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Synthesis of Novel Potential Proteasome Inhibitors Based on Tripeptide Backbone
Published: 31 October 2013 by MDPI in The 17th International Electronic Conference on Synthetic Organic Chemistry session Bioorganic, Medicinal and Natural Products
Abstract: O-Benzyl-5-chlorsalicyl-tripeptide aldehydes are novel organic compounds aimed for inhibition of the proteasome. The inhibition of proteasome via blocking his protein recycling function is one of promising ways to treat tumor cells or multiple myeloma. In the present days a series of similar compounds are clinically used or in clinical trials (MG132, marizomib, CEP-18770, MLN-9708, ONX-0912) and some of them are already approved and available for the public (carfilzomib, bortezomib). Synthesis starts with O-benzyl-5-chlorsalicylic acid and methylesters of aminoacid hydrochlorides. The amidic bond is formed via carbodiimides (especialy EDCI∙HCl) in presence of 1‑hydroxybenzotriazole (HOBt) and N,N-diisopropylethylamine (DIPEA) to liberate the amino group. During the synthesis of the peptide backbone after joining the second amino acid a partial racemization occured. Steps have been taken to prevent this undesirable event. By adjusting the reaction conditions 92% ee was achieved. Further details will be discused in the Communication paper. The goal of my work is to prepare a series of compounds with tripeptide backbone and aldehyde or oxirane moiety and test cytotoxicity, inhibition of proteasome, inhibition of protein kinases, type of caused apoptosis and antimicrobial activity.
Keywords: proteasome, inhibitors, tripeptide, bortezomib, carflizomib, MG132, CEP-18770, carbodiimides