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Indolizine-Based Scaffolds as Efficient and Versatile Tools: Application to the Synthesis of Biotin-Tagged Antiangiogenic Drugs
journal contribution
posted on 2017-12-27, 09:13 authored by Marie Arvin-Berod, Agnès Desroches-Castan, Simon Bonte, Sabine Brugière, Yohann Couté, Laurent Guyon, Jean-Jacques Feige, Isabelle Baussanne, Martine DemeunynckWe describe the design
and optimization of polyfunctional scaffolds
based on a fluorescent indolizine core derivatized with various orthogonal
groups (amines, esters, oximes, alkynes, etc.). To show one application
as tools in biology, the scaffold was used to prepare drug–biotin
conjugates that were then immobilized onto avidin-agarose for affinity
chromatography. More specifically, the antiangiogenic drug COB223,
whose mechanism of action remained unclear, was chosen as a proof-of-concept
drug. The drug-selective discrimination of proteins observed after
elution of the cell lysates through the affinity columns, functionalized
either with the biologically active COB223 or a structurally related
inactive analogue (COB236), is a clear indication that the presence
of the indolizine core does not limit drug–protein interaction
and confirms the usefulness of the indolizine scaffold. Furthermore,
the separation of COB223-interacting proteins from human placental
extracts unveiled unanticipated protein targets belonging to the family
of regulatory RNA-binding proteins, which opens the way to new hypotheses
on the mode of action of this antiangiogenic drug.
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Keywords
proof-of-concept drugindolizine coreaffinity chromatographyCOB 223affinity columnsVersatile Toolsorthogonal groupsCOB 223-interacting proteinsplacental extractsindolizine core derivatizedcell lysatesIndolizine-Based ScaffoldsBiotin-Tagged Antiangiogenic DrugsRNA-binding proteinsprotein targetsdrug-selective discriminationantiangiogenic drugindolizine scaffoldpolyfunctional scaffolds