Ian R. Baxendale

The molecular basis for selective inhibition of unconventional mRNA splicing by an IRE1-binding small molecule

IRE1 couples endoplasmic reticulum unfolded protein load to RNA cleavage events that culminate in the sequence-specific splicing of the Xbp1 mRNA and in the regulated degradation of diverse membrane-bound mRNAs. We report on the identification of a small molecule inhibitor that attains its selectivity by forming an unusually stable Schiff base with lysine 907 in the IRE1 endonuclease domain, explained by solvent inaccessibility of the imine bond in the enzyme-inhibitor complex. The inhibitor (abbreviated 4μ8C) blocks substrate access to the active site of IRE1 and selectively inactivates both Xbp1 splicing and IRE1-mediated mRNA degradation. Surprisingly, inhibition of IRE1 endonuclease activity does not sensitize cells to the consequences of acute endoplasmic reticulum stress, but rather interferes with the expansion of secretory capacity. Thus, the chemical reactivity and sterics of a unique residue in the endonuclease active site of IRE1 can be exploited by selective inhibitors to interfere with protein secretion in pathological settings.

An overview of the synthetic routes to the best selling drugs containing 6-membered heterocycles.

Summary This review which is the second in this series summarises the most common synthetic routes as applied to the preparation of many modern pharmaceutical compounds categorised as containing a six-membered heterocyclic ring. The reported examples are based on the top retailing drug molecules combining synthetic information from both scientific journals and the wider patent literature. It is hoped that this compilation, in combination with the previously published review on five-membered rings, will form a comprehensive foundation and reference source for individuals interested in medicinal, synthetic and preparative chemistry.

An overview of the key routes to the best selling 5-membered ring heterocyclic pharmaceuticals

Summary This review presents a comprehensive overview on selected synthetic routes towards commercial drug compounds as published in both journal and patent literature. Owing to the vast number of potential structures, we have concentrated only on those drugs containing five-membered heterocycles and focused principally on the assembly of the heterocyclic core. In order to target the most representative chemical entities the examples discussed have been selected from the top 200 best selling drugs of recent years.

Flow Ozonolysis Using a Semipermeable Teflon AF-2400 Membrane To Effect Gas−Liquid Contact

A flow-through chemistry apparatus has been developed which allows gases and liquids to contact via a semipermeable Teflon AF-2400 membrane. In this preliminary investigation, the concept was proven by application to the ozonolysis of a series of alkenes.

Multistep Synthesis Using Modular Flow Reactors: Bestmann-Ohira Reagent for the Formation of Alkynes and Triazoles**

Multistep in flow: The Seyferth-Gilbert reagent 1 has been applied in a flow system to rapidly synthesize terminal alkynes. The system has been further applied to synthesize triazole 3 from alcohol 2 in a three-step oxidation/homologation/copper(I)-catalyzed azide-alkyne cycloaddition sequence without isolation of intermediates (see scheme).

New tools and concepts for modern organic synthesis

The increasing need to efficiently assemble small molecules as potential modulators of therapeutic targets that are emerging from genomics and proteomics is driving the development of novel technologies for small-molecule synthesis. Here, we describe some of the general applications and approaches to synthesis using one such technology — solid-supported reagents — that has been shown to significantly improve productivity in the generation of combinatorial libraries and complex target molecules.

The continuous-flow synthesis of carboxylic acids using CO2 in a tube-in-tube gas permeable membrane reactor.

