LiBr-Catalyzed C3-Disulfuration between Indole and N-Dithiophthalimide.

A simple, green halide-catalyzed protocol for disulfuration of indole derivatives with N-dithiophthalimides has been developed. This C-H disulfide reaction proceeded smoothly at room temperature with economical LiBr as catalyst, providing an effective method for the synthesis of novel unsymmetrical disulfides. A series of 3-dithioindole derivatives were obtained in high yields with good functional group tolerance; moreover, the wide scope of Harpp reagents (aryl, benzyl, primary, secondary, tertiary) confirmed the practicability of this approach.

6-Glycosylaminoquinoline-assisted LDI MS for detection and imaging of small molecules with enhanced detection selectivity and sensitivity.

Matrix-assisted laser desorption/ionization (MALDI) mass spectrometry (MS) is a powerful tool in the analysis and imaging of small molecules. However, MALDI MS analysis is easily subjected to poor signal reproducibility and selectivity, especially for complex samples. In this study, a matrix glycosylation strategy was proposed to synthesize glycosylated matrices with excellent performances by enhancing the interaction of the matrix with small molecules. A series of glycosylated matrices including 3-glycosylaminoquinoline (3-GAQ), 6-glycosylaminoquinoline (6-GAQ), and 1-amino-5-glycosylaminoquinoline (GDAN) were synthesized by connecting glucose with the existing amine matrices. Compared with their parent matrices and the existing matrix (1,5-diaminonaphathelene, 1,5-DAN), the glycosylated matrices exhibited remarkably-improved sensitivity, higher signal reproducibility (RSD < 9%) in detecting metabolites, demonstrating the effectiveness of the glycosylation strategy. Among them, 6-GAQ exhibited the best performance. Using 6-GAQ, the detection limit of citric acid reached the low fmol range, and the calibration curve of citric acid had ideal linearity (R2 > 0.99), proving that 6-GAQ was capable of accurate quantitative analysis of metabolites. Furthermore, 6-GAQ was used for the imaging of metabolites in the mouse kidney section, showing higher sensitivity and lower background noise than the commonly-used matrices, 9-aminoquinoline (9-AA), and 1,5-DAN. More importantly, 6-GAQ can selectively detect the hydrophilic metabolites, especially the hydrophilic lipids in the mouse kidney. Overall, 6-GAQ is an ideal matrix potentially applied in the imaging and quantitative analysis of hydrophilic small molecules in complex samples.

In situ localization of tris(2,3-dibromopropyl) isocyanurate in mouse organs by MALDI-IMS with auxiliary matrix strategy.

Tris(2,3-dibromopropyl) isocyanurate (TBC) is one of the novel brominated flame retardants that has been widely used in consumer goods. Humans may be exposed to TBC daily. Studies showed that TBC can induce significant toxicity. However, there is currently no report on its in situ localization in organs. In this study, we aimed to develop a reliable and reproductive method to determine the in situ localization of TBC in mouse organs by matrix-assisted laser desorption/ionization imaging mass spectrometry (MALDI-IMS). As commercially available matrices were not able to detect TBC in tissue section, we then developed a novel MALDI-IMS method based on 1,5-diaminonaphthalene hydrochloride and silver trifluoromethanesulfonate (NDA/AgOTf) as the matrix for the in situ localization of TBC. AgOTf used as the auxiliary matrix in the negative-ion mode showed an excellent MS signal of TBC. The detection limit of [2AgOTf + Br]- was at the µg/mL level. The developed MALDI-IMS method was successfully employed to obtain the TBC spatial distribution in the mouse organs collected from mice exposed to 160 mg/kg/day of TBC for 30 days. High-pressure liquid chromatography-tandem mass spectroscopy (HPLC-MS/MS) was also used to evaluate the accumulation of TBC in liver, kidney, heart, and brain. The combination of MALDI-IMS and HPLC-MS/MS showed that TBC can accumulate in mice organs and it is mainly distributed in the renal parenchyma. In summary, an innovative method was developed for the analysis of TBC spatial distribution by MALDI-IMS using a novel NDA/AgOTf matrix, extending the application of MALDI-IMS in environmental pollutants.

Discovery of novel 2-aryl-3-sulfonamido-pyridines (HoAns) as microtubule polymerization inhibitors with potent antitumor activities.

Microtubules play a vital role in cell mitosis. Drugs targeting taxol or vinca binding site of tubulin have been proved an effective way to against cancer. However, drug resistance and cancer recurrence are inevitable, there is an urgent need to search for new microtubule-targeting agents (MTAs). In our study, a series of novel 2-aryl-3-sulfonamido-pyridines (HoAns) had been designed, synthesized, and evaluated for their antiproliferative activities in vitro and in vivo. Among them, compound HoAn32 exhibited the most potent activity with IC50 values ranging from 0.170 to 1.193 µM in a panel of cancer cell lines. Mechanism studies indicated that compound HoAn32 bound to the colchicine site of ß-tubulin, resulting in colony formation inhibition, G2/M phase cell cycle arrest, cell apoptosis as well as increased the generation of ROS in both RKO and SW620 cells. In addition, compound HoAn32 showed potent anti-vascular activity in vitro. Furthermore, compound HoAn32 also exhibited outstanding antitumor activity in SW620 xenograft tumor models without observable toxic effects, which was more potent than that of ABT-751. In conclusion, our findings suggest that compound HoAn32 may be a promising microtubule destabilizing agent and deserves for further development in cancer therapy.

Copper/Palladium Bimetallic System for the Synthesis of Isobenzofuranones through [4 + 1] Annulation between Propiophenones and Benzoic Acids.

A copper/palladium-catalyzed annulation from benzoic acids and propiophenones for the synthesis of isobenzofuranones was reported. The Cu-(2,2,6,6-tetramethylpiperidin-1-yl)oxyl system showed a great ability to activate the C-H bond on the α- and ß-carbons of a carbonyl group, and the in situ-generated enone intermediate in this reaction could be further transformed to construct isobenzofuranones with the catalysis of Pd(dba)2 (dba = dibenzylideneacetone). Various isobenzofuranones could be obtained in moderate to good yields, and a great atom economy was highlighted by utilizing this method.