with N-N bounds, oximes, N -oxides, nitroso compounds and, nitro compounds.

This chapter looks into the synthesis and reactions of N-oxides. The N-heteroatom bond of N-oxides is not introduced intact in the synthesis of compounds. However, it is delivered in an oxidation reaction. It notes peracid as the usual oxidant which is either used directly or generated in place from a carboxylic acid or hydrogen peroxide mixture. It also highlights how N-oxides are vital for aeffecting syn eliminations as the N-oxide acts similarly to a quaternary ammonium compound with an internal alkoxide base. Finally, the chapter uses diagrams to emphasise how the synthesis and reactions occurs.

This chapter discusses ammonium compounds. It looks into the general formula of ammonium compounds wherein it could be linked to alkyl, aryl, or hydrogen. The chapter notes the two distinct classes of compounds: hydrogen R groups and ammonium cations formed by the protonation of an amine. It lists the properties of quaternary ammonium ions as chirality, solubility in solvents and phase transfer catalysis. Elimination and reduction are regarded as the only important reactions in line with quaternary ammonium ions. Additionally, the chapter highlights quarternary ammonium ions being used as phase transfer catalysts to help transport counter-anions into an organic phase.

This chapter looks into urethanes, ureas, imides, and diimides, which encompasses the most important remaining nitrogen-containing functional groups aside from those which have N-N or N-O bonds. It highlights the importance of urethanes as readily removable N-protective groups. Additionally, the chapter discusses the synthesis and reaction of urethanes, ureas, imides, and diimides. Urethanes are significant for protecting amines, while imides are useful for preparing primary amines. Diimides are one of the best types of reagent for the coupling of carboxylic acids to amines. Finally, the chapter lists other unsaturated nitrogen-containing groups such as amidines, imidines, guanidines, and imidate esters.

This chapter focuses on amines. Saturated amines are regarded as the simplest organonitrogen compound. The chapter highlights the importance of amines as they occur widely in nature and are used often as building blocks for more complex compounds and co-reagents in numerous organic reactions. The chapter notes nitrogen acting as nucleophile or base to facilitate the reactions on the nitrogen lone pair. Additionally, the chapter discusses the interplay between nucleophilicity and basicity alongside the reactions of amines. It concludes amines as bases that are readily protonated. Next, amines are also powerful nucleophiles following their reactivity with alkyl halides, carboxylic acid derivatives, aldehydes, ketones, and nitrous acid.

This chapter looks into nitrogen bases. Nitrogen compounds are widely used as bases in organic synthesis. The chapter also looks into the types of nitrogen bases such as tertiary amines and metal amides. It also discusses the reactions employing nitrogen bases by referencing the absence of base, concerted removal of a proton, and giving an anionic intermediate. Diazabicyclo amines can help a proton leave as part of a concerted reaction. Additionally, the chapter notes deprotonation is usually conducted at low temperatures. It explains the good bases for mopping up protons while the most popular base for deprotonation is lithium diisopropylamide (LDA).

This chapter focuses on nitroso compounds. It refers to nitroso compounds as tautomeric with oximes that are thermodynamically more stable. The chapter shares diagrams to reference the bonding. C-nitroso compounds are readily turned to the corresponding oxime if there is a hydrogen-? linked to the nitroso group. Additionally, the chapter discusses the synthesis of aliphatic C-nitroso compounds, aromatic C-nitroso compounds, α-diketones via nitrosis compounds, N-nitroso compounds, and O-nitroso compounds. It mentions how aliphatic C-nitroso compounds tautomerizse to the oxime if an α-hydrogen is present. The α-chloro and acyl Cnitroso compounds are useful in terms of achieving the Diels-Alder reaction.

The broad substrate capacity of the intestinal oligopeptide transporter, PepT1, has made it a key target of research into drug delivery. Whilst the substrate capacity of this transporter is broad, studies have largely been limited to small peptides and peptide-like drugs. Here, we demonstrate for the first time that a diverse range of drugs can be targeted towards transport by PepT1 using a hydrolysis resistant carrier. Eleven prodrugs were synthesized by conjugating modified dipeptides containing a thioamide bond to the approved drugs ibuprofen, gabapentin, propofol, aspirin, acyclovir, nabumetone, atenolol, zanamivir, baclofen and mycophenolate. Except for the aspirin and acyclovir prodrugs, which were unstable in the assay conditions and were not further studied, the prodrugs were tested for affinity and transport by PepT1 expressed in Xenopus laevis oocytes: binding affinities ranged from approximately 0.1 to 2 mM. Compounds which showed robust transport in an oocyte trans-stimulation assay were then tested for transcellular transport in Caco-2 cell monolayers: all five tested prodrugs showed significant PepT1-mediated transcellular uptake. Finally, the ibuprofen and propofol prodrugs were tested for absorption in rats: following oral dosing the intact prodrugs and free ibuprofen were measured in the plasma. This provides proof-of-concept for the idea of targeting poorly bioavailable drugs towards PepT1 transport as a general means of improving oral permeability.

