Alkyl-functional polycaprolactones were prepared via direct and well-controlled ring-opening polymerisation and the relationship between the substituent position and polymerisation rate was investigated.

Varying the size of an alkyl side-chain group, installed by thiol–ene addition of alkylthiols to poly(ε-allyl caprolactone), the semi-crystallinity and lipophilicity of functional PCLs could be modulated to achieve divergent physico-chemical properties.

Mitochondrial diseases (MDs) are a heterogeneous group of disorders resulting from mutations in nuclear or mitochondrial DNA genes encoding mitochondrial proteins1,2. MDs cause pathologies with severe tissue damage and ultimately death3,4. There are no cures for MDs and current treatments are only palliative5-7. Here we show that tetracyclines improve fitness of cultured MD cells and ameliorate disease in a mouse model of Leigh syndrome. To identify small molecules that prevent cellular damage and death under nutrient stress conditions, we conduct a chemical high-throughput screen with cells carrying human MD mutations and discover a series of antibiotics that maintain survival of various MD cells. We subsequently show that a sub-library of tetracycline analogues, including doxycycline, rescues cell death and inflammatory signatures in mutant cells through partial and selective inhibition of mitochondrial translation, resulting in an ATF4-independent mitohormetic response. Doxycycline treatment strongly promotes fitness and survival of Ndufs4-/- mice, a preclinical Leigh syndrome mouse model8. A proteomic analysis of brain tissue reveals that doxycycline treatment largely prevents neuronal death and the accumulation of neuroimmune and inflammatory proteins in Ndufs4-/- mice, indicating a potential causal role for these proteins in the brain pathology. Our findings suggest that tetracyclines deserve further evaluation as potential drugs for the treatment of MDs.

5-Oxatetracyclines were synthesized from d-arabinose using sequential Michael-Claisen cyclization reactions via a 5-oxa-AB enone substrate. The 5-oxatetracyclines were found to have poor stability in aqueous buffer (pH 7.4, 37 °C) and showed little to no inhibition of bacterial growth (S. aureus, E. coli).

The chemical modification of structurally complex fermentation products, a process known as semisynthesis, has been an important tool in the discovery and manufacture of antibiotics for the treatment of various infectious diseases. However, many of the therapeutics obtained in this way are no longer effective, because bacterial resistance to these compounds has developed. Here we present a practical, fully synthetic route to macrolide antibiotics by the convergent assembly of simple chemical building blocks, enabling the synthesis of diverse structures not accessible by traditional semisynthetic approaches. More than 300 new macrolide antibiotic candidates, as well as the clinical candidate solithromycin, have been synthesized using our convergent approach. Evaluation of these compounds against a panel of pathogenic bacteria revealed that the majority of these structures had antibiotic activity, some efficacious against strains resistant to macrolides in current use. The chemistry we describe here provides a platform for the discovery of new macrolide antibiotics and may also serve as the basis for their manufacture.

Stainless steel reactors are unsuitable for polymerizations catalyzed by EtAlCl2 due to a side reaction between Cr2O3 in stainless steel and EtAlCl2.

Fetal magnetic resonance imaging (MRI) is currently offered in a limited number of centers but is predominantly used for suspected fetal central nervous system abnormalities. This article concentrates on the role of the different imaging sequences and their value to clinical practice. It also discusses the future of fetal MRI.

We report the one-pot copolymerization of ω-pentadecalactone (PDL) to produce tri- and diblock-like copolymers with the ability to undergo postpolymerization modification. The ε-substituted ε-lactone (εSL), menthide (MI), was copolymerized with PDL to introduce side chain functionality into poly(ω-pentadecalactone) (PPDL) copolymers. The copolymerization was followed by quantitative 13C NMR spectroscopy, which revealed that the polymerization of MI occurred before the incorporation of PDL into the polymer chain to form a block-like copolymer. Transesterification side reactions were not found to occur interblock, although intrablock transesterification side reactions occurred only within the PPDL section. The same effect was demonstrated across a range of relative molar equivalents of monomers, and the generality of the approach was further demonstrated with the copolymerization of PDL with other εSL monomers. Finally, the copolymerization of PDL with an alkene-functionalized εSL was shown to produce one-pot PDL block-like copolymers that could undergo postpolymerization modification by thiol-ene addition to produce block copolymers with a range of characteristics in a simple procedure.

