3,5-Dioxopimelates as new synthetic building blocks. Cyclocondensation with 1,2-, 1,3- and 1,4-dinucleophiles

Cyclocondensation reactions of 3,5-dioxopimelates, new and versatile synthetic building blocks, with hydrazines, urea, thiourea and phenylene-1,2-diamines allow for a convenient synthesis of various heterocycles containing two ester-substituted side-chains.     

A concise synthesis of (-)-centrolobine via a diastereoselective ring rearrangement metathesis-isomerisation sequence

A total synthesis of (-)-centrolobine (1) based on a diastereoselective ring rearrangement metathesis-double bond isomerisation sequence and a one-pot cross metathesis-hydrogenation procedure is described.     

Average case complexity results for a centering algorithm for linear programming problems under Gaussian distributions

To solve linear programming problems by interior point methods an approximately centered interior point has to be known. Such a point can be found by an algorithmic approach – a so-called phase 1 algorithm or centering algorithm. For random linear programming problems distributed according to the rotation symmetry model, especially with normal distribution, we present probabilistic results on the quality of the origin as starting point and the average number of steps of a centering algorithm.     

Synthesis,Biological Evaluation,and Docking Studies of Antagonistic Hydroxylated Arecaidine Esters Targeting mAChRs

The muscarinic acetylcholine receptor family is a highly sought-after target in drug and molecular imaging discovery efforts aimed at neurological disorders. Hampered by the structural similarity of the five subtypes’ orthosteric binding pockets, these efforts largely failed to deliver subtype-selective ligands. Building on our recent successes with arecaidine-derived ligands targeting M₁, herein we report the synthesis of a related series of 11 hydroxylated arecaidine esters. Their physicochemical property profiles, expressed in terms of their computationally calculated CNS MPO scores and HPLC-logD values, point towards blood–brain barrier permeability. By means of a competitive radioligand binding assay, the binding affinity values towards each of the individual human mAChR subtypes hM₁–hM₅ were determined. The most promising compound of this series 17b was shown to have a binding constant towards hM₁ in the single-digit nanomolar region (5.5 nM). Similar to our previously reported arecaidine-derived esters, the entire series was shown to act as hM1R antagonists in a calcium flux assay. Overall, this study greatly expanded our understanding of this recurring scaffolds’ structure–activity relationship and will guide the development towards highly selective mAChRs ligands.     

Effects of Extracts and Flavonoids from Drosera rotundifolia L. on Ciliary Beat Frequency and Murine Airway Smooth Muscle

Extracts from Drosera rotundifolia are traditionally used to treat cough symptoms during a common cold. The present study aimed to investigate the impact of extracts from D. rotundifolia and active compounds on the respiratory tract. Tracheal slices of C57BL/6N mice were used ex vivo to examine effects on airway smooth muscle (ASM) and ciliary beat frequency (CBF). Phosphodiesterase (PDE) inhibition assays were carried out to test whether PDE1 or PDE4 are targeted by the active compounds. An ethanol–water extract, as well as an aqueous fraction of this extract, exerted antispasmodic properties against acetylcholine-induced contractions. In addition, contractions induced by 60 mM K⁺ were abrogated by the aqueous fraction. Effects on ASM could be attributed to the flavonoids quercetin, 2″-O-galloylhyperoside and hyperoside. Moreover, the Drosera extract and the aqueous fraction increased the CBF of murine tracheal slices. Quercetin and 2″-O-galloylhyperoside were identified as active compounds involved in the elevation of CBF. Both compounds inhibited PDE1A and PDE4D. The elevation of CBF was mimicked by the subtype-selective PDE inhibitor rolipram (PDE4) and by 8-methoxymethyl-IBMX. In summary, our study shows, for the first time, that a Drosera extract and its flavonoid compounds increase the CBF of murine airways while antispasmodic effects were transferred to ASM.     

Thermolysis,photolysis, and oxidation of an overcrowded 1,3,2-dithiastannetane derivative

Reactions of a sterically crowded 1,3,2-dithiastannetane derivative bearing 2,4,6-tris[bis(trimethylsilyl)methyl]phenyl (=Tbt) and 2,4,6-triisopropylphenyl (=Tip) groups on the tin atom are described. Both thermolysis and photolysis of the 1,3,2-dithiastannetane [Tbt(Tip)SnS₂CPh₂] resulted in the formation of products derived from the corresponding stannanethione [Tbt(Tip)Sn=S], while the oxidation reaction by m -chloroperbenzoic acid gave a novel tincontaining heterocyclic system, an 1,2,4,5-oxadithiastannolane derivative.