Synthetic Progress Towards a TMC-95 Analogue as a Potential Proteasome Inhibitor

Abstract

Recently, four novel compounds, TMC 95A-D 1 (R₁, R₂ = H or OH; R₃, R₄ = H, OH or CH₃), have been isolated from the fermentation broth of Apiospora montagnei Sacc. TC 1093 [1,2], and shown to inhibit the 20S proteasome (IC₅₀ = 5.4–60 nM), an eukaryotic threonine protease responsible for the degradation of most cell proteins [3]. Increased levels of this enzyme and subsequent protein breakdown have been related to different diseases such as malaria, inflammation and cancer. Thus, inhibition of the proteasome is currently becoming a promising therapeutic target. In this work, we describe the synthetic approaches towards the synthesis of a novel indole analog 2 of the core of 1 to evaluate its possible activity as a proteasome inhibitor (Figure 1).