The use of flow chemistry methods, and immobilized reagents and scavengers is leading to recognizable advances in the praxis of molecular assembly. The operation of these processes can bring wide-ranging benefits, not the least of which releases human resources so necessary for the intellectual design and planning of the synthesis pathways. The increasingly competitive climate of chemical research in industrial and academic programs has necessitated a shift from the previous inefficient downstream chemical processing methods towards more sustainable approaches that better reflect the challenges of the discovery process. To address these issues, we have advocated the use of tools and techniques that facilitate more of a “machine-assisted” approach, of which flow chemistry has been particularly useful for conducting efficient, multistep sequences leading directly to a drug molecule or even natural products. When these methods are coupled with the use of immobilized reagents, scavengers, catch and release, and phase switching methods, our group has shown that flow chemistry can lead to demonstrable improvements particularly as they relate to reaction work-ups by avoiding conventional methods of chromatography, crystallization, distillation and aqueous extractions or pH adjustments. Furthermore, flow chemistry methods can accommodate improved safety through incorporation of appropriate monitoring and remote control methods. The use of reactive gases in organic synthesis provides advantages in terms of cost efficiency and work-up. Reactive gases can often be used in excess and are readily removed from the reaction mixture, affording cleaner synthesis processes. However, there is a general reluctance to use reactive gases in research laboratories largely owing to problems related to the containment of pressurized gases, associated safety factors, and the high capital costs and infrastructure requirements of large scale gas-liquid reactors. Flow chemical methods may overcome some of the obstacles to their adoption in useful synthetic transformations. The introduction of gases into flow streams can be achieved through plug-flow techniques, microreactors, or mechanical mixing of gas-liquid phases, however, the resulting ambient pressures or low throughput can restrict these approaches. We have previously reported upon the use of gas permeable membrane tubing (Teflon AF-2400) as a particularly effective method of delivering gas to a liquid flow stream in a controlled manner. Teflon AF-2400 is a chemically inert copolymer of tetrafluoroethylene (TFE) and 2,2-bis(trifluoromethyl)-4,5-difluoro-1,3-dioxole (Figure 1). The resulting polymer is an extensively microporous, amorphous material with high gas permeability.

MULTI-STEP ORGANIC SYNTHESIS USING SOLID-SUPPORTED REAGENTS AND SCAVENGERS: A NEW PARADIGM IN CHEMICAL LIBRARY GENERATION

1 Review 1.1 Overview 1.2 Solid-phase organic synthesis (SPOS) 1.3 Beyond conventional solid-phase organic synthesis 1.4 The review 1.5 Some definitions 1.6 Solid-supported reagents and scavengers 1.7 Multi-step use of solid-supported reagents and scavenging reagents 1.8 Conclusions and future perspective 2 Introduction to the tables 2.1 Organisation of tables (reagent and catalyst section) 2.2 Representative data entry (reagent and catalyst section) 2.3 Organisation of tables (scavenging agents section) 2.4 Representative data entry (scavenging agents section) 3 Tables of reagents and catalysts 4 Tables of scavengers 5 Other relevant reviews 5.1 Insoluble polymers 5.1.1 Structure and physical properties (insoluble polymers) 5.1.2 General (insoluble polymers) 5.1.3 Reactions (insoluble polymers) 5.1.4 Miscellaneous (insoluble polymers) 5.2 Soluble polymers 5.2.1 General (soluble polymers) 5.2.2 Reactions (soluble polymers) 5.3 Inorganic solids 5.3.1 Structure and physical properties (inorganic solids) 5.3.2 General (inorganic solids) 5.3.3 Reactions (inorganic solids) 5.3.4 Miscellaneous (inorganic solids) 5.4 Miscellaneous supports 5.4.1 Structure and physical properties (miscellaneous supports) 5.4.2 General (miscellaneous supports) 5.4.3 Reactions (miscellaneous supports) 5.4.4 Miscellaneous (miscellaneous supports) 5.5 Purification strategies 5.5.1 Various supports (purification strategies) 5.5.2 Insoluble polymers (purification strategies) 6 Acknowledgements 7 Abbreviations 8 References 1 Review

KMnO4-Mediated Oxidation as a Continuous Flow Process

An efficient and easily scalable transformation of alcohols and aldehydes to carboxylic acids and nitroalkane derivatives to the corresponding carbonyls and carboxylic acids using permanganate as the oxidant within a continuous flow reactor is reported. Notably, the generation and downstream processing of MnO(2) slurries was not found to cause any blocking of the reactor when ultrasound pulses were applied to the flow system.

The flow synthesis of heterocycles for natural product and medicinal chemistry applications

This article represents an overview of recent research from the Innovative Technology Centre in the field of flow chemistry which was presented at the FROST2 meeting in Budapest in October 2009. After a short introduction of this rapidly expanding field, we discuss some of our results with a main focus on the synthesis of heterocyclic compounds which we use in various natural product and medicinal chemistry programmes.