Rh-catalyzed arylation of fluorinated ketones with arylboronic acids

The Rh-catalyzed arylation of fluorinated ketones with boronic acids is reported. This efficient process allows access to fluorinated alcohols in high yields under mild conditions. Competition experiments suggest that difluoromethyl ketones are more reactive than trifluoromethyl ketones in this process, despite their decreased electronic activation, an effect we postulate to be steric in origin

The synthesis of novel olfactory receptor agonists and explorations in the selective fluorination of the tert-butyl group for bioactives discovery

In Chapter 1, an introduction to fluorine chemistry is given. The physical properties of fluorine are discussed, and examples of how the introduction of fluorine into a molecule can influence the structure and properties of a molecule are provided. Strategies for the incorporation of fluorine within a molecule are also discussed. In Chapter 2, the structure and properties of (R)-muscone are discussed. The mechanism of olfaction is outlined, and the debate between the conformation and vibrational theories of olfaction is discussed. The development of a series of derivatives of (R)-muscone is explored, in particular trifluoromethyl, chloro and sulfoxide derivatives. Their effectiveness as olfactory molecules is compared to that of (R)-muscone to determine how altering the structure of (R)-muscone effects interactions with known olfactory receptors. In Chapter 3, the structure and properties of synthetic musk compounds previously developed as alternatives to (R)-muscone is developed. The development of a new series of bis-acetylene compounds as prospective musk odorants is outlined. Their effectiveness as odorants is measured and targets are developed to determine the optimal shape and configuration of this class of molecule for interacting with olfactory receptors. In Chapter 4, the effect of fluorine on the lipophilicity of compounds is outlined, and the tert-butyl group is discussed, particularly its uses in medicinal chemistry. The development of a new motif, the aryl trifluoro tert-butyl group is outlined, followed by an investigation into the structure, reactivity and properties of the group, to measure the effect of the fluorination of the tert-butyl group. In Chapter 5, the chiral methyl group is introduced, and its use in biosynthetic studies is discussed. The development of a chiral tert-butyl group is outlined, and attempts to develop ¹H and ¹³C NMR assays of the group are discussed

Next generation organofluorine containing blockbuster drugs

Funding: the National Natural Science Foundation of China (No. 21761132021), the Hungarian Research Foundation (NKFIH No. K 119282), and Ministry of Human Capacities, Hungary grant 20391-3/2018/FEKUSTRAT. The Qinlan Project of Jiangsu Province, and IKERBASQUE, the Basque Foundation for Science are also acknowledged.The role of organo-fluorine compounds in modern health, food and energy related industries is widely-appreciated. The unique properties that fluorine imparts to organic molecules, stemming from its high electronegativity and stability when bound to carbon, finds it increasing being used in the development of new bioactivities. Around 25% of the current blockbuster drugs contain fluorine and this number is increasing to well above 30% for recent FDA approvals. In this Review we highlight a selection of the most successful organo-fluorine drugs, that have achieved blockbuster status, namely, sitagliptin (diabetes), sofosbuvir (hepatitis C), emtricitabine (HIV), glecaprevir/pibrentasvir (hepatitis C), elvitegravir (HIV), dolutegravir (HIV), bictegravir (HIV), efavirenz (HIV), enzalutamide (prostate cancer), aubagio (immunomodulatory) and paliperidone palmitate (schizophrenia). For each compound we discuss their discovery, their relevant disease state and how they are made, emphasizing the source of fluorine-containing moieties, and where known, their mode of action.PostprintPeer reviewe

