Structure-Activity Relationship and Crystallographic Studies on 4-Hydroxypyrimidine HIF Prolyl Hydroxylase Domain Inhibitors

The 2-oxoglutarate-dependent hypoxia inducible factor prolyl hydroxylases (PHDs) are targets for treatment of a variety of diseases including anaemia. One PHD inhibitor is approved for use for the treatment of renal anaemia and others are in late stage clinical trials. The number of reported templates for PHD inhibition is limited. We report structure–activity relationship and crystallographic studies on a promising class of 4-hydroxypyrimidine-containing PHD inhibitors.     

Design,Synthesis, Radiosynthesis and Biological Evaluation of Fenretinide Analogues as Anticancer and Metabolic Syndrome-Preventive Agents

Fenretinide (4-HPR) is a synthetic derivative of all-trans-retinoic acid (ATRA) characterised by improved therapeutic properties and toxicological profile relative to ATRA. 4-HPR has been mostly investigated as an anti-cancer agent, but recent studies showed its promising therapeutic potential for preventing metabolic syndrome. Several biological targets are involved in 4-HPR's activity, leading to the potential use of this molecule for treating different pathologies. However, although 4-HPR displays quite well-understood multitarget promiscuity with regards to pharmacology, interpreting its precise physiological role remains challenging. In addition, despite promising results in vitro, the clinical efficacy of 4-HPR as a chemotherapeutic agent has not been satisfactory so far. Herein, we describe the preparation of a library of 4-HPR analogues, followed by the biological evaluation of their anti-cancer and anti-obesity/diabetic properties. The click-type analogue 3 b showed good capacity to reduce the amount of lipid accumulation in 3T3-L1 adipocytes during differentiation. Furthermore, it showed an IC₅₀ of 0.53±0.8 μM in cell viability tests on breast cancer cell line MCF-7, together with a good selectivity (SI=121) over noncancerous HEK293 cells. Thus, 3 b was selected as a potential PET tracer to study retinoids in vivo, and the radiosynthesis of [¹⁸F] 3b was successfully developed. Unfortunately, the stability of [¹⁸F] 3b turned out to be insufficient to pursue imaging studies.     

Divergent Synthesis of Novel Cylindrocyclophanes that Inhibit Methicillin-Resistant Staphylococcus aureus (MRSA)

The cylindrocyclophanes are a family of macrocyclic natural products reported to exhibit antibacterial activity. Little is known about the structural basis of this activity due to the challenges associated with their synthesis or isolation. We hypothesised that structural modification of the cylindrocyclophane scaffold could streamline their synthesis without significant loss of activity. Herein, we report a divergent synthesis of the cylindrocyclophane core enabling access to symmetrical macrocycles by means of a catalytic, domino cross-metathesis-ring-closing metathesis cascade, followed by late-stage diversification. Phenotypic screening identified several novel inhibitors of methicillin-resistant Staphylococcus aureus. The most potent inhibitor has a unique tetrabrominated [7,7]paracyclophane core with no known counterpart in nature. Together these illustrate the potential of divergent synthesis using catalysis and unbiased screening methods in modern antibacterial discovery.     

Targeting SARS-CoV-2 RBD Interface: a Supervised Computational Data-Driven Approach to Identify Potential Modulators

Coronavirus disease 2019 (COVID-19) has spread out as a pandemic threat affecting over 2 million people. The infectious process initiates via binding of SARS-CoV-2 Spike (S) glycoprotein to host angiotensin-converting enzyme 2 (ACE2). The interaction is mediated by the receptor-binding domain (RBD) of S glycoprotein, promoting host receptor recognition and binding to ACE2 peptidase domain (PD), thus representing a promising target for therapeutic intervention. Herein, we present a computational study aimed at identifying small molecules potentially able to target RBD. Although targeting PPI remains a challenge in drug discovery, our investigation highlights that interaction between SARS-CoV-2 RBD and ACE2 PD might be prone to small molecule modulation, due to the hydrophilic nature of the bi-molecular recognition process and the presence of druggable hot spots. The fundamental objective is to identify, and provide to the international scientific community, hit molecules potentially suitable to enter the drug discovery process, preclinical validation and development.     

