Synthesis of a Novel RAS Farnesyl Protein Transferase Inhibitor

Mutant RAS proteins are associated with 30% of all human cancers. Unregulated cell growth caused by mutant RAS proteins can be prevented by RAS farnesyl protein transferase (FPTase) inhibitors. A novel FPTase inhibitor has been synthesized incorporating a modified farnesyl “tail” and a customized diphosphate “head”. It is anticipated that the modified “tail”, incorporating a phenyl substituent, will bind more tightly to FPTase due to nonbonding interactions between the aromatic ring and ten aromatic amino acid residues that line the enzyme active site. The altered polar “head”, designed from L-aspartic acid, has already been shown to mimic the natural substrate’s diphosphate moiety. It is anticipated that the bioactivity of the novel compound presented in this research will illustrate the relevance of modifications to the farnesyl “tail” in the design of farnesyl diphosphate mimetics

Feasibility and usefulness of rapid 2-channel-EEG-monitoring (point-of-care EEG) for acute CNS disorders in the paediatric emergency department: an observational study

IntroductionThe aim of this study was to determine the feasibility and clinical utility of point-of-care electroencephalogram (pocEEG) in the paediatric emergency department (ED) for children presenting with acute non-traumatic central nervous system (CNS) disorders.MethodsRetrospective observational study of prospectively collected data in paediatric patients (0–16 years) with acute non-traumatic CNS-disorders presenting between April 2014 and February 2017 to a single paediatric ED in Switzerland.The 2-channel EEG was applied to all patients presenting with acute seizures or impaired consciousness to the ED. For a pocEEG, scalp surface electrodes are applied in five locations, thus allowing registration of fronto-temporal bilateral cortical activity. Neurology consultants assisted with interpretation of readings. EEG findings and clinical characteristics were collected. Feasibility and usefulness were rated via Likert scale.Results36 patients with acute seizures or altered mental status were analysed. Age range was 9 months to 15 years, median age of 34 months. 21 of 36 (58%) patients arrived out of hours. Application of electrodes was rated as ‘easy’ in 28 (77.8%) patients and rated as ‘difficult’ in 8 (22.2%). The utility of the EEG was rated by physicians as ‘very useful/diagnostic’ in 13 cases (36%), ‘useful’ in 21 cases (58%), ‘not useful’ in two cases (8%). None were rated ‘negative.’ConclusionUptake of pocEEG introduction has been very encouraging. Provider ratings were overwhelmingly positive. Recognition of non-convulsive status epilepticus was improved and pocEEG facilitated more targeted interventions

The Case of the Missing Music: An Outreach Activity Sparks Interest in Science and Density

From Scooby Doo and Nancy Drew to the countless other detectives that fill children’s bookshelves and television programs, it is clear that children are fascinated with solving crimes. As a result, a chemistry professor who performs outreach activities at local elementary schools exploited this interest in mysteries as a method to spark curiosity in science. This was accomplished through the development of an outreach activity in which students solve a mystery using density and fingerprint analysis

The Design and Synthesis of Novel Goniothalamin Analogues

Every two minues a woman in the United States is diagnosed with breast cancer. In recent years, one method to identify potential chemotherapeutic agents has been the mass screening of natural products of cytotoxicity. One compound discovered in this manner was goniothalamin. Gonothalamin was isolated from the dried stem bark of the plant Goniothalamus sesuipedalis and exhibits cell specific anticancer activity against breast cancer. Goniothalamin has been extensively studies and a large number of synthetic analogues have been prepared in an attempt to determine the structural features necessary for bioactivity. These studies have focused primarily on the manipulation of goniothalmin\u27s styryl substituent. The focus of this research is on the lactone core of goniothalamin. Analogues have been prepared that replace the lactone ring with lactam. It is anticipated that alteration of the lactam nitrogen substituent will potentially lead to analogues with better bioavailability and reactivity than the natural product

Chemotherapeutic Drug Design: An Efficient Synthesis of 4-Substituted Alpha-Methylene-Gamma-Lactones