AbstractDie Entdeckung und Einführung der Antibiotika im frühen zwanzigsten Jahrhundert hatte gewaltige Auswirkungen auf das Gesundheitwesen. Die chemische Synthese ermöglichte die Entwicklung der ersten antibakteriellen Substanzen, Organoarsenverbindungen und Sulfa‐Medikamente, die jedoch bald von wirksameren und weitaus komplexeren natürlichen Antibiotika verdrängt wurden: unter anderem Penicillin, Streptomycin, Tetracyclin und Erythromycin. Diese ersten Abwehrstoffe sind inzwischen – als unvermeidbare Folge der raschen Resistenzentwicklung bei pathogenen Bakterien – deutlich weniger wirksam, was durch die weit verbreitete falsche Anwendung von Antibiotika noch verstärkt wurde. Jahrzehntelang ergänzten Medizinchemiker das Repertoire der Antibiotika durch semisynthetische und in geringerem Maße vollsynthetische Routen, aber ökonomische Faktoren haben einen Rückgang dieser Bemühungen ausgelöst, was die Gesellschaft an den Rand einer Katastrophe führt. Wir sind überzeugt, dass die strategische Anwendung moderner chemischer Synthesemethoden zur Entwicklung antibakterieller Wirkstoffe von entscheidender Bedeutung ist, wenn eine globale Krise abgewendet werden soll.

The discovery and implementation of antibiotics in the early twentieth century transformed human health and wellbeing. Chemical synthesis enabled the development of the first antibacterial substances, organoarsenicals and sulfa drugs, but these were soon outshone by a host of more powerful and vastly more complex antibiotics from nature: penicillin, streptomycin, tetracycline, and erythromycin, among others. These primary defences are now significantly less effective as an unavoidable consequence of rapid evolution of resistance within pathogenic bacteria, made worse by widespread misuse of antibiotics. For decades medicinal chemists replenished the arsenal of antibiotics by semisynthetic and to a lesser degree fully synthetic routes, but economic factors have led to a subsidence of this effort, which places society on the precipice of a disaster. We believe that the strategic application of modern chemical synthesis to antibacterial drug discovery must play a critical role if a crisis of global proportions is to be averted.

Polymerization of methyl acrylate (MA) catalyzed by Cu(0) is carried out in toluene using a range of alcohols and phenol as additives to facilitate the reaction. The polar/coordinating additives promote disproportionation of Cu(I) to Cu(0), the proposed active species in single electron transfer living radical polymerization (SET-LRP), and Cu(II) whilst toluene maintains solubility of the reagents and products. In this work, the use of alcohols as additives is optimized. Polymerizations are monitored in real time using rapid chromatography to obtain conversion and molecular weight distribution data without the necessity of manual sampling. Rapid gel permeation chromatography with low angle laser light scattering detection is shown to be a viable method of obtaining molecular weight distribution data in real time compared with conventional analytical techniques. Moreover, the changes in CuBr2 concentration during SET-LRP reactions are monitored online using a photodiode array detector. Finally, the kinetics of SET-LRP of MA using an ultra pure highly porous Cu(0) is performed and a detailed discussion on the role of Cu(II) is provided. (C) 2011 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 49:1753-1763, 2011

Here we describe chemical innovations that enable the preparation of fully synthetic tetracyclines containing an all-carbon quaternary, stereogenic center at position C5a, a structurally novel class of compounds in this important family of therapeutic agents. In the key transformation and an important extension of the powerful Michael-Claisen cyclization (AB plus D) approach to the construction of fully synthetic tetracyclines, we show that the six-membered C ring comprising a C5a quaternary carbon center can be assembled by highly stereocontrolled coupling reactions of β-substituted AB enones and o-toluate ester anion D-ring precursors. Novel and versatile β-functionalization reaction sequences employing tris(methylthio)methyllithium and 2-lithio-1,3-dithiane have been developed to transform the AB enone 1 (the key precursor to fully synthetic tetracyclines) into a diverse range of β-substituted AB enone products, including a highly efficient, single-operation method for the synthesis of a β-methyl ester-substituted AB enone. A C5a-C11a-bridged cyclopropane tetracycline precursor was found to undergo efficient and regioselective ring-opening reactions with a range of nucleophiles in the presence of magnesium bromide, thus providing another avenue for the preparation of fully synthetic tetracyclines containing an all-carbon quaternary center at position C5a. Two compounds prepared from the bridged cyclopropane intermediate served as (further) diversifiable branch-points, allowing maximally expedient synthesis of C5a-substituted tetracyclines by final-step diversification.