β-Selective C−H Arylation of Electron-Deficient Thiophenes,Pyrroles, and Furans

A general β-C−H arylation of electron-deficient thiophenes, pyrroles, and furans has been developed using ligand-modulated palladium catalyst. The use of a modified norbornene is crucial for reversing the conventional α-selectivity of these substrates. This method features good yields, high β-selectivity, and good tolerance of functional groups.     

ANN modeling applied to NO x reduction with octane in a new microreactor

A silver/alumina catalyst was tested for its NO _x reduction activity during oxygen-rich conditions and during variation in the input parameters (nitric oxide, octane and oxygen). The experimental data using the microreactor was investigated by means of artificial neural networks (ANN).     

High resolution NMR study of tropical fruit seed starches

The nuclear magnetic resonance spectroscopy (NMR) studies of starches obtained by fruit seeds such as melon and watermelon were carried out as an analytical methodology to understand the molecular dynamic behavior. This study was also accompanied by the conventional X‐ray diffraction and thermal analysis. The NMR results give us a complete behavior of the samples at the molecular level. Thus, the information obtained from NMR will complement the data obtained from X‐ray and thermal analysis allowing us having responses on samples structure and dynamical behavior. © 2007 Wiley Periodicals, Inc. J Appl Polym Sci 2007     

Einfluß der Luftspaltweite auf die Verluste schnellaufender Asynchronmaschine mit Käfigläufer

Übersicht Die Zusatzverluste von asynchronen Käfigläufermotoren können durch Vergrößerung der Luftspaltweite beträchtlich vermindert werden. Es wird ein Berechnungsverfahren zur Bestimmung der luftspaltabhängigen Verluste vorgestellt. Die Ergebnisse wurden durch Messungen an drei verschiedenen Motoren im Leistungsbereich zwischen 10 und 50 kW überprüft. Bei Betrieb mit erhöhter Ständerfrequenz wird eine Reduzierung der Gesamtverluste um bis zu 32% erzielt. Dies gilt bei Betrieb der Motoren mit sinusförmiger Spannung. Bei Speisung über Frequenzumrichter mit nichtsinusförmigen Ausgangsgrößen reduzieren sich die Gesamtverluste um den gleichen absoluten Betrag.

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The influence of air gap length on the power losses of squirrel cage induction motors

Contents The additional losses of squirrel cage induction motors can be reduced considerably by increasing the air gap. A calculation method is presented how to determine the power losses which are influenced by air gap length. The results are verified by measurements of three various motors with a power output between 10 and 50 kW. In operation with inereased stator frequency a reduction of total losses ranging up to 32 p.u. is achieved. This is valid for operation with sinusoidal voltage. For supply by frequency inverters with nonsinusoidal output the total losses are reduced about the same absolute amount.

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Herrn Prof. Dr.-Ing. E. Ch. Andresen zum 60. Geburtstag gewidmet     

Zur Inhomogenität des inneren Feldes und der Flußdichte von kornorientierten Elektroblechen aus Silizium-Eisen bei Fehlorientierungen in der Blechebene

Übersicht Ausgehend von einem Modell eines kornorientierten Silizium-Eisenbleches mit idealer Goss-Textur und einem in der Blechebene fehlorientierten Korn im Zentrum werden die Magnetisierung, die Struktur des inneren Feldes und die Flußdichte berechnet. Die Struktur des inneren Feldes und der Flußdichte wird in Abhängigkeit vom aussteuernden Feld dargestellt, so daß die Verschlechterung der Flußführung durch derartig fehlorientierte Körner sichtbar wird.

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On the inhomogenity of the inner field and the flux density of grain-oriented silicon-iron sheets concerning misorientations in the sheet plane

Contents Starting from a model of a g.o. silicon-iron sheet with ideal goss-texture and an in-plane misoriented grain in the center the magnetization, the structure of the inner field and of the flux density in dependence on the external applied field are shown so that the deterioration of the flux guidance caused by such misoriented grains becomes visible.