ABSTRACT
A convenient synthesis of novel bifunctional poly(amino carboxylate) chelating agents allowing chemoselective attachment to highly functionalized biomolecules is described. Based on the well known chelator 1,4,7,10-tetraazacyclodecane-1,4,7,10-tetraacetic acid (DOTA), we synthesized novel bifunctional chelating agents bearing additional functional groups by alkylating 1,4,7,10-tetraazacyclododecane (cyclen) with one equivalent of para-functionalized alkyl 2-bromophenyl-acetate and three equivalents of tert-butyl 2-bromoacetate. The resulting compounds, which contain an additional carbonyl or alkyne functionality, allow site specific labeling of appropriately functionalized unprotected biomolecules in a rapid manner via click reactions. This was demonstrated by the attachment of our new DOTA derivatives to the somatostatin analogue Tyr3-octreotate by chemoselective oxime ligation and CuI-catalyzed azide-alkyne cycloaddition. Initial biodistribution studies in mice with the radiometalated compound demonstrated the applicability of the described DOTA conjugation.
Subject(s)
Heterocyclic Compounds, 1-Ring/chemistry , Alkynes/chemistry , Amination , Animals , Azides/chemistry , Carbonic Acid/chemistry , Catalysis , Cell Line, Tumor , Chromatography, High Pressure Liquid , Copper/chemistry , Cyclization , Female , Heterocyclic Compounds, 1-Ring/chemical synthesis , Heterocyclic Compounds, 1-Ring/pharmacokinetics , Heterocyclic Compounds, 1-Ring/therapeutic use , Ketones/chemistry , Mice , Mice, Nude , Molecular Structure , Neoplasms/drug therapy , Neoplasms/pathology , Oximes/chemistry , Oxygen/chemistry , Peptides/chemistry , Rats , Tyrosine/chemistry , Xenograft Model Antitumor AssaysABSTRACT
As part of our ongoing research in the development of alpha4beta7 integrin antagonists, we are interested in peptidomimetics based on a rigid scaffold to allow the display of essential side chains in a suitable binding conformation while eliminating backbone amide bonds and therefore improving pharmacokinetic parameters of the drug. Except for a few examples, peptidomimetics scaffolds have only been moderately successful and often yield molecules that lack the potency of their peptide counterparts. However, we present herein a successful application of using a rigid scaffold. Starting from a mannopyranoside analogue previously discovered in our laboratory as an inhibitor of the alpha4beta1/vascular cell adhesion molecule interaction, a biased library of functionalized carbohydrates was developed. One compound emerged from this library as an active and selective antagonist toward the alpha4beta7/mucosal addressin cell adhesion molecule interaction. Conformational implications and the relevance of different pharmacophoric patterns will be discussed in order to explain the reverse selectivity and enhanced affinity.
