A rigid linker-scaffold for solid-phase synthesis of dimeric pharmacophores.

Bifunctional linker-scaffolds (compounds 1−3) were designed to meet several criteria for solid-phase syntheses of bivalent ligands. They have two amine-functionalized arms that can be differentially protected. Elaboration of these arms could give ligand-pharmacophore dimers wherein the two active components are held reasonably rigidly at around 10 A separation. Their bifunctional design also enables reactions of libraries with libraries to amplify diversity in a truly combinatorial fashion. Molecules 1−3 are also designed so that cleavage of the linker liberates the scaffold entity into solution under conditions that create only byproducts that should not interfere with biological assays. Thus they contain 2-nitrobenzene sulfonamide components that cleave in the presence of good nucleophiles. In the event, the linker-scaffolds 1−3 were prepared (Schemes 1 and 2). The N-benzyl system 2 was shown to have good stability to the types of conditions that might be used to functionalize the scaffold arms and to b...