Sulfinamide Crossover Reaction.

This study unveils a new catalytic crossover reaction of sulfinamides. Leveraging mild acid catalysis, the reaction demonstrates a high tolerance to structural variations, yielding equimolar products across diverse sulfinamide substrates. Notably, small sulfinamide libraries can be selectively oxidized to sulfonamides, providing a new platform for ligand optimization and discovery in medicinal chemistry. This crossover chemotype provides a new tool for high-throughput experimentation in discovery chemistry.

Complementary strategies for synthesis of sulfinamides from sulfur-based feedstock.

We describe a straightforward one-pot reductive protocol for the synthesis of sulfinamides from sulfonyl chlorides. This method enables the preparation of sulfinamides with a broad range of functional groups. Furthermore, we have expanded a known oxidative pathway to sulfinamides starting from thiols. These methods together provide a general strategy for the synthesis of sulfinamides from common sulfur-based feedstock that is available with large structural and functional group diversity.

Design, Synthesis, and Evaluation of Probes for Spatially Resolved Imaging of Enantioselective Sulfoxide Reductases.

A novel concept of nonhydrolytic enzyme sensing based on aggregation-induced emission is described. As a proof of principle, fluorogenic probes for methionine sulfoxide reductases have been developed. Changes in the polarity and electronic nature upon reduction of sulfoxide to sulfide are translated to the aggregation potential of the probe. The new probes enable sensitive and highly spatially resolved imaging of the enzymatic activity.

Development of a simple high-throughput assay for directed evolution of enantioselective sulfoxide reductases.

We report on the development of high-throughput fluorogenic assay that can streamline directed evolution of enantioselective sulfoxide reductases. As a model, methionine sulfoxide reductase A (MsrA) has been evolved to expand its limited substrate scope. The resulting mutant MsrA can resolve a range of new challenging racemic sulfoxides with high efficiency including the pharmaceutically relevant albendazole sulfoxide. The simplicity and the level of throughput make this method also suitable for the screening of metagenomic libraries in future for the discovery of new enzymes with similar reactivities.

Enzymatic kinetic resolution of chiral sulfoxides - an enantiocomplementary approach.

A new enzymatic assay for the preparation of chiral sulfoxides that is enantiocomplementary to the known (S)-enantiomer-reducing activity of methionine sulfoxide reductase A (MsrA) is described. To this end, we have utilized the enzyme DMSO reductase (DmsABC), recently discovered by us being highly upregulated in stationary phase E. coli bacteria.

Chemoenzymatic Deracemization of Chiral Sulfoxides.

The highly enantioselective enzyme methionine sulfoxide reductase A was combined with an oxaziridine-type oxidant in a biphasic setup for the deracemization of chiral sulfoxides. Remarkably, high ee values were observed with a wide range of substrates, thus providing a practical route for the synthesis of enantiomerically pure sulfoxides.

Natural orifice transluminal endoscopic surgery vs laparoscopic ovariectomy: complications and inflammatory response.

AIM: To compare natural orifice transluminal endoscopic surgery (NOTES) vs standard laparoscopic ovariectomy in mini pigs with respect to technical aspects, complications and parameters of systemic inflammatory response. METHODS: This was a randomized, experimental, survival study. Ten female mini pigs underwent NOTES transgastric ovariectomy (NOTES group) and ten female mini pigs underwent laparoscopic ovariectomy (LAP group). A "percutaneous endoscopic gastrostomy" approach with guidewire and sphincterotome was used for gastrotomy creation. The ovary was resected using standard biopsy forceps and a snare. The access site was closed using a "KING" closure with a single endoloop and several clips. In the laparoscopic group, a three-port laparoscopy and an ovariectomy were performed with the use of standard laparoscopic devices. C-reactive protein (CRP), white blood count and interleukin (IL)-6 plasma levels were used as indicators of systemic inflammatory response. All animals were euthanized 28 d after surgery. RESULTS: All animals survived without complications. The mean procedure time was 41.3 min ± 17.6 min (NOTES group) and 25.7 min ± 5.25 min (LAP group, P < 0.02). Postmortem examinations demonstrated that 50% and 70% of animals were free of any complications in the NOTES and LAP groups, respectively. The remaining animals developed minor complications (adhesions) in a comparable frequency between the two groups. In the NOTES group, one animal developed a small intramural gastric abscess close to the gastrotomy site. A minor serous exudate that was present in 50% and 40% of the animals in the NOTES and laparoscopy groups, respectively, was not considered a complication. In both groups CRP levels increased significantly on the 2nd and 7th postoperative days (POD) and returned to normal after 28 d. On POD 2, an increase of CRP level was significantly higher in the NOTES group compared to the LAP group. Values of IL-6 did not differ from baseline values in either of the groups postoperatively. Interestingly, the platelet count decreased significantly on POD 2, but returned close to baseline values on POD 7 and PODs 28-30. CONCLUSION: Both NOTES and laparoscopic ovariectomies had a similar frequency of minor complications. However, the NOTES technique produced an increased systemic inflammatory response on POD 2.

Mutation status of K-ras, p53 and allelic losses at 9p and 18q are not prognostic markers in patients with pancreatic cancer.

BACKGROUND: K-ras mutations and allelic losses of tumor suppressors p16 and DPC4 are perceived as potential markers for screening of pancreatic malignancy. In this study, molecular data is compared with survival statistics of the patients and whether they correlate with patients' prognosis is questioned. PATIENTS AND METHODS: Fifty three consecutive patients with advanced pancreatic cancer (stage III and IV) who underwent EUS-guided fine needle aspiration (FNA) were enrolled into the study (28 males, 25 females, 63+/-10.5 years). Samples were evaluated on-site for presence of malignant cells. DNA was extracted from Giemsa stained smears using laser microdissection, and mutation status of K-ras and p53 was tested by cycling-gradient capillary electrophoresis (CGCE). In addition, allelic losses of tumor suppressor genes p16 (INK4, CDKN2A) and DPC4 (MADH4, SMAD4) were detected by monitoring the loss of heterozygosity (LOH) at 9p and 18q loci. Molecular data were compared with survival statistics using Kaplan-Meier method. RESULTS: The median survival in K-ras positive group was 7.0+/-2.4 months (95% CI 2.3-11.7) and in K-ras negative group was 10.0+/-0.6 months (95% CI 8.7-11.3). The median survival in p53 positive group was 10.0+/-2.2 months (95% CI 5.6-14.4) and in p53 negative group was 6.0+/-2.5 months (95% CI 1.1-10.9). The median survival in LOH 9p positive group was 9.0+/-5.1 months (95% CI 0-18.9), in LOH 9p negatives was 10.0+/-5.0 months (95% CI 0.2-19.8). The median survival in LOH 18q positive group was 10.0+/-4.2 months (95% CI 1.8-18.2) and in LOH 18q negative group was 3.0+/-1.3 months (95% CI 0.5-5.5). After the adjustment for age using Cox proportional hazards model, none of the evaluated molecular markers was shown to be an independent prognostic marker for survival of patients with pancreatic cancer. CONCLUSION: None of the studied molecular markers was identified as an independent factor determining survival prognosis.