Synthetic Progress Towards a TMC-95 Analogue as a Potential Proteasome Inhibitor
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 . 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).
KeywordsFermentation Malaria Indole Threonine Biaryl
- 2. (a)
- 3. (a)
- 3. (c)
- 4. (a)
- 4. (b)Elder, A.M., Rich, D.H. Org. Lett. 2001, submitted.Google Scholar