iRGD (CRGDKGPDC) peptide has been commonly used as a tumor targeting vehicle that helps in tumor penetration and cargoes delivery inside the tumor tissue. iRGD peptide contains disulfide bridge between two cysteines. Additional cysteine can be introduced for conjugation with cargos. The synthesis of this cyclic peptide containing an additional cysteine residue for drug conjugation has been challenging. Herein we report a simple and efficient methodology for the synthesis of iRGD analog using Fmoc/tBu solid-phase chemistry. The protected peptide was assembled on the Rink amide resin with three different cysteine analogs namely, Fmoc-Cys(Mmt)-OH, Fmoc-Cys(StBu)-OH, and Fmoc-Cys(Trt)-OH. The removal of StBu group in peptidyl resin followed by mercapto activation in the presence of 5,5'-dithiobis-(2-nitrobenzoic acid) afforded the peptide containing the activated cysteine. The peptide was cyclized in situ by agitating the resin with 1% TFA to form a disulfide bond. The final peptide was cleaved with cleavage cocktail; trifluoroacetic acid/triisopropylsilane/water (92.5:5:2.5, v/v/v) to afford iRGD peptide in 60% yield. 

Efficient solid-phase synthesis of iRGD analog containing a cysteine anchor as tumor homing peptide

248th National Meeting (2014)

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