Metal-ion-assisted synthesis of cyclic homopeptides

In the recent years cyclic peptides have attracted attention since they find applications in many fields from drug discovery to nanomaterials. These compounds have been difficult to prepare due to the fact that the activated peptide must adopt an entropically disfavoured conformation before forming the desired product[1]. The most important factor for successful peptide macrocyclization is ring size. Peptides that contain less than seven aminoacids are troublesome to cyclize[2]. In this work we will describe synthesis of small homocyclopeptides containig 4-6aminoacids. Cyclic peptides are also known as versatile ion-binders[3] but their binding affinities are often reduced by the inadequate orientation of amide functional group. To overcome these problems, cyclopeptides will be conjugated to a molecules with rigid geometry, such as calixarenes. Homocyclolysine and homocycloserine will be bind, , to calixarenes exploiting functional groups via amide bond on peptide's side chain. Influence of lenght of side chains on affinities of this conjugates towards different anions will be investigated. Linear precursors were sinthesized using standard solution phase peptide synthesis and HOBt, HBTU as a coupling reagents. A three-dimensional orthogonal protection scheme was required to built the linear peptides, to deprotect the N- and C-termini and to cyclize them in a head-to-tail fashion. To promote the cyclization,different alkali metal ions were used depending on a the size of the desired cyclic peptide. These ions coordinate amidic oxygen atoms along the chain forcing the linear peptide to form a strong turn structure and to bring the N- and C-termini closer, allowing helping in that way cyclization to occur.