Tetracyclines and tetracycline analogues are prepared by a convergent, single-step Michael-Claisen condensation of AB precursor 1 or 2 with D-ring precursors of wide structural variability, followed by removal of protective groups (typically in two steps). A number of procedural variants of the key C-ring-forming reaction are illustrated in multiple examples. These include stepwise deprotonation of a D-ring precursor followed by addition of 1 or 2, in situ deprotonation of a D-ring precursor in mixture with 1 or 2, and in situ lithium-halogen exchange of a benzylic bromide D-ring precursor in the presence of 1 or 2, followed by warming. The AB plus D strategy for tetracycline synthesis by C-ring construction is shown to be robust across a range of different carbocyclic and heterocyclic D-ring precursors, proceeding reliably and with a high degree of stereochemical control. Evidence suggests that Michael addition of the benzylic anion derived from a given D-ring precursor to enones 1 or 2 is quite rapid at -78 degrees C, while Claisen cyclization of the enolate produced is rate-determining, typically occurring upon warming to 0 degrees C. The AB plus D coupling strategy is also shown to be useful for the construction of tetracycline precursors that are diversifiable by latter-stage transformations, subsequent to cyclization to form the C ring. Results of antibacterial assays and preliminary data obtained from a murine septicemia model show that many of the novel tetracyclines synthesized have potent antibiotic activities, both in bacterial cell culture and in vivo. The platform for tetracycline synthesis described gives access to a broad range of molecules that would be inaccessible by semisynthetic methods (presently the only means of tetracycline production) and provides a powerful engine for the discovery and, perhaps, development of new tetracycline antibiotics.

Polymers containing poly(ethylene glycol) methacrylate and 2-(2-methoxyethoxy)ethyl methacrylate have been synthesized by Cu(0)-mediated radical polymerisation for use as thermoresponsive water-dispersants for carbon nanotubes.

Phenol has been used as an additive to enhance the rate of SET-LRP in toluene at ambient temperature. A direct relationship between reaction time and amount of phenol added has been found with the optimum amount being similar to 20 equiv. of phenol with respect to initiator. Polymerization of methyl acrylate (MA) has been carried out in the presence of varying amounts of phenol and the rate of polymerization depends on the concentration of phenol relative to initiator. With a 20-fold excess 93% conversion is observed after 218 min (PDI = 1.06, M-n = 11,500 g mol(-1)) when compared with 80% conversion with a 5-fold excess (PDI = 1.21, M-n = 5310 g mol(-1)). When nonsterically hindered phenols are employed in a 20 molar excess with respect to the initiator the polymerizations have good linear first-order kinetics and give polymers with PDI between 1.06 and 1.16. When a highly hindered phenol is employed there is a significant induction period prior to polymerization taking place which is similar to when using no phenol. Less hindered phenols accelerated the polymerization when compared with polymerizations with no added phenol. Increasing steric hindrance at the -OH prevents this coordination which indicates that the role of phenol is different with either copper(0) or copper(I). Aliphatic and aromatic esters and amides were used successfully as initiators giving polymers with M-n close to that predicted at similar to 10,000 g mol(-1) and PDI typically less than 1.10. An induction period is observed in most cases which can be removed by a pre-equilibrium step before the addition of monomer. This results in excellent first-order kinetics being observed in the polymerization of MA in toluene solution (50 vol %). Here Cu(0) (powder)/Me-6-TREN with 20 equiv. of phenol and all of the reactants, except the monomer, were added to the reaction flask and stirred for 45 min at 25 degrees C. The structure of the polymer is shown by MALDI TOF MS to contain bromide chain ends derived from the alkyl bromide initiator. The retention of this end group is consistent with living radical polymerization. (C) 2008 Wiley Periodicals, Inc. J Polym Sci Part A: Polym. Chem 46: 7376-7385, 2008