Синтез функціоналізованих 4,5-дигідроізоксазолів, які містять диметилфосфіноїльну групу

Aim. To synthesize a hybrid molecular platform incorporating dimethylphosphinoyl and 4,5-dihydroisoxazole moieties suitable for the creation of focused combinatorial libraries of compounds.Results and discussion. The base-promoted interaction of halogenoxides with dimethyl(vinyl)phosphine oxide under mild conditions allowed us to obtain 11 isoxazoline–dimethylphosphine oxide hybrids in moderate yields. The reaction was found to be regio- though non-stereoselective. Furoxans were identified as possible side products of the reaction.Experimental part. The one-pot interaction with dimethyl(vinyl)phosphine oxide was used for the synthesis of the target compounds. Nitrile oxides were obtained in situ from the corresponding halogenoximes by base-promoted generation. The ADME parameters for a synthesized 5-P(O)Me2-isoxazoline compared to its isosters with the same core structure were predicted using a SwissADME Web Tool. The compounds obtained were characterized by 1H, 13C, 19F, 31P NMR spectroscopy and HPLC-MS spectrometry methods, as well as the elemental analysis.Conclusions. A practical approach to the isoxazoline platform decorated with a 5-P(O)Me2 “magic” group and containing 3-substituent with an easy-to-modify functionality has been developed. On example of the piperidine derivative, the effect of the dimethylphosphinoyl group on physicochemical properties and ADME parameters compared to its isosters has been determined.Мета. Синтезувати гібридну молекулярну платформу, яка містить диметилфосфіноїльну групу та фрагмент 4,5-дигідроізоксазолу і в подальшому може бути використана для створення фокусованих комбінаторних бібліотек сполук.Результати та їх обговорення. Взаємодія галогеноксимів із диметил(вініл)фосфіноксидом у присутності основи у м’яких умовах дозволила одержати із помірними виходами 11 гібридних сполук, які містять фрагменти ізоксазоліну та диметилфосфіноксиду. Виявлено, що реакція є регіо-, хоча й нестереоселективною. Фуроксани було ідентифіковано як можливі побічні продукти реакції.Експериментальна частина. Для синтезу цільових сполук було використано взаємодію нітрилоксидів з диметил(вініл)фосфіноксидом. Нітрилоксиди було одержано in situ з відповідних галогеноксимів дією основи. Для одного з представників цільових 5-P(O)Me2-ізоксазолінів було спрогнозовано ADME-профіль та порівняно одержані значення з аналогічними характеристиками для його ізостерів з базовою структурою ізоксазоліну. Розрахунки було здійснено за допомогою вебресурсу SwissADME. Одержані сполуки схарактеризовано методами 1H, 13C, 19F, 31P ЯМР-спектроскопії та ВЕРХ-мас-спектрометрії, а також елементного аналізу.Висновки. Розроблено практичний підхід до одержання ізоксазолінової платформи, що містить «магічну» 5-P(O)Me2 групу та функціоналізований замісник у положенні 3. На прикладі похідної піперидину окреслено вплив диметилфосфіноїльної групи на фізико-хімічні властивості та ADME параметри порівняно з її ізостерами

Virtual CT-colonoscopy resources in large intestine neoplasia

The research goal is to state possibility of virtual colonoscopy and to determine the localization and nature of neoplasms in the large intestine. Materials and methods: 38 patients have been examined by the method of virtual colonoscopy. The preceding stage of diagnosis by total fibrocolonoscopy has not been a success. Results: Virtual colonoscopy has been performed in 94.7% of patients. The same tumors have been identified in the proximal colon, direct examination of which has not been possible. Conclusion: Virtual colonoscopy is the method of choice for topical diagnosis of tumors of the colo

Reduction of cholesterol and markers of oxidation in serum of hypercholestrolemic patients treated with lycosome formulation of simvastatin

