Catalyst- and excess reagent recycling in aza-Michael additions.

16α-Azolyl-pregnenolone derivatives were prepared 2-butyl-1,1,3,3-tetramethylguanidine (-Bu-TMG) catalysed aza-Michael addition of 16-dehydropregnenolone (16-DHP) carried out in [bmim][BF]. The application of the guanidine base and the imidazolium ionic liquid made it possible to recycle not only the catalyst/solvent mixture but also the excess of the N-heterocyclic reagent. By the introduction of CO at the end of the reaction, both the guanidine base and the unreacted (excess) reagent could be converted into ionic species that remained dissolved in the ionic liquid phase, while the steroid components were extracted with an apolar solvent.

Size and shape heterodonty in the early Permian synapsid Mesenosaurus efremovi.

Paleozoic synapsids represent the first chapter in the evolution of this large clade that includes mammals. These fascinating terrestrial vertebrates were the first amniotes to successfully adapt to a wide range of feeding strategies, reflected by their varied dental morphologies. Evolution of the marginal dentition on the mammalian side of amniotes is characterized by strong, size and shape heterodonty, with the late Permian therapsids showing heterodonty with the presence of incisiform, caniniform, and multicuspid molariform dentition.

Discovery of Novel Steroid-Based Histamine H Receptor Antagonists/Inverse Agonists.

Steroid-based histamine H receptor antagonists (d-homoazasteroids) were designed by combining distinct structural elements of HTS hit molecules. They were characterized, and several of them displayed remarkably high affinity for H receptors with antagonist/inverse agonist features. Especially, the 17a-aza-d-homolactam chemotype demonstrated excellent HR activity together with significant in vivo H antagonism.

Professional Development in Health Sciences: Scoping Review on Equity, Diversity, Inclusion, Indigeneity, and Accessibility Interventions.

Introduction: Equity, diversity, inclusion, indigeneity, and accessibility (EDIIA) are critical considerations in the formation of professional development (PD) programs for health care workers. Improving EDIIA competency in health care serves to enhance patient health, staff confidence and well-being, delivery of care, and the broader health care system. There is a gap in the literature as to the efficacy of EDIIA-based PD programs and their individual components.

Convergent cross-species pro-cognitive effects of RGH-235, a new potent and selective histamine H receptor antagonist/inverse agonist.

The histamine H receptor is a favourable target for the treatment of cognitive deficits. Here we report the in vitro and in vivo profile of RGH-235, a new potent, selective, and orally active H receptor antagonist/inverse agonist developed by Gedeon Richter Plc. Radioligand binding and functional assays were used for in vitro profiling.

A Temperature-Controlled Switch between Fürst-Plattner Rule and Anti-Fürst-Plattner Rule Ring Opening of 2,3-Epoxy-steroids with Various Halide Sources in the Presence of Imidazolium Ionic Liquids.

The ring opening of 2α,3α- and 2β,3β-epoxy-5α-androstan-17-one with halide reagents (AlCl, TMSCl, LiCl, and LiBr) was investigated using imidazolium ionic liquids in the dual role of solvent and catalyst. The application of the ionic liquid was shown to result in an increase in the amount of the unusual diequatorial halohydrins especially at temperatures above 100 °C. With a careful choice of reaction conditions, the latter derivatives could be produced with 43-96% selectivity depending on the nature of the halide ion.

HTS-based discovery and optimization of novel positive allosteric modulators of the α7 nicotinic acetylcholine receptor.

HTS campaign of the corporate compound collection resulted in a novel, oxalic acid diamide scaffold of α7 nACh receptor positive allosteric modulators. During the hit expansion, several derivatives, such as 4, 11, 17 demonstrated not only high in vitro potency, but also in vivo efficacy in the mouse place recognition test. The advanced hit molecule 11 was further optimized by the elimination of the putatively mutagenic aromatic-amine building block that resulted in a novel, aminomethylindole compound family.

Discovery of novel positive allosteric modulators of the α7 nicotinic acetylcholine receptor: Scaffold hopping approach.

The paper focuses on the scaffold hopping-based discovery and characterization of novel nicotinic alpha 7 receptor positive modulator (α7 nAChR PAM) ligands around the reference molecule (A-867744). First, substantial efforts were carried out to assess the importance of the various pharmacophoric elements on the in vitro potency (SAR evaluation) by chemical modifications. Subsequently, several new derivatives with versatile, heteroaromatic central cores were synthesized and characterized.

A new varanopid synapsid from the early Permian of Oklahoma and the evolutionary stasis in this clade.

