Synthesis of new pyrazolo[1,2,3]triazines by cyclative cleavage of pyrazolyltriazenes

We describe the synthesis of so far synthetically not accessible 3,6-substituted-4,6-dihydro-3H-pyrazolo[3,4-d][1,2,3]triazines as nitrogen-rich heterocycles. The target compounds were obtained in five steps, including an amidation and a cyclative cleavage reaction as key reaction steps. The introduction of two side chains allowed a variation of the pyrazolo[3,4-d][1,2,3]triazine core with commercially available building blocks, enabling the extension of the protocol to gain other derivatives straightforwardly. Attempts to synthesize 3,7-substituted-4,7-dihydro-3H-pyrazolo[3,4-d][1,2,3]triazines, the regioisomers of the successfully gained 3,6-substituted 4,6-dihydro-3H-pyrazolo[3,4-d][1,2,3]triazines, were not successful under similar conditions due to the higher stability of the triazene functionality in the regioisomeric precursors and thus, the failure of the removal of the protective group.

Silylated Sugars – Synthesis and Properties

Silicon has been used in carbohydrate chemistry for half a century, but mostly as a protective group for sugar alcohols. Recently, the use of silicon has expanded to functionalization via C–H activation, conformational arming of glycosyl donors, and conformational alteration of carbohydrates. Silicon has proven useful as more than a protective group and during the last one and a half decades we have demonstrated how it influences both the reactivity of glycosyl donors and stereochemical outcome of glycosylations. Silicon can also be attached directly to the sugar C-backbone, which has even more pronounced effects on the chemistry and properties of the molecules. In this Account, we will give a tour through our work involving silicon and carbohydrates.1 Introduction2 Conformational Arming of Glycosyl Donors with Silyl Groups3 Silyl Protective Groups for Tethering Glycosyl Donors4. Si–C Glycosides via C–H Activation4.1 C–H Activation and Oxidation of Methyl 6-Deoxy-l-glycosides4.2 Synthesis of All Eight 6-Deoxy-l-sugars4.3 Synthesis of All Eight l-Sugars by C–H Activation4.4 Modification of the Oxasilolane Ring5 C–Si in Glycosyl Donors – Activating or Not?6 Si–C-Substituted Pyranosides7 Perspective

Synthesis of new pyrazolo[1,2,3]triazines by cyclative cleavage of pyrazolyltriazenes

We describe the synthesis of so far synthetically not accessible 3,6-substituted-4,6-dihydro-3H-pyrazolo[3,4-d][1,2,3]triazines as nitrogen-rich heterocycles. The target compounds were obtained in five steps, including an amidation and a cyclative cleavage reaction as key reaction steps. The introduction of two side-chains allowed a variation of the pyrazolo[3,4-d][1,2,3]triazine-core with commercially available building blocks, enabling the extension of the protocol to gain other derivatives straightforwardly. Attempts to synthesize 3,7-substituted-4,7-dihydro-3H-pyrazolo[3,4-d][1,2,3]triazines, the regio-isomers of the successfully gained 3,6-substituted-4,6-dihydro-3H-pyrazolo[3,4-d][1,2,3]-3H-triazines, were not successful under similar conditions due to the higher stability of the triazene functionality in the regio-isomeric precursors and thus the failure of the removal of the protective group.

Synthesis of a Glycosylphosphatidylinositol (GPI) fragment as a potential substrate for mannoprotein transglycosidases

A Glycophosphatidylinositol (GPI) tetrasaccharide fragment was synthesized to mimic the core features of premiere model Saccharomyces cerevisiae. The salient feature of this approach is centered on the quick access to different α-1,2 α-1,6-mannosyl and α-1,4-glycosyl linkages using simple glycosylation and protective group techniques. 1D and 2D-J-resolved NMR was used verify the α-configuration for the new linkages. Tetrasaccharides in this work are useful to examine fungal cell wall glycoprotein cross-linking by transglycosidase enzymes for antifungal drug development.

