No abstract

Induction of a series of anti-hypoxic proteins protects cells during exposure to hypoxic conditions. Hypoxia-inducible factor-α (HIF-α) is a major transcription factor that orchestrates this protective effect. To activate HIF exogenously, without exposing cells to hypoxic conditions, many small-molecule inhibitors targeting prolyl hydroxylase domain-containing protein have been developed. In addition, suppression of factor inhibiting HIF-1 (FIH-1) has also been shown to have the potential to activate HIF-α. However, few small-molecule inhibitors of FIH-1 have been developed. In this study, we synthesized a series of furan- and thiophene-2-carbonyl amino acid derivatives having the potential to inhibit FIH-1. The inhibitory activities of these compounds were evaluated in SK-N-BE(2)c cells by measuring HIF response element (HRE) promoter activity. Several furan- and thiophene-2-carbonyl amino acid derivatives inhibited FIH-1 based on correlations among the docking score of the FIH-1 active site, the chemical structure of the compounds, and biological HIF-α/HRE transcriptional activity.

Phthalide is an important scaffold found in several biologically active compounds. Therefore, effective methods for the synthesis of phthalides are strongly desired. Herein, we describe the metal‐free synthesis of 3‐substituted phthalides by the reductive hydroiodination of 2‐alkynylbenzoates through an I2/PPh3/H2O‐triggered cascade reaction. A variety of 3‐substituted phthalides were synthesized in excellent yields by a one‐pot reaction involving four processes: desilylation, hydroiodination, cyclization, and reduction.

The Front Cover shows a cascade reaction under metal‐free conditions. The reaction depicts a waterfall (cascade) and a place that is not usually associated with a metal (forest). Easily available reagents, i.e., triphenylphosphine, iodine, and water, trigger the cascade reaction, which includes desilylation, hydroiodination, cyclization, and reduction to give phthalides from 2‐(trimethylsilylalkynyl)benzoates. We acknowledge Tamami Yamaguchi for taking the picture of a waterfall at Plitvice Lakes National Park. More information can be found in the https://doi.org/10.1002/ejoc.201700839

Depending on the substituents of asymmetric alkynes, the hydroiodination may proceed regio‐ or non‐regioselectively while forming either the (E)‐ or the (Z)‐isomer of the product or a mixture of the latter.