Varanopids are a basal clade of small- to medium-sized non-therapsid synapsids, whose range extends from the late Pennsylvanian to the late middle Permian, and are found in North America, Russia, Europe and South Africa. The greatest varanopid diversity is observed at the fossiliferous cave deposits near Richards Spur, Oklahoma, well known for the preservation of a complex early Permian upland community. Two previously described varanopids, and , are known only from fragmentary disarticulated material at Richards Spur.

Stereocontrolled synthesis of the four possible 3-methoxy and 3-benzyloxy-16-triazolyl-methyl-estra-17-ol hybrids and their antiproliferative activities.

The four possible isomers of each of 3-methoxy- and 3-benzyloxyestra-1,3,5(10)-trien-17-ols (5-8 and 9-12) were converted through 16-p-tosyloxymethyl- or 16-bromomethyl derivatives into their 3-methoxy- and 3-benzyloxy-16-azidomethylestra(1,3,5(10)-triene derivatives (13-16 and 17-20). The regioselective Cu(I)-catalyzed 1,3-dipolar cycloaddition of these compounds with different terminal alkynes afforded novel 1,4-disubstituted diastereomers (21a-f, 22a-f, 23a-f, 24a-f and 25a-f, 26a-f, 27a-f, 28a-f). The antiproliferative activities of the structurally related triazoles were determined in vitro with the microculture tetrazolium assay on four malignant human cell lines of gynecological origin (Hela, SiHa, MCF-7 and MDA-MB-231).

Discovery of novel steroidal histamine H receptor antagonists/inverse agonists. Part 2. Versatile steroidal carboxamide derivatives.

To further proceed with our previous work, novel steroid-based histamine H receptor antagonists were identified and characterized. Using an 'amine-to-amide' modification strategy at position 17, in vitro and in vivo potent monoamino steroid derivatives were found during the lead optimization. Usage of the non-basic amide moiety resulted in beneficial effects both in activity and selectivity.

Discovery of novel steroidal histamine H receptor antagonists/inverse agonists.

Emerging from an HTS campaign, novel steroid-based histamine H receptor antagonists were identified and characterized. Structural moieties of the hit compounds were combined to improve binding affinities which resulted in compound 4 as lead molecule. During the lead optimization due to the versatile modifications of diamino steroid derivatives, several in vitro potent compounds with subnanomolar binding affinities to histamine H receptors were found.

Detection by HPLC and structural characterization by NMR and MS of a natural deuterium isotopologue of ulipristal acetate.

Herein we discuss the structure elucidation of an unknown peak detected by HPLC in the active pharmaceutical ingredient ulipristal acetate during analytical method development. An extensive chromatographic, MS and NMR spectroscopic study gave the surprising result that the detected component is the natural-abundance mono-deuterium isotopologue of the API. To the best of our knowledge this is the first example where such a mono-deuterium isotopologue could be resolved from its mother component by HPLC and structurally fully characterized by NMR and MS.

New oxidative decomposition mechanism of estradiol through the structural characterization of a minute impurity and its degradants.

Herein we discuss the structure elucidation of a labile estradiol-related degradant, X1. X1 was detected at Gedeon Richter as an unknown trace impurity in a pharmaceutical formulation containing estradiol (1a) and norethisterone acetate (NA) as active ingredients. The structural identification of X1 proved to be an unusually complex task involving an initial structural hypothesis based on some limited analytical data (UV) obtained from the formulation, synthetic work targeting the proposed structure, chromatographic enrichment from the synthetic reaction mixture, (HPLC)-MS and MS-MS studies of the formulation and of samples from the synthesis using almost all available ionization modes, preparative LC enrichment, and the complementary use of off-line and on-line NMR techniques.

A systematic approach to the synthesis of androstane-based 3,17-dicarboxamides (homo- and mixed dicarboxamides) via palladium-catalyzed aminocarbonylation.

3,17-Dicarboxamido-androst-3,5,16-triene derivatives possessing various amine moieties were synthesized under mild conditions using palladium-catalyzed homogeneous aminocarbonylation as key reaction. Compounds containing the corresponding iodoalkene functionalities, i.e.

Estrogens regulate neuroinflammatory genes via estrogen receptors α and β in the frontal cortex of middle-aged female rats.

Background: Estrogens exert anti-inflammatory and neuroprotective effects in the brain mainly via estrogen receptors α (ERα) and β (ERβ). These receptors are members of the nuclear receptor superfamily of ligand-dependent transcription factors. This study was aimed at the elucidation of the effects of ERα and ERβ agonists on the expression of neuroinflammatory genes in the frontal cortex of aging female rats.

Ionic liquid-promoted Wagner-Meerwein rearrangement of 16α,17α-epoxyandrostanes and 16α,17α-epoxyestranes.