Protective mechanical ventilation with optimal PEEP during RARP improves oxygenation and pulmonary indexes

Background This trial aimed to evaluate the effects of a protective ventilation strategy on oxygenation/pulmonary indexes in patients undergoing robot-assisted radical prostatectomy (RARP) in the steep Trendelenburg position. Methods In phase 1, the most optimal positive end-expiratory pressure (PEEP) was determined in 25 patients at 11 cmH2O. In phase 2, 64 patients were randomized to the traditional ventilation group with tidal volume (VT) of 9 ml/kg of predicted body weight (PBW) and the protective ventilation group with VT of 7 ml/kg of PBW with optimal PEEP and recruitment maneuvers (RMs). The primary endpoint was the intraoperative and postoperative PaO2/FiO2. The secondary endpoints were the PaCO2, SpO2, modified clinical pulmonary infection score (mCPIS), and the rate of complications in the postoperative period. Results Compared with controls, PaO2/FiO2 in the protective group increased after the second RM (P=0.018), and the difference remained until postoperative day 3 (P=0.043). PaCO2 showed transient accumulation in the protective group after the first RM (T2), but this phenomenon disappeared with time. SpO2 in the protective group was significantly higher during the first three postoperative days. Lung compliance was significantly improved after the second RM in the protective group (P=0.025). The mCPIS was lower in the protective group on postoperative day 3 (0.59 (1.09) vs. 1.46 (1.27), P=0.010). Conclusion A protective ventilation strategy with lower VT combined with optimal PEEP and RMs could improve oxygenation and reduce mCPIS in patients undergoing RARP. Trial registration ChiCTR ChiCTR1800015626. Registered on 12 April 2018.

Protective and curative mechanisms of echinochrome against 7, 12-Dimethylbenz[a]anthracene -induced renal toxicity in rats

Echinochrome (Ech) is one of the most important bioactive substance which is found in shells, spines, and eggs of the sea urchins. Aim: the present study was carried out to evaluate the curative and protective effects of Ech pigment against DMBA -induced renal toxicity in rats. Methods: Experimental rats were assigned into two main groups; protective group (treated with Ech for 14 days then administrated DMBA) and curative group (administrated DMBA then treated with Ech for 14 days). Each group is divided into 3 sub-groups; control, DMBA (15 mg/ kg body, weight orally), and Ech (1 mg/ kg body, weight orally). Results: The oral administration of Ech decreased the concentrations of urea, creatinine, uric acid, and MDA and increased GSH and CAT levels in both protective and curative groups. Moreover, histology of kidney tissue improved after the treatment with Ech. Conclusions: The results of the present study demonstrated the potential protective and curative activities of Ech against renal toxicity induced by DMBA through inhibiting the metabolism of DMBA and restoring the balance between ROS formation and internal antioxidant enzymes by its powerful antioxidant activity.

Esterification of 2-(4-(4-Hydroxy-3, 5-Iiodophenoxy)-3, 5-Diiodophenyl) Acetic Acid (Tetrac)

: Tetrac, a deaminated derivative of the thyroid hormome, has received some broad interest for its ability to inhibit the spread of new blood vessels, i.e., angiogenesis. For an optimum activity, the action of the dug shall be limited at the cell surface for interaction with the integrin alpha v beta 3. This was shown to be achieved via a nanoparticle formulation that would be grafted to Tetrac phenol’s OH. While the principle of this study has been disclosed elsewhere, the broad results have never been disclosed entirely. Here all outcomes of the synthesis strategy, e.g. protection and activation steps , confirmed Triisopropylsillyl as a protective group of choice to access the nanopaticle. Catalyst assisted esterification have been probed and discussed . Then a HPLC-MS study allowed to clarify reaction conditions that could subsequently yield to the desired activated Tetrac moiety. The reaction products were all characterized by 1H and 13C-NMR.

PROTECTIVE AND CURATIVE EFFECTS OF FRESH ORANGE JUICE (CITRUS SINENSIS L.) SUPPLEMENTATION AGAINST LIVER INJURIES, HEPATIC LIPID, PROTEIN, AND DNAOXIDATIVE DAMAGE INDUCED CYCLOOXYGENASE-2/PROSTAGLANDIN E2 INFLAMMATORY PATHWAY IN FEMALE IRRADIATED RATS

