The Preparation of azido amino acids and the application of native chemical ligation in the synthesis of chlorotoxin

Karaca, Ulvi Oral
In this project, the pharmaceutically and biologically important peptide, chlorotoxin (CLTX), and some derivatives of CLTX containing azido amino acids was synthesized by using solid phase peptide synthesis (SPPS) based on 9-fluorenylmethyloxycarbonyl (Fmoc) chemistry strategy and native chemical ligation. The native chemical ligation provides more efficient than only SPPS. Directly synthesis of CLTX by SPPS has very low yield, by using native chemical ligation, the yield is aimed much higher. The CLTX can bind to matrix metalloproteinase-2 (MMP-2), which is involved in the breakdown of extracellular matrix in normal physiological processes and inhibit this enzyme. The important role of MMP-2 for spreading cancer cell is known from literature and the inhibition of this enzyme could potentially be used for treatment of cancer in the future. The inhibition mechanism of CLTX on MMP-2 has not been determined yet. There are imaging methods which involves functionalization of CLTX using fluorescence dyes from lysine residue which is not selective. The synthesis of CLTX derivatives containing azido amino acids could provide the selective functionalization of of CLTX using Huisgen ‘Click Chemistry’ together with propargyl dyes. The azido amino acids that are used for CLTX was synthesized by using new method 2-Azido-1,3-dimethylimidazolinium hexafluorophosphate (ADMP) from that own to free amine and hydroxyl group. ADMP can make di-azo transfer to primary amine group and also replacement between azide and hydroxyl group.


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Citation Formats
U. O. Karaca, “The Preparation of azido amino acids and the application of native chemical ligation in the synthesis of chlorotoxin,” M.S. - Master of Science, Middle East Technical University, 2014.