Showing papers on "Click chemistry published in 2002"

Click Chemistry In Situ: Acetylcholinesterase as a Reaction Vessel for the Selective Assembly of a Femtomolar Inhibitor from an Array of Building Blocks

Abstract: The generation and/or optimization of lead compounds by combinatorial methods has become widely accepted in medicinal chemistry, and is the subject of continued improvement.[1±3] However, most combinatorial strategies remain dependent upon iterative cycles of synthesis and screening. The direct involvement of the target, usually a receptor or enzyme, in the selection, evolution, and screening of drug candidates can accelerate the discovery process by shortcircuiting its traditionally stepwise