4-Bromophenylhydrazinyl benzenesulfonylphenylureas as indoleamine 2,3-dioxygenase inhibitors with in vivo target inhibition and anti-tumor efficacy.

Indoleamine 2,3-dioxygenase is a heme-containing enzyme implicated in the down regulation of the anti-tumor immune response, and considered a promising anti-cancer drug target. Several pharmaceutical companies, including Pfizer, Merck, and Bristol-Myers Squibb, are known to be in pursuit of IDO inhibitors, and Incyte recently reported good results in the phase II clinical trial of the IDO inhibitor Epacadostat. In previous work, we developed a series of IDO inhibitors based on a sulfonylhydrazide core structure, and explored how they could serve as potent IDO inhibitors with good drug profiles. Herein, we disclose the development of the 4-bromophenylhydrazinyl benzenesulfonylphenylurea 5k, a potent IDO inhibitor which demonstrated 25% tumor growth inhibition in a murine CT26 syngeneic model on day 18 with 100 mg/kg oral administration twice daily, and a 30% reduction in tumor weight. Pharmacodynamic testing of 5k found it to cause a 25% and 21% reduction in kyn/trp ratio at the plasma and tumor, respectively. In the CT26 tumor model, 5k was found to slightly increase the percentage of CD3+ T cells and lymphocyte responsiveness, indicating that 5k may have potential in modulating anti-tumor immunity. These data suggest 5k to be worthy of further investigation in the development of anti-tumor drugs.

The geochemical and environmental characteristics of trace metals in surface sediments of the river estuarine mouths around the Taiwan Island and the Taiwan Strait.

The trace metals species in surface sediments of the Taiwanese river estuarine mouths and the Taiwan Strait were examined by sequential extraction method. Based on the metal species present in sediments, trace metals can be divided into three groups: (1) Co, Cr, Fe, Ni and Zn; (2) Cu and Hg; and (3) Mn and Pb. The total concentrations of trace metals in the first two groups are dominated by the residual fraction. While, Cu and Hg their organic species also contributes a significant percentage and reduces the residual fraction portion. Lead and Mn are dominated by the labile fraction. The total metal concentrations in the analyzed sediments seem to be influenced by Fe oxides, TOC and grain size. The metals contamination status assessed by three environmental indices suggests that the analyzed sediments are minor contaminated by trace metals, with a few exceptions of Cu and Hg at some stations.