SIDH Proof of Knowledge

We show that the soundness proof for the De Feo-Jao-Plut identification scheme (the basis for supersingular isogeny Diffie--Hellman (SIDH) signatures) contains an invalid assumption, and we provide a counterexample for this assumption---thus showing the proof of soundness is invalid. As this proof was repeated in a number of works by various authors, multiple pieces of literature are affected by this result. Due to the importance of being able to prove knowledge of an SIDH key (for example, to prevent adaptive attacks), soundness is a vital property. Surprisingly, the problem of proving knowledge of a specific isogeny turns out to be considerably more difficult than was perhaps anticipated. The main results of this paper are a sigma protocol to prove knowledge of a walk of specified length in a supersingular isogeny graph, and a second one to additionally prove that the isogeny maps some torsion points to some other torsion points (as seen in SIDH public keys). Our scheme also avoids the SIDH identification scheme soundness issue raised by Ghantous, Pintore and Veroni. In particular, our protocol provides a non-interactive way of verifying correctness of SIDH public keys, and related statements, as protection against adaptive attacks. Post-scriptum: Some months after this work was completed and made public, the SIDH assumption was broken in a series of papers by several authors. Hence, in the standard SIDH setting, some of the statements studied here now have trivial polynomial time non-interactive proofs. Nevertheless our first sigma protocol is unaffected by the attacks, and our second protocol may still be useful in present and future variants of SIDH that escape the attacks

Aryl (β, β', β''-trifluoro)-tert-butyl : a candidate motif for the discovery of bioactives

Funding: UK Engineering and Physical Sciences Research Council - EP/S030506/1; Commonwealth Scholarship Commission.The (β,β′,β″-trifluoro)-tert-butyl (TFTB) group has received very little attention in the literature. This work presents a direct synthesis of this group and explores its properties. The TFTB group arises when the methyl groups of a tert-butyl moiety are exchanged for fluoromethyl groups. Sequential fluoromethylations result in a decrease of Log P (increasing hydrophilicity), ultimately by 1.7 Log P units in the TFTB group relative to that of tert-butyl benzene itself. A focus is placed on synthetic transformations, conformational analysis, and metabolism of the TFTB group in the context of presenting a favorable profile as a motif for the discovery of bioactives.Publisher PDFPeer reviewe

Microalgal enzymes with biotechnological applications

Enzymes are essential components of biological reactions and play important roles in the scaling and optimization of many industrial processes. Due to the growing commercial demand for new and more efficient enzymes to help further optimize these processes, many studies are now focusing their attention on more renewable and environmentally sustainable sources for the production of these enzymes. Microalgae are very promising from this perspective since they can be cultivated in photobioreactors, allowing the production of high biomass levels in a cost-efficient manner. This is reflected in the increased number of publications in this area, especially in the use of microalgae as a source of novel enzymes. In particular, various microalgal enzymes with different industrial applications (e.g., lipids and biofuel production, healthcare, and bioremediation) have been studied to date, and the modification of enzymatic sequences involved in lipid and carotenoid production has resulted in promising results. However, the entire biosynthetic pathways/systems leading to synthesis of potentially important bioactive compounds have in many cases yet to be fully characterized (e.g., for the synthesis of polyketides). Nonetheless, with recent advances in microalgal genomics and transcriptomic approaches, it is becoming easier to identify sequences encoding targeted enzymes, increasing the likelihood of the identification, heterologous expression, and characterization of these enzymes of interest. This review provides an overview of the state of the art in marine and freshwater microalgal enzymes with potential biotechnological applications and provides future perspectives for this field

Effect of pituitary‐dependent hypercortisolism on the survival of dogs treated with radiotherapy for pituitary macroadenomas

Background: Radiotherapy (RT) is an effective treatment for dogs presented with neurologic signs caused by pituitary tumors. However, its impact on the outcome of concurrent pituitary-dependent hypercortisolism (PDH) is controversial. Objectives: Determine whether dogs with PDH have longer survival after pituitary RT compared with dogs with nonhormonally active pituitary masses and to evaluate whether clinical, imaging, and RT variables affect survival. Animals: Ninety-four dogs divided into 2 groups: PDH and non-PDH, based on the presence of hypercortisolism. Forty-seven dogs were allocated to the PDH group and 47 to the non-PDH group. Methods: Retrospective cohort study in which clinical records of dogs undergoing RT for pituitary macroadenomas between 2008 and 2018 at 5 referral centers were retrospectively evaluated. Results: Survival was not statistically different between PDH and non-PDH groups (median survival time [MST], 590 days; 95% confidence interval [CI], 0-830 days and 738 days; 95% CI, 373-1103 days, respectively; P = .4). A definitive RT protocol was statistically associated with longer survival compared with a palliative protocol (MST 605 vs 262 days, P = .05). The only factor statistically associated with survival from multivariate Cox proportional hazard analysis was total radiation dose (Gy) delivered (P < .01). Conclusions and Clinical Importance: No statistical difference in survival was identified between the PDH and non-PDH groups, and longer survival was associated with higher Gy delivered

