%0 Journal Article
%T Large Scale Solid Phase Synthesis of Peptide Drugs: Use of Commercial Anion Exchange Resin as Quenching Agent for Removal of Iodine during Disulphide Bond Formation
%A K. M. Bhaskara Reddy
%A Y. Bharathi Kumari
%A Dokka Mallikharjunasarma
%A Kamana Bulliraju
%A Vanjivaka Sreelatha
%A Kuppanna Ananda
%J International Journal of Peptides
%D 2012
%I Hindawi Publishing Corporation
%R 10.1155/2012/323907
%X The S-acetamidomethyl (Acm) or trityl (Trt) protecting groups are widely used in the chemical synthesis of peptides that contain one or more disulfide bonds. Treatment of peptides containing S-Acm protecting group with iodine results in simultaneous removal of the sulfhydryl protecting group and disulfide formation. However, the excess iodine needs to be quenched or adsorbed as quickly as possible after completion of the disulfide bond formation in order to minimize side reactions that are often associated with the iodination step. We report here a simple method for simultaneous quenching and removal of iodine and isolation of disulphide bridge peptides. The use of excess inexpensive anion exchange resin to the oxidized peptide from the aqueous acetic acid/methanol solution affords quantitative removal of iodine and other color impurities. This improves the resin life time of expensive chromatography media that is used in preparative HPLC column during the purification of peptide using preparative HPLC. Further, it is very useful for the conversion of TFA salt to acetate in situ. It was successfully applied commercially, to the large scale synthesis of various peptides including Desmopressin, Oxytocin, and Octreotide. This new approach offers significant advantages such as more simple utility, minimal side reactions, large scale synthesis of peptide drugs, and greater cost effectiveness. 1. Introduction Many naturally occurring peptides contain intradisulphide bridges, which play an important role in biological activities. Disulfide bond-containing peptides have long presented a particular challenge for their chemical synthesis [1]. There are many ways to form a disulphide bridge in solution, and solid phase synthesis is well known and widely used in peptide community. Solution phase cyclization is most commonly carried out using air oxidation and or mild basic conditions [2]. The cyclization of free thiols by air oxygen usually leads to low yields of target peptides (10¨C15%) [3]. The application of potassium ferricyanide [4] or dimethyl sulphoxide [5] usually results in homogeneous reaction mixtures, and yields of cyclic peptides are considerably higher. However, a multistage purification of peptide is necessary for the removal of excess of these oxidative reagents [6]. Beginning with the initial discovery by Kamber et al. [7] that in peptides, where thiols are protected by Acm groups, iodine offered the potential to carry out removal and simultaneous oxidative disulphide bond formation in one-single step, several disulphide-bonded peptides have been
%U http://www.hindawi.com/journals/ijpep/2012/323907/