Lithiation of 4-membered heterocycles as useful strategy for the preparation of new molecular scaffolds: addressing the regioselectivity in azetidines and thietanes

Four-membered heterocycles (4-MH) with one or two heteroatoms are of great importance in medicinal chemistry and synthetic organic chemistry. This kind of scaffolds show peculiar structural features, related to the ring “puckering”, and biological properties. Our recent research efforts have been focused on the stereoselective synthesis and functionalization of some 4-MH such as azetidines, thietanes and oxazetidines

Wavelet Analysis of Blood Pressure Waves in Vasovagal Syncope

We describe the multiresolution wavelet analysis of blood pressure waves in vasovagal syncope affected patients compared with healthy people one. We argue that there exist subtle discriminating criteria which allow us to isolate particular features, common to the syncope-affected patients sample, indicating an alternative diagnosis method for this syndrome. The approach is similar to that followed by Thurner et al. but on a different temporal data series

Response of Autonomic Nervous System to Body Positions: Fourier and Wavelet Analysis

Two mathematical methods, the Fourier and wavelet transforms, were used to study the short term cardiovascular control system. Time series, picked from electrocardiogram and arterial blood pressure lasting 6 minutes, were analyzed in supine position (SUP), during the first (HD1), and the second parts (HD2) of $90^{\circ}$ head down tilt and during recovery (REC). The wavelet transform was performed using the Haar function of period $T=2^j$ ($$,2,$...$,6) to obtain wavelet coefficients. Power spectra components were analyzed within three bands, VLF (0.003-0.04), LF (0.04-0.15) and HF (0.15-0.4) with the frequency unit cycle/interval. Wavelet transform demonstrated a higher discrimination among all analyzed periods than the Fourier transform. For the Fourier analysis, the LF of R-R intervals and VLF of systolic blood pressure show more evident difference for different body positions. For the wavelet analysis, the systolic blood pressures show much more evident difference than the R-R intervals. This study suggests a difference in the response of the vessels and the heart to different body positions. The partial dissociation between VLF and LF results is a physiologically relevant finding of this work.Comment: RevTex,8 figure

Transfer of electrophilic NH using convenient sources of ammonia: direct synthesis of N–H sulfoximines from sulfoxides

The transfer of nitrogen atoms is extremely valuable in the preparation of medicinal compounds. Here, a new system for NH transfer is developed to prepare sulfoximines, which are emerging as valuable motifs for drug discovery. This is achieved using readily available sources of nitrogen without the requirement for pre-activation or for metal catalysts in an operationally simple protocol. Mixing ammonium salts with diacetoxyiodobenzene in a choice of solvents directly converts sulfoxides to sulfoximines. The protocol is tolerant of many other functional groups and heterocycles that are important in drug compounds. This is the first example of the use of ammonia sources with diacetoxyiodobenzene providing a source of electrophilic nitrogen. Control and mechanistic studies suggest a short-lived electrophilic intermediate, likely to be PhINH or PhIN+

Synthesis of NH-sulfoximines from sulfides by chemoselective one-pot N- and O-transfers

Direct synthesis of NH-sulfoximines from sulfides has been achieved through O and NH transfer in the same reaction, occurring with complete selectivity. The reaction is mediated by bisacetoxyiodobenzene under simple conditions and employs inexpensive N-sources. Preliminary studies indicate that NH-transfer is likely to be first, followed by oxidation, but the reaction proceeds successfully in either order. A wide range of functional groups and biologically relevant compounds are tolerated. The use of AcO15NH4 affords 15N-labeled compounds

Imaging of Inflammation in Spinal Cord Injury: Novel Insights on the Usage of PFC-Based Contrast Agents

Labeling of macrophages with perfluorocarbon (PFC)-based compounds allows the visualization of inflammatory processes by 19F-magnetic resonance imaging (19F-MRI), due to the absence of endogenous background. Even if PFC-labeling of monocytes/macrophages has been largely investigated and used, information is lacking about the impact of these agents over the polarization towards one of their cell subsets and on the best way to image them. In the present work, a PFC-based nanoemulsion was developed to monitor the course of inflammation in a model of spinal cord injury (SCI), a pathology in which the understanding of immunological events is of utmost importance to select the optimal therapeutic strategies. The effects of PFC over macrophage polarization were studied in vitro, on cultured macrophages, and in vivo, in a mouse SCI model, by testing and comparing various cell tracking protocols, including single and multiple administrations, the use of MRI or Point Resolved Spectroscopy (PRESS), and application of pre-saturation of Kupffer cells. The blood half-life of nanoemulsion was also investigated by 19F Magnetic Resonance Spectroscopy (MRS). In vitro and in vivo results indicate the occurrence of a switch towards the M2 (anti-inflammatory) phenotype, suggesting a possible theranostic function of these nanoparticles. The comparative work presented here allows the reader to select the most appropriate protocol according to the research objectives (quantitative data acquisition, visual monitoring of macrophage recruitment, theranostic purpose, rapid MRI acquisition, etc.). Finally, the method developed here to determine the blood half-life of the PFC nanoemulsion can be extended to other fluorinated compounds

Sigmatropic Rearrangement of Vinyl Aziridines: Expedient Synthesis of Cyclic Sulfoximines from Chiral Sulfinimines

A novel rearrangement of 2-vinyl aziridine 2-carboxylates to unusual chiral cyclic sulfoximines is described herein. The method allows the synthesis of substituted cyclic sulfoximines in high yields with complete stereocontrol, displaying a wide substrate scope under mild conditions. Further development of a one-pot process directly from sulfinimines shows the synthetic applicability of this protocol, providing access to complex chiral sulfoximines in only two steps from commercially available aldehydes. A mechanistic hypothesis and synthetic application in the formal synthesis of trachelanthamidine by transformation of a cyclic sulfoximine into a pyrroline is also disclosed

Exploration of novel chemical space: synthesis and in vitro evaluation of N-functionalized tertiary sulfonimidamides

An unprecedented set of structurally diverse sulfonimidamides (47 compounds) has been prepared by various N‐functionalization reactions of tertiary =NH sulfonimidamide 2 aa. These N‐functionalization reactions of model compound 2 aa include arylation, alkylation, trifluoromethylation, cyanation, sulfonylation, alkoxycarbonylation (carbamate formation) and aminocarbonylation (urea formation). Small molecule X‐ray analyses of selected N‐functionalized products are reported. To gain further insight into the properties of sulfonimidamides relevant to medicinal chemistry, a variety of structurally diverse reaction products were tested in selected in vitro assays. The described N‐functionalization reactions provide a short and efficient approach to structurally diverse sulfonimidamides which have been the subject of recent, growing interest in the life sciences

Synthesis of Sulfoximine Carbamates by Rhodium-Catalyzed Nitrene Transfer of Carbamates to Sulfoxides

Sulfoximines are of considerable interest for incorporation into medicinal compounds. A convenient synthesis of <i>N</i>-protected sulfoximines is achieved, under mild conditions, by rhodium-catalyzed transfer of carbamates to sulfoxides. The first examples of 4-membered thietane-oximines are prepared. Sulfoximines bearing Boc and Cbz groups are stable to further cross coupling reactions, and readily deprotected. This method may facilitate the preparation of <i>NH</i>-sulfoximines providing improved (global) deprotection strategies, which is illustrated in the synthesis of methionine sulfoxide (MSO)