A modular approach to the synthesis of sensors is described. In this approach a central dye scaffold, prepared from the SNAr reaction between a halo-substituted azo-dye and a disubstituted phenol, was decorated with a representative carbohydrate or macrocycle using Sharpless click chemistry. Regiochemical issues in the click reaction are also addressed.

The mammalian proton-coupled oligopeptide transporter PepT1 is recognised as an important route of oral drug delivery. Peptide-based compounds offer great potential as drugs but their application is limited by poor membrane permeability, amongst other challenges. Using cyclosporin A as a proof-of-concept, we demonstrate for the first time that peptidic molecules over 1000 Da in size can be targeted towards and transported by PepT1.

The development of a modular approach to macrocycle assembly has enabled the synthesis of a library of pyridine-based macrocycles possessing multiple donor sites where chirality was readily introduced from (R)- or (S)- alanine, a representative amino acid. The facile, regioselective, nucleophilic ring opening of aziridines by dithiols enabled the synthesis of thioether-based linkers which on subsequent alkylation provided access to optically pure macrocycles.

Careful choice of the N-protecting group provides crucial conformational control, allowing ring-closure to the indole 3-position in the late stages of the synthesis of ajmaline alkaloids; the choice of protecting group and reducing agent can also provide access to either the natural or epi configuration at the indole 2-position. (C) 2013 Elsevier Ltd. All rights reserved.

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In addition to being responsible for the majority of absorption of dietary nitrogen, the mammalian proton-coupled di- and tri-peptide transporter PepT1 is also recognised as a major route of drug delivery for several important classes of compound, including beta-lactam antibiotics and angiotensin-converting enzyme inhibitors. Thus there is considerable interest in the PepT1 protein and especially its substrate binding site. In the absence of a crystal structure, computer modelling has been used to try to understand the relationship between PepT1 3D structure and function. Two basic approaches have been taken: modelling the transporter protein, and modelling the substrate. For the former, computer modelling has evolved from early interpretations of the twelve transmembrane domain structure to more recent homology modelling based on recently crystallised bacterial members of the major facilitator superfamily (MFS). Substrate modelling has involved the proposal of a substrate binding template, to which all substrates must conform and from which the affinity of a substrate can be estimated relatively accurately, and identification of points of potential interaction of the substrate with the protein by developing a pharmacophore model of the substrates. Most recently, these two approaches have moved closer together, with the attempted docking of a substrate library onto a homology model of the human PepT1 protein. This article will review these two approaches in which computers have been applied to peptide transport and suggest how such computer modelling could affect drug design and delivery through PepT1.

Thiodipeptide prodrugs of the ketone nabumetone are shown to have affinity for, and be transported by, PepT1 in vitro.

A thiodipeptide carrier system is shown to be effective at enabling a range of covalently bound molecules, including benzyl, benzoyl and ibuprofen conjugates, to be transported via the intestinal peptide transporter PepT1, demonstrating its potential as a rational drug delivery target.

Whilst cis:trans selectivity of about 4:1 can be obtained from Pictet–Spengler reactions between tryptophan methyl esters and aldehydes using conditions of kinetic control, much higher cis selectivity (>95:5) can be obtained when both the tryptophan derivative and the aldehyde possess a suitable π-system; preliminary results on the scope and limitations of this exceptional stereocontrol are presented in this Letter.

The mammalian proton-coupled peptide transporter PepT1 is widely accepted as the major route of uptake for dietary nitrogen, as well as being responsible for the oral absorption of a number of classes of drugs, including beta-lactam antibiotics and angiotensin-converting enzyme (ACE) inhibitors. Using site-directed mutagenesis and zero-trans transport assays, we investigated the role of conserved tyrosines in the transmembrane domains (TMDs) of rabbit PepT1 as predicted by hydropathy plots. All the individual TMD tyrosines were substituted with phenylalanine and shown to retain the ability to traffic to the plasma membrane of Xenopus laevis oocytes. These single substitutions of TMD tyrosines by phenylalanine residues did not affect the proton dependence of peptide uptake, with all retaining wild-type PepT1-like pH dependence. Individual mutations of four of the nine TMD residue tyrosines (Y64, Y287, Y345 and Y587) were without measurable effect on PepT1 function, whereas the other five (Y12, Y56, Y91, Y167 and Y345) were shown to result in altered transport function compared to the wild-type PepT1. Intriguingly, the affinity of Y56F-PepT1 was found to be dramatically increased (approximately 100-fold) in comparison to that of the wild-type rabbit PepT1. Y91 mutations also affected the substrate affinity of the transporter, which increased in line with the hydrophilicity of the substituted amino acid (F>Y>Q>R). Y167 was demonstrated to play a pivotal role in rabbit PepT1 function since Y167F, Y167R and Y167Q demonstrated very little transport function. These results are discussed with regard to a proposed mechanism for PepT1 substrate binding.