Blocking of functional groups

The preferred substrates of acetyltransferases are amino-groups of antibiotics, like chloramphenicol, strepto-gramin derivatives, and the various aminoglycosides. The modification is believed to block a functional group involved in the drug-target-interaction. All acetyltransferases use acetyl-coenzyme A as cofactor. 

However, most coupling chemistries do not go to completion so that the substrate will contain a mixture of functional groups capped with attached probe (SR) while others remain free (S ). These residual reachve functional groups must be capped or blocked in some manner to reduce nonspecific binding to the microarray. Residual surface amines may be capped by reaction with succinic anhydride. This renders the support neutral (SR). Using this abbreviated nomenclature, we can describe common surface modifications for microarray substrates. 

Derivatization of functional groups in a natural-product scaffold can also be effectively performed on the solid-phase. An example of this is the synthesis of a small compound collection (27-compounds) based on the tetrahydroquinoline scaffold. A chiral tetrahydroquinoline scaffold was synthesized in solution from 5-hydroxy-2-nitrobenzaldehyde (Scheme 4). The synthesis involved a key asymmetric aminohydroxylation step. This building block was anchored to the solid support with a Wang linker and diversity was introduced by selective deprotection and derivatization of the protected hydroxyl and amino substituents. 

Both methods require that the polymerization of the first monomer not be carried to completion, usually 90% conversion is the maximum conversion, because the extent of normal bimolecular termination increases as the monomer concentration decreases. This would result in loss of polymer chains with halogen end groups and a corresponding loss of the ability to propagate when the second monomer is added. The final product would he a block copolymer contaminated with homopolymer A. Similarly, the isolated macroinitiator method requires isolation of RA X prior to complete conversion so that there is a minimum loss of functional groups for initiation. Loss of functionality is also minimized by adjusting the choice and amount of the components of the reaction system (activator, deactivator, ligand, solvent) and other reaction conditions (concentration, temperature) to minimize normal termination. 

MACROMER (10) is a trademark by CPC International of a new family of monomers. Because they are synthesized via anionic chemistry, their molecular weight is controlled by the ratio of monomer to initiator and they also have very narrow molecular weight distributions. The typical polymeric portions of MACROMEHf that have been investigated are polystyrene, polydiene, and blocks of the two (5, lCi). Some of the typical MACROMER functional groups that were examined are shown in Figure 8. These are shown to indicate the wide variety of functional groups that are useful for various polymerization mechanisms (4). 

---