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In order to minimize the volume of resin to be used for disulfide bond formation, wedecided to increase the number of methionine oxide motifs on the resin. To this aim, asalternative to the stepwise synthesis of Oxyfold, we explored another strategy of synthesisbased on the on-support oligomerization of methionine N-carboxy anhydride (NCA)followed by oxidation (Figure 2). This method allows the preparation of resins with anumber of Met[O] between 3 and 18 and it opens the way of large scale economicpreparation of supported reactant to promote disulfide bond in peptides.Further oxidation experiments have demonstrated that using the same number of eq ofMet[O] we obtain comparable result with different poly Met oxide chain length (n=1,3,5and 7). Moreover, we have proved that Oxyfold prepared by Met NCA is as effective asOxyfold with the same number of Met (n=7) prepared by stepwise solid phase synthesis.Overall, all the described characteristics make the use of Oxyfold a fast, cheap, effective,facile and green procedure for disulfide bridge formation.H 2 NOOHH 2 NOOONHanh. THF, 18hBTC, anh.THFS2h, 65°C under refluxH HNSONHSnAc 2 O/DCM, 30minOHNONHH 2 O 2 35%, 3hOHNONHSOnSnFig. 2. Oxyfold synthesis: oligomerization of Met NCA on solid support.AcknowledgmentsThe authors acknowledge financial support from “La Région Languedoc Roussillon” and “FEDER”.References1. Tam, J.P., Wu, C.-R., Liu,W., Zhang, J.-W. J. Am. Chem. Soc. 113, 6657-6662 (1991).2. Shi, R., Wang, F., Yan, B. Int. J. Pept. Res. Ther. 13, 213-219 (2006).3. Nicholls, R., Kaminski, S., Walling, E., Zornik, E. Peptides 20, 1153-1158 (1999).183