Ionic liquids 1-butyl-3-methylimidazolium hexafluorophosphate ([bmim](+)[PF(6)](-)) and 1-butyl-3-methylimidazolium tetrafluoroborate ([bmim](+)[BF(4)](-)) were found to promote an unusual Wagner-Meerwein rearrangement of steroidal 16α,17α-epoxides leading to unnatural 13-epi-18-nor-16-one derivatives as the main products. These compounds were isolated in good to excellent yields. 16α-Hydroxy-Δ(13)-18-norsteroids, the results of the usual rearrangement, were obtained as minor components of the reaction mixtures.

Systematic investigation on the synthesis of androstane-based 3-, 11- and 17-carboxamides via palladium-catalyzed aminocarbonylation.

3,17-Dicarboxamido-androst-3,5,16-triene, 3-carboxamido-androst-3,5-dien-17-one, 17-carboxamido-androst-4,16-dien-3-one and 11-carboxamido-androst-5,9(11)-dien-3,17-dione derivatives were synthesized in homogeneous carbonylation reactions from the corresponding 3,17-diiodo-androst-3,5,16-triene, 3-iodo-androst-3,5-diene-17-ethylene ketal, 17-iodo-androst-5,16-dien-3-ethylene ketal, 11-iodo-androst-5,9(11)-diene-3,17-bis(ethylene ketal) derivatives, respectively. A highly chemoselective palladium-catalyzed aminocarbonylation of the corresponding iodo-alkene, carried out under mild reaction conditions, can be considered as the key-step for the introduction of the carboxamide functionalities. The synthesis of the iodo-alkene substrate is based on the transformation of the corresponding keto derivative to hydrazone, which was treated with iodine in the presence of a base (1,1,3,3-tetramethyl guanidine).

[The psychological experience of the mothers whose babies were born deformed in the neonatological ward of the academic hospital center of Treichville (Côte-d'Ivoire)].

Objective: When a baby is born deformed, his birth breaks up plans his family has made for his life as well as for the family itself. So, our objective was to describe the experience undergone by the mothers who gave birth to babies with serious deformities.

Method: A prospective and descriptive study was carried out during 12 months about 35 mothers whose babies were born seriously deformed.

Facile synthesis of 12-carboxamido-11-spirostenes via palladium-catalyzed carbonylation reactions.

12-Carboxamido- and 12-carboxyl-11-spirostenes were synthesized from the corresponding 12-iodo-11-ene derivative in palladium-catalyzed carbonylation reactions under mild reaction conditions. The synthesis of the iodo-alkene substrate is based on the transformation of the 12-keto derivative (hecogenin) to hydrazone, which was treated with iodine in the presence of a base (1,1,3,3-tetramethyl guanidine). While various 12-carboxamides were synthesized in moderate to high yields by using simple alkyl/arylamines or amino acid methylesters as N-nucleophiles, low yields can be achieved with alcohols as O-nucleophiles.

Facile ring opening of 2,3-epoxy-steroids with aromatic amines in ionic liquids.

Efficient ring opening of steroidal 2,3-epoxides with stoichiometric amount of aromatic amines has been carried out using an ionic liquid ([bmim](+)[BF(4)](-)) both as solvent and catalyst. The reactions were completely regio- and stereoselective in each case. The aminoalcohol products have chair conformations in ring A.

A new short-acting non-depolarizing muscle relaxant (SZ1677) without cardiovascular side-effects.

Background: In order to facilitate rapid tracheal intubation, the development of a rapid onset, short duration, non-depolarizing muscle relaxant without cardiovascular side-effects would be a significant accomplishment in the field of anesthesiology. The aim of the present study was to test the action of a new non-depolarizing muscle relaxant (SZ1677) on neuromuscular transmission, muscarinic (M2, M3) receptors and cardiovascular reactions and to compare it with clinically used muscle relaxants.

Methods: Neuromuscular transmission was studied by recording muscle contractions elicited by indirect electrical stimulation, using (i).

Synthesis and structure-activity relationships of neuromuscular blocking agents.

The first use of neuromuscular blocking agents (muscle relaxants) in clinical practice (1942) revolutionised the practice of anaesthesia and started the modern era of surgery. Since 1942 introduction of tubocurarine (18) neuromuscular blocking agents have been used routinely to provide skeletal muscle relaxation during surgical procedures allowing access to body cavities without hindrance from voluntary or reflex muscle movement. After the introduction of tubocurarine and the depolarizing suxamethonium chloride (4) (1949) several nondepolarizing steroidal and nonsteroidal neuromuscular blocking agents with different onset time and duration of effect were introduced e.