Social marketing and healthy eating : Findings from young people in Greece

This document is the Accepted Manuscript version. The final publication is available at Springer via http://dx.doi.org/10.1007/s12208-013-0112-xGreece has high rates of obesity and non-communicable diseases owing to poor dietary choices. This research provides lessons for social marketing to tackle the severe nutrition-related problems in this country by obtaining insight into the eating behaviour of young adults aged 18–23. Also, the main behavioural theories used to inform the research are critically discussed. The research was conducted in Athens. Nine focus groups with young adults from eight educational institutions were conducted and fifty-nine participants’ views towards eating habits, healthy eating and the factors that affect their food choices were explored. The study found that the participants adopted unhealthier nutritional habits after enrolment. Motivations for healthy eating were good health, appearance and psychological consequences, while barriers included lack of time, fast-food availability and taste, peer pressure, lack of knowledge and lack of family support. Participants reported lack of supportive environments when deciding on food choices. Based on the findings, recommendations about the development of the basic 4Ps of the marketing mix, as well as of a fifth P, for Policy are proposedPeer reviewe

Transmission Heterogeneity and Control Strategies for Infectious Disease Emergence

The control of emergence and spread of infectious diseases depends critically on the details of the genetic makeup of pathogens and hosts, their immunological, behavioral and ecological traits, and the pattern of temporal and spatial contacts among the age/stage-classes of susceptible and infectious host individuals.We show that failing to acknowledge the existence of heterogeneities in the transmission rate among age/stage-classes can make traditional eradication and control strategies ineffective, and in some cases, policies aimed at controlling pathogen emergence can even increase disease incidence in the host. When control strategies target for reduction in numbers those subsets of the population that effectively limit the production of new susceptible individuals, then control can produce a flush of new susceptibles entering the population. The availability of a new cohort of susceptibles may actually increase disease incidence. We illustrate these general points using Classical Swine Fever as a reference disease.Negative effects of culling are robust to alternative formulations of epidemiological processes and underline the importance of better assessing transmission structure in the design of wildlife disease control strategies

A method for probing the mutational landscape of amyloid structure

Motivation: Proteins of all kinds can self-assemble into highly ordered β-sheet aggregates known as amyloid fibrils, important both biologically and clinically. However, the specific molecular structure of a fibril can vary dramatically depending on sequence and environmental conditions, and mutations can drastically alter amyloid function and pathogenicity. Experimental structure determination has proven extremely difficult with only a handful of NMR-based models proposed, suggesting a need for computational methods. Results: We present AmyloidMutants, a statistical mechanics approach for de novo prediction and analysis of wild-type and mutant amyloid structures. Based on the premise of protein mutational landscapes, AmyloidMutants energetically quantifies the effects of sequence mutation on fibril conformation and stability. Tested on non-mutant, full-length amyloid structures with known chemical shift data, AmyloidMutants offers roughly 2-fold improvement in prediction accuracy over existing tools. Moreover, AmyloidMutants is the only method to predict complete super-secondary structures, enabling accurate discrimination of topologically dissimilar amyloid conformations that correspond to the same sequence locations. Applied to mutant prediction, AmyloidMutants identifies a global conformational switch between Aβ and its highly-toxic ‘Iowa’ mutant in agreement with a recent experimental model based on partial chemical shift data. Predictions on mutant, yeast-toxic strains of HET-s suggest similar alternate folds. When applied to HET-s and a HET-s mutant with core asparagines replaced by glutamines (both highly amyloidogenic chemically similar residues abundant in many amyloids), AmyloidMutants surprisingly predicts a greatly reduced capacity of the glutamine mutant to form amyloid. We confirm this finding by conducting mutagenesis experiments.National Institutes of Health (U.S.) (grant 1R01GM081871)National Institutes of Health (U.S.) (grant GM25874