Objective: Our study aimed to examine the protective and curative ability of fresh orange juice (OJ) (Citrus sinensis L.) to counteract the adverse side effects of ionizing radiation (IR) on hepatic tissues of female irradiated rats and that has not been studied in advance. Methods: Forty-nine adult female Sprague-Dawley albino rats (170±5 g) were divided into four sets of 12 animals, except the healthy control group contained 10 rats only and the irradiated control group contained 15 rats and was divided as follow Group I: Healthy control; Group II: Irradiated control, rats receiving a single dose (20 gray absorbed dose [Gy]) of whole-body γ-rays; Group III: Protective group, rats received (5 ml OJ/kg body weight) once daily for 14 days and after 24 h exposed to irradiation; and Group IV: Curative group, then rats were submitted to irradiation than after 24 h, treated with (5 ml OJ/kg body weight) once every day for 14 successive days. Results: Our results explored that fresh OJ contains significant amounts of antioxidants as flavonoids and polyphenols and consequently pre- or post-fresh OJ supplementation to female irradiated rats attenuated significantly (p≤0.05) hepatic lipid, protein, and DNA-oxidative damage, hepatic inflammation, and activated inflammatory cyclooxygenase-2/prostaglandin E2 pathway, liver fibrosis, impaired liver functions, and hepatic lipid metabolism when compared with irradiated control rats. Furthermore, fresh OJ improved significantly (p≤0.05) the hepatic antioxidant capacity in protective and curative groups in comparison with the irradiated control group. Conclusion: The current research illustrated that fresh OJ may improve and normalize the various hepatic biochemical abnormalities resulted from irradiation due to its high content of active constituents of flavonoids and polyphenols. It is advised for people who exposed to IR, especially females, to consume about (5 ml OJ/kg body weight) before exposure as the most significant improvements were recorded in the protective group that supplemented with OJ before irradiation.

Azidation of Partially Protected Carbohydrate Derivatives: Efficient Suppression of Acyl Migration

Although azidation by nucleophilic substitution is widely used in organic chemistry, it has a limitation for partially protected carbohydrate derivatives under typical reaction conditions used for azidation (heating with NaN3, phase-transfer catalyst (optional), DMF or DMSO) as it can cause substantial migration (70%) of O-acyl protective groups. Several approaches, including the use of a temporary protective group for the unprotected hydroxyl group, to avoid acyl migration have been compared. Addition of excess of ethyl trifluroacetate effectively suppressed benzoyl migration but inhibited substitution of the chlorine atom with the azido group. The most robust procedure involved addition of excess n-butyl formate to the reaction mixture. When this protocol was followed, migration of benzoyl groups in lactose derivatives with free hydroxy group at C-3′ or C-4′ was reduced to 4%, with the yield of the target, partially protected derivatives with an azido group in the aglycone approaching 92%.

Red Blood Cell Polyunsaturated Fatty Acids and Vascular Diseases: A Mendelian Randomization Study

Objectives To evaluate the causal association of omega-3 and omega-6 polyunsaturated fatty acids (PUFAs), as measured in red blood cells (RBC), with cardiovascular disease (CVD), cerebrovascular disease (CBVD), and peripheral vascular disease (PVD). Methods Applying a two-sample Mendelian Randomization approach, we first developed genetic instruments for RBC-PUFAs by utilizing summary statistics from previous genome-wide association study in the Framingham Heart Study. We then evaluated the association of these instrumental variables with CVD, CBVD, PVD, and their subtypes in the UK Biobank cohort. Results Strong evidence of causal association with at least one RBC-PUFAs was observed for the overall risk of PVD and three of its subtypes (aortic aneurysm and dissection, arterial embolism and thrombosis, and other PVDs), but only for two CVD subtypes (hypertensive heart disease, and chronic ischemic heart disease) and for two CBVD subtypes (stroke, and cerebral infarction). Based on their effects on all examined diseases, RBC-PUFAs clustered into two groups: a protective group with alpha-Linolenic acid (ALA), linoleic acid (LA), eicosadienoic acid (EDA), and dihomo-gamma-linolenic acid (DGLA); and the other risk group with docosapentaenoic acid (DPA), gamma-linolenic acid (GLA), arachidonic acid (AA), and adrenic acid (AdrA). PUFAs in the protective group are protective, while those in the risk group are risk-increasing, for all diseases with significant associations except for hypertensive heart diseases. In the metabolic pathway converting short-chain PUFAs into long-chain ones, the protective group is mapped to precursors of desaturases, while the risk group corresponds to their products. Conclusions Genetically regulated RBC-PUFAs are associated with the risk of PVD, and subtypes of PVD, CVD, and CBVD. Funding Sources University of Georgia Research Foundation.