We report a one-pot ligation/cyclization technology for the rapid and clean conversion of linear peptides into tricyclic peptides that is based on using tetravalent scaffolds containing two benzyl bromide and two alkyne moieties. These react via CLIPS/CuAAC reactions with cysteines and azides in the peptide. Flexibility in the scaffolds is key to the formation of isomerically pure products as the flexible scaffolds T4 and T4 mostly promote the formation of single isomeric tricycles while the rigid scaffolds T4 and T4 do not yield clean products. There seems to be no limitation to the number and types of amino acids present as 18 canonical amino acids were successfully implemented. We also observed that azides at the peptide termini and cysteine residues in the center gave better results than compounds with the functional groups placed the other way round.
We report aone-pot ligation/cyclization technology for the rapid and clean conversion of linear peptides into tricyclic peptides that is based on using tetravalent scaffolds containing two benzyl bromide and two alkyne moieties.These react via CLIPS/CuAACreactions with cysteines and azides in the peptide.Flexibility in the scaffolds is key to the formation of isomerically pure products as the flexible scaffolds T4 1 and T4 2 mostly promote the formation of single isomeric tricycles while the rigid scaffolds T4 3 and T4 4 do not yield clean products. There seems to be no limitation to the number and types of amino acids present as 18 canonical amino acids were successfully implemented. We also observed that azides at the peptide termini and cysteine residues in the center gave better results than compounds with the functional groups placed the other wayr ound.Cyclic peptides have emerged as ap romising class of drug compounds [1][2][3][4] showing aw ide therapeutic window that ranges from antifertility [5] to anticancer [6][7][8] and antiviral [9][10][11] applications.A st he number of cyclic peptides entering clinical trials has drastically increased over the last years, [6] the search for novel synthetic routes to multicyclic peptides has received significant interest. [12][13][14][15][16][17][18][19][20][21][22][23] In 2005, our group introduced "CLIPS technology" (chemical linkage of peptides onto scaffolds), which involves the tandem ligation/cyclization of tris(cysteine)-containing linear peptides with a,a',a''-tribromomesitylene (T3)t og ive the corresponding bicyclic peptides. [12] Heinis and co-workers applied this technology in phage display libraries,r eaching diversity levels as high as 10 9 -10 13 different bicycles. [13] Biological evaluation against various proteins [13][14][15][16] identified potent bicyclic peptides with K i values in the nanomolar range.I ns ome cases,t he best inhibitors displayed only (sub)micromolar activities, [24] suggesting that higher-order structures,such as tricycles,may be needed to reach improved activity levels.V ancomycin, alast-resort antibiotic consisting of aglycopeptide wrapped around an aromatic core,provides an illustrative example of such ac omplex architecture (Figure 1). [25] Currently,c omplex syntheses impede the large-scale production of vancomycin-like drugs,and complicate structural diversification processes aimed at optimizing their biological activities. [26] Examples of synthetic tricyclic peptides have been reported as the groups of both Ruchala [17] and Wu [18] used either a T h -o raD 2h -symmetric scaffold to assemble linear peptides into tricycles,w hile Suga, [19] Nuijens, [20] and our group [21] used various types of backbone cyclization in combination with T3 CLIPS.T hese and other examples emphasize the interest in multicyclic peptides although the formation of multiple isomers,laborious reaction procedures, as well as difficulties in generating structural diversity remain delicate issues.CLIPS reactions of tetrakis(cysteine)-containing pept...
Mit flexiblen tetravalenten Gerüsten gelingt die Umwandlung linearer Peptide in tricyclische Peptide durch CLIPS/CuAAC‐Ligation/Multicyclisierung. In der Zuschrift auf S. 510 zeigen J. H. van Maarseveen, P. Timmerman et al., dass es für die Art und Anzahl der Aminosäuren in den Schlaufen keinerlei Einschränkungen gibt. Die Methode ermöglicht die Hochdurchsatzsynthese tricyclischer Peptide gefolgt von Screenings zur Identifizierung wirksamer Peptid‐Therapeutika.
A scaffold‐assisted one‐pot CLIPS/CuAAC ligation/multicyclization reaction based on the use of flexible tetravalent scaffolds enables the conversion of linear peptides into single‐isomeric tricyclic peptides. In their Communication on page 501 ff., J. H. van Maarseveen, P. Timmerman et al. show that there are no practical limitations to the nature and amount of amino acids present in the loops. This method can be used for the high‐throughput synthesis of tricyclic peptides followed by subsequent screenings for the identification of potent peptide therapeutics.
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