Background: Use of microencapsulated HMG-CoA reductase inhibitors (statins) might be extremely helpful in the prevention of their side effects.Methods: 24 volunteers with hypercholesterolemia were given once daily 20 mg of lycosome-formulated Simvastatin fused with 7 mg lycopene (Lyco-Simvastatin) or the same amount of unmodified Simvastatin with no lycopene. Control patients received 7 mg of lycopene alone. Plasma lipids and oxidative markers were measured after 4 weeks of treatment.Results: Both formulations of Simvastatin, but not lycopene, caused a reduction in serum total cholesterol and LDL at the intermediate (end of 2nd week) and final (end of 4th week) points of interventional period. Notably, reduction of total cholesterol and LDL in the 4th week of the trial was more profound in patients treated with Lyco-Simvastatin versus unmodified Simvastatin (P<0.05). Patients treated with Lyco-Simvastatin showed a reduction in serum Apo B level, which was not observed in other groups. Lycopene treatment caused a modest but statistically significant decrease in serum triglyceride. However, the triglyceride-lowering effect of Simvastatin was more profound in the case of Lyco-Simvastatin treatment. Lycopene as well as unmodified Simvastatin gave a marginal reduction of Inflammatory Oxidative Damage. Remarkably, the combined formulation of Simvastatin and lycopene gave a significant reduction in the values for oxidative damage (reduction of median by 112.5 µM, P<0.05). Similar synergistic effect was observed when levels of oxidized LDL were analyzed.Conclusions: Lycosome-formulated microencapsulated Simvastatin has a better cholesterol-lowering and antioxidant capacity presumably due to enhanced bioavailability of the drug and synergism with lycopene

Evaluation of severity and prognosis of the disease course in ulcerative gastroduodenal bleeding

The systems of evaluation for severity and prognosis of the disease course constitute an important resource for the improvement of treatment parameters in patients with gastroduodenal bleeding. Although in practice more common methods with limited accuracy and high percentage of subjectivity are often used. The work shows the analysis of the situation and possible ways of resolution.</p

The cientificWorldJOURNAL Clinical Study Whey Protein Lycosome Formulation Improves Vascular Functions and Plasma Lipids with Reduction of Markers of Inflammation and Oxidative Stress in Prehypertension

Parameters reflecting cardiovascular health and inflammation were studied in a pilot clinical trial conducted on 40 patients with prehypertension. The patients were treated with a new proprietary formulation of a whey protein (WP) isolate embedded into lycopene micelles (WPL) during a 1-month period. Control groups received lycopene or WP as a singular formulation or placebo pills for the same period of time. Combined WPL formulation of whey protein and lycopene has caused multiple favorable changes in the cardiovascular function (including a tendency to the reduced systemic blood pressure), the plasma lipid profile, and the inflammatory status of patients with prehypertension, whereas singular formulations of the compounds and placebo did not have such an effect. The reduction of plasma triglycerides and cholesterol fractions and almost two-fold decline in C-reactive protein (CRP) and inflammatory oxidative damage (IOD) levels as well as an increase in nitric oxide (NO), tissue oxygenation (StO 2 ), and flow-mediated dilation values constitute the most significant benefit/outcome of the treatment with the combined formulation of whey protein and lycopene. The treatment did not affect the values of ankle-brachial index (ABI), body weight, and body mass index (BMI)

C–H insertion as a key step to spiro-oxetanes, scaffolds for drug discovery

A new route to spiro-oxetanes, potential scaffolds for drug discovery, is described. The route is based on the selective 1,4-C–H insertion reactions of metallocarbenes, generated from simple carbonyl precursors in flow or batch mode, to give spiro-β-lactones that are rapidly converted into spiro-oxetanes. The three-dimensional and lead like-properties of spiro-oxetanes is illustrated by the conversion of the 1-oxa-7-azaspiro[3,5]nonane scaffold into a range of functionalized derivatives

Cycloaddition Strategies for the Synthesis of Diverse Heterocyclic Spirocycles for Fragment-Based Drug Discovery.

In recent years the pharmaceutical industry has benefited from the advances made in fragment-based drug discovery (FBDD) with more than 30 fragment-derived drugs currently marketed or progressing through clinical trials. The success of fragment-based drug discovery is entirely dependent upon the composition of the fragment screening libraries used. Heterocycles are prevalent within marketed drugs due to the role they play in providing binding interactions; consequently, heterocyclic fragments are important components of FBDD libraries. Current screening libraries are dominated by flat, sp2-rich compounds, primarily owing to their synthetic tractability, despite the superior physicochemical properties displayed by more three-dimensional scaffolds. Herein, we report step-efficient routes to a number of biologically relevant, fragment-like heterocyclic spirocycles. The use of both electron-deficient and electron-rich 2-atom donors was explored in complexity-generating [3+2]-cycloadditions to furnish products in 3 steps from commercially available starting materials. The resulting compounds were primed for further fragment elaboration through the inclusion of synthetic handles from the outset of the syntheses