Solid-phase synthesis of chiral bicyclic guanidinium oligomers.
A simple solid-phase synthesis of thioether-linked chiral bicyclic guanidinium oligomers for cell internalization purposes has been developed. The approach is based on a Merrifield-like peptide synthesis on Rinkamide-p-methylbenzhydrylamine resin functionalized with Cys(methoxytrityl). A difunctionalized bicyclic guanidinium synthon, bearing both electrophile (O-mesyl) and protected nucleophile (S-methoxytrityl) group, is repeatedly grafted via a nucleophilic substitution. The sequence requires removal of methoxytrityl, reduction with 1,4-dithiothreitol to cleave any adventitious disulfides, coupling and capping with benzyl bromide. Moreover, Alloc protection of the alpha-amino group of the initial cysteine, provides a potential handle for cargo attachment after oligomer elongation to the desired internalizing agent and prior to cleaving it from the resin. Finally, a bicyclic guanidinium monomer containing an amino group and a carboxylic acid function has been evaluated as an alternative building block for novel amide-bridged oligomers or peptidomimetics.
Martos
Vera
V
Institute of Chemical Research of Catalonia (ICIQ), Tarragona, Spain.
Castreño
Pilar
P
Royo
Miriam
M
Albericio
Fernando
F
de Mendoza
Javier
J
D001559:Benzhydryl Compounds / Q000138:chemical synthesis / Q000737:chemistry; D001593:Benzyl Compounds / Q000138:chemical synthesis / Q000737:chemistry; D001643:Bridged Bicyclo Compounds / Q000138:chemical synthesis* / Q000737:chemistry; D020650:Combinatorial Chemistry Techniques / Q000191:economics / Q000379:methods*; D003545:Cysteine / Q000138:chemical synthesis / Q000737:chemistry; D004229:Dithiothreitol / Q000138:chemical synthesis / Q000737:chemistry; D019791:Guanidine / Q000138:chemical synthesis* / Q000737:chemistry; D013237:Stereoisomerism; D013440:Sulfides / Q000138:chemical synthesis / Q000737:chemistry*
C030545:4-methylbenzhydrylamine resin; D001559:Benzhydryl Compounds; D001593:Benzyl Compounds; D001643:Bridged Bicyclo Compounds; D013440:Sulfides; D019791:Guanidine; D003545:Cysteine; D004229:Dithiothreitol; C038682:benzyl bromide