Sesquiterpene lactones are plant-derived compounds that have been shown to possess significant activity against inflammation and cancer. Comparative studies of sesquiterpene lactone structure and tumor cytotoxicity indicate that the presence of an α-methylene-γ-lactone moiety is necessary for bioactivity. This observation has led to the hypothesis that simple compounds containing this pharmacophore may also exhibit similar anti-cancer properties. To test this theory, an efficient synthesis of 4-substituted α-methylene-γ-lactone has been developed. The model compound in this study, α-methylene-γ-dodecalactone, has been prepared from commercially available 1-decene in six steps. The synthesis features a nucleophilic epoxide ring-opening reaction followed by an intramolecular cyclization to prepare a key lactone intermediate. The described sequence should provide access to a large number of 4-substituted α-methylene-γ-lactone analogues that can be used to better understand the role alkyl substituents play in the bioactivity of this class of compounds

On the application of Bayesian statistics to protein structure calculation from nuclear magnetic resonance data

In the present work, we use concepts of Bayesian statistics to infer the three-dimensional structures of proteins from experimental data. We thus build upon the method of inferential structure determination (ISD) as introduced by Rieping et al. (2005). In line with their probabilistic approach, we factor the probability of a three-dimensional protein structure given the experimental data, into a prior distribution that captures the protein-likeness of a structure and the likelihood that describes how likely the experimental data were generated from a given three-dimensional structure. In this Bayesian framework, we attempt to develop structure calculation from NMR experiments into a highly accurate, objective and parameter-free process. We start by focusing on integrating new types of data, as ISD currently does not entail a mechanism to incorporate chemical shifts in the calculation process. To alleviate this shortcoming, we propose a hidden Markov Model that captures the relationship between protein structures and chemical shifts. Based on our probabilistic model, we are able to predict the secondary structure and dihedral angles of a protein from chemical shifts. Another means to high quality structures involves improving the potential functions that form the core of ISD’s prior distributions. Although potential functions are designed to approximate physical forces, there are still parameters, such as force constants and temperatures, that are set on an ad hoc basis and can bias the structure calculation. As an alternative, we propose an algorithm based on Bayesian model comparison to determine these parameters from the data. Further, we demonstrate that optimal data-dependent parameters lead to improved accuracy and quality of the final structure, especially with sparse and noisy data. These findings dismiss the notion of a single universal parameter and advocate the estimation of free parameters based on experimental data instead. Third, we focus on the estimation of new potential functions to include even more prior information in the structure calculation process. Currently, only a few methods allow the estimation of potential functions from a database of known structures. Our method provides a sound mathematical solution of this problem, which is also known as the inverse problem of statistical mechanics.We demonstrate the effectiveness of our approach on the examples of simple fluids and a coarse-grained protein model.Im Rahmen dieser Arbeit stellen wir neue Ansätze, basierend auf der Bayes’schen Statistik, zur Interpretation von experimentellen Daten in der NMR-Spektroskopie vor. Dabei bauen wir auf den Ergebnissen von Rieping et al. (2005) auf, die das Prinzip der inferentiellen Strukturbestimmung (ISD) eingeführt haben. Ihr probabilistischer Ansatz beruht auf der Faktorisierung der A-posteriori-Verteilung in die A-priori-Verteilung, welche die Proteinähnlichkeit einer möglichen Struktur bewertet, und die Likelihood-Funktion, welche die Übereinstimmung mit den experimentellen Daten beschreibt. Ziel dieser Arbeit ist es, die Qualität, aber auch die Vergleichbarkeit der Strukturberechnung in der NMR- Spektroskopie zu verbessern. Zuerst beschäftigen wir uns mit der Integration neuer experimenteller Datentypen in die Strukturrechnung. Dazu schlagen wir ein Hidden-Markov-Modell vor, das beruhend auf der chemischen Verschiebung die Dihedralwinkel und Sekundärstruktur vorhersagt. Eine Alternative zur Integration zusätzlicher experimenteller Information ist die Verbesserung der A-priori-Verteilung. In ISD beruht die A-priori-Verteilung auf einer Po- tentialfunktion, welche die frei Energie approximiert. Dennoch gibt es freie Parameter in Potentialfunktionen, wie die Temperatur oder doe Kraftkonstante, die festgelegt werden müssen. Wir benutzen Bayes’sche Hypothesentests, um die freien Parameter objektiv und beruhend auf den experimentellen Daten zu bestimmen. Die Anwendung der Bayes’schen Hypothesentests ermöglicht es uns, verschiedene Potentialfunktionen zu kombinieren, um aus verrauschten und unvollständigen Daten noch exakte Strukturen zu bestimmen. Weiterhin zeigen unsere Studien, dass für statistische Potentiale keine allgemeingültige Kraftkonstante existiert und diese anhand der experimentellen Daten bestimmt werden sollte. Im dritten Teil dieser Arbeit führen wir eine Methode ein, um neue Kraftfelder aus Strukturdatenbanken zu erlernen und damit die A-priori-Verteilung noch weiter zu verbessern. Dieses nichtlineare Problem ist auch als inverses Problems der statistischen Mechanik bekannt, das wir durch eine Generalisierung des Konzepts der "Configurational Temperature" lösen. Wir benutzen unsere Methode, um die Potentialfunktionen von vereinfachten Moleküldynamik Kraftfeldern zu rekonstruieren

Acute necrotizing encephalopathy (ANE1): rare autosomal-dominant disorder presenting as acute transverse myelitis

The term "acute transverse myelitis (ATM)” comprises various non-traumatic disorders that eventually can be associated with a focal myelopathy. Patients characteristically present with an acutely occurring paraparesis/plegia and require a comprehensive and timely diagnostic work up for the initiation of an appropriate treatment. We present a case of a 36-year-old female patient with a rare genetic disorder (ANE1: Acute Necrotizing Encephalopathy due to a RANBP2 mutation) who presented with an acute quadriplegia. Following an acute pulmonal infection, she rapidly (< 24h) developed a severe quadriplegia (total motor score 38) with some facial sensory symptoms (perioral hypoesthesia). Magnetic resonance imaging (MRI) revealed a combination of longitudinal extensive transverse myelitis and symmetrical thalamic lesions. A work-up for infectious and systemic diseases was negative; specifically, no findings related to multiple sclerosis, neuromyelitis optica or vascular disorders. After empirical high dose steroid treatment and rehabilitation therapy, the patient gained almost normal gait and upper limb function. She was found to carry an autosomal-dominant missense mutation in the RANBP2 gene predisposing for ANE. Gene segregation was confirmed in other family members that had been affected by other episodes of acute steroid-responsive encephalopathies. We propose that a redefined diagnostic workup of ATM might include ANE1, as the frequency of this rare disorder might be underestimate

Design and Synthesis of a Potential Chemotherapeutic Agent Using Goniothalamin as a Natural Product Template

Goniothalamin, a natural product extracted from the tree bark of the Goniothalamus genus, has been shown to induce apoptosis in cancer cells. It is hypothesized that goniothalamin\u27s biological activity is due to its ability to react with thiols. Goniothalamin has been shown to decrease levels of glutathione, a natural antioxidant, found in cancer cells. This causes a redox imbalance, which ultimately leads to cell death. Thiol-reactive compounds, like goniothalamin, have also been shown to inhibit nuclear factor-κB (NF-κB). NF-κB is a transcription factor that has been implicated in unregulated cell growth. Through a nine step sequence, a novle analogue of goniothalamin has been prepared that replaces the lactone core of the nature product with a cyclohexenone. The synthetic sequence features a unique enol ether protection of beta-diketone which allows facile preparation of the desired analogue. It is anticipated that the novel goniothalamin derivative will demonstrate increaed cytotoxicity against cancer cells

Chemotherapeutic Agents from Natural Product Templates: The Design and Synthesis of Novel Indanone Analogues

Coumarin is a natural product found in many plants. Recently, simple coumarin analogues containing an α-methylene functional group have been synthesized and shown to exhibit cytotoxicity against cancer cell lines. The α,β-unsaturated carbonyl found in these analogues is thought to be responsible for their bioactivity. Other natural products containing this functional group have been shown to react with intracellular thiols causing tumor growth suppression. Using these analogues as a template, two new compounds have been designed that feature a novel α-methylene indanone structural framework. Since ketones are better electrophiles that esters, it is hypothesized that these analogues will react more rapidly with thiols that their coumarin counterparts. The two α-methylene indanone analogues, one incorporating an isopropyl and the other an n-butyl substituent, have been prepared in five and seven steps respectively. Both synthetic sequences feature a 1,4-organometallic addition reaction, in intramolecular Friedel-Crafts acylation, and an α-methylenation of the key inadone intermediates