Novel tricyclic diamines 1. Synthesis of 1,4-diazaisotwistane and 1,4-diazahomoisotwistane as constrained 3-aminoquinuclidine isosteres

Synthesis of the novel tricyclic diamines 1,4-diazaisotwistane and 1,4-diazahomoisotwistane are described. These compact tricyclic cores have one tertiary and one secondary amine and may serve as ring-constrained isosteres of 3-aminoquinuclidine. Both tricycles were prepared by a similar strategy involving saturation of an appropriately substituted aromatic azaindole, functionalization and intramolecular alkylation.     

A whole-cell assay for the high throughput screening of calmodulin antagonists

Cell-based screening systems for pharmaceuticals are desired over molecular biosensing systems because of the information they provide on toxicity and bioavailability. However, the majority of sensing systems developed are molecular biosensing type screening systems and cannot be easily adapted to cell-based screening. In this study, we demonstrate that protein-based molecular sensing systems that employ a fluorescent protein as a signal transducer are amenable to cell-based sensing by expressing the protein molecular sensing system in the cell and employing these cells for screening of desired molecules. To achieve this, we expressed a molecular sensing system based on the fusion protein of calmodulin (CaM) and enhanced green fluorescent protein (EGFP) in bacterial cells, and utilized these cells for the screening of CaM antagonists. In the presence of Ca²⁺, CaM undergoes a conformational change exposing a hydrophobic pocket that interacts with CaM-binding proteins, peptides, and drugs. This conformational change induced in CaM leads to a change in the microenvironment of EGFP, resulting in a change in its fluorescence intensity. The observed change in fluorescence intensity of EGFP can be correlated to the concentration of the analyte present in the sample. Dose-response curves for various tricyclic antidepressants were generated using cells containing CaM-EGFP fusion protein. Additionally, we demonstrate the versatility of our system for studying protein-protein interactions by using cells to study the binding of a peptide to CaM. The study showed that the CaM-EGFP fusion protein within the intact cells responds similarly to that of the isolated fusion protein, hence eliminating the need for any isolation and purification steps. We have demonstrated that this system can be used for the rapid screening of various CaM antagonists that are potential antipsychotic drugs.     

Application of Bar Adsorptive Microextraction for the Determination of Levels of Tricyclic Antidepressants in Urine Samples

This work entailed the development, optimization, validation, and application of a novel analytical approach, using the bar adsorptive microextraction technique (BAμE), for the determination of the six most common tricyclic antidepressants (TCAs; amitriptyline, mianserin, trimipramine, imipramine, mirtazapine and dosulepin) in urine matrices. To achieve this goal, we employed, for the first time, new generation microextraction devices coated with convenient sorbent phases, polymers and novel activated carbons prepared from biomaterial waste, in combination with large-volume-injection gas chromatography-mass spectrometry operating in selected-ion monitoring mode (LVI-GC-MS(SIM)). Preliminary assays on sorbent coatings, showed that the polymeric phases present a much more effective performance, as the tested biosorbents exhibited low efficiency for application in microextraction techniques. By using BAμE coated with C₁₈ polymer, under optimized experimental conditions, the detection limits achieved for the six TCAs ranged from 0.2 to 1.6 μg L⁻¹ and, weighted linear regressions resulted in remarkable linearity (r² > 0.9960) between 10.0 and 1000.0 μg L⁻¹. The developed analytical methodology (BAμE(C18)/LVI-GC-MS(SIM)) provided suitable matrix effects (90.2–112.9%, RSD ≤ 13.9%), high recovery yields (92.3–111.5%, RSD ≤ 12.3%) and a remarkable overall process efficiency (ranging from 84.9% to 124.3%, RSD ≤ 13.9%). The developed and validated methodology was successfully applied for screening the six TCAs in real urine matrices. The proposed analytical methodology proved to be an eco-user-friendly approach to monitor trace levels of TCAs in complex urine matrices and an outstanding analytical alternative in comparison with other microextraction-based techniques.     

一类三圈图的Wiener指数

图G的Wiener指数是指图G中所有顶点对间的距离之和,即W（G）=∑dc（u,u）,{u,u}CG其中de（u,u）表示G中顶点u,u之间的距离.三圈图是指边数与顶点数之差等于2的连通图,任意两个圈至多只有一个公共点的三圈图记为T_n~3.研究了三圈图T_n~3的Wiener指数,给出了其具有最小、次小Wiener指数的图结构.     

Chemie der Pleuromutiline,VII. Basisch induzierte transanulare 1,4-Hydridverschiebung in 8-substituierten Pleuromutilinderivaten

The syntheses of the pleuromutilin derivatives12 and16 are described. Both compounds on treatment with base rearrange to the isomeric ketol13. The results of the deuteration experiment as well as the kinetic measurements are in agreement with the hypothesis of an intramolecular 1,4-hydride shift.

Die 3-Hydroxyverbindung4 ist nicht isolierbar.     

Synthesis of angularly fused cyclopentanoids and analogous tricycles via photoinduced ketyl radical/radical anion fragmentation-cyclization reactions

Angular fused tricycles were synthesized through intramolecular tandem fragmentation-cyclization reactions by photochemically induced electron transfer (PET) of tricyclic α-cyclopropyl ketones with an unsaturated side chain at the position γ to the carbonyl group. The reactions resulted in regioselective cleavage of a β-cyclopropyl bond with formation of angular fused tricyclic ring systems via ketyl radical/radical anions as reactive intermediates. In general, triethylamine (TEA) was used as a strong reducing reagent in acetonitrile. The preferred regioselectivity of the cyclization step (exo vs endo) depending on the substitution pattern at the quaternary carbon center (Cβ′) of the tricyclic α-cyclopropyl ketones was investigated. In addition, we also checked a two-step pathway for the synthesis of angular dioxa-triquinanes including photolysis of an allyloxy-substituted cyclopenta[c]furanone derivative and subsequent β-cleavage of the resulted dioxa-[4.5.5.5]fenestrane under reductive PET conditions.     

Use of a highly effective intramolecular Pauson-Khand cyclisation for the formal total synthesis of (±)-α- and β-cedrene by preparation of cedrone

The cedrene carbon skeleton was directly and efficiently assembled from a simple monocyclic precursor by the strategic use of a high yielding intramolecular Pauson-Khand cyclisation reaction. A small number of further synthetic manipulations provided a concise formal total synthesis of α- and β-cedrene. The cyclisation precursor was readily prepared, with a stereoselective ketone alkenylation selectively providing the olefin required for efficient access to the natural target.     

A [2+2+2]-cyclotrimerization approach for the synthesis of enantiopure isochromans using a carbohydrate derived dialkyne template

An easy access to enantiopure isochromans through cross alkyne trimerization of a glucose derived dialkyne was developed. One of the synthesized isochromans was converted into a novel tricyclic nucleoside by simple transformations.     

An efficient synthesis of fused tricycles with a benzene core via intramolecular double ring-closing enyne metathesis

A double enyne metathesis reaction has been developed for the efficient synthesis of tricyclic products with a benzene core in good yields. By this protocol, bisannulated benzenes with different ring sizes may be simultaneously constructed from the corresponding precursors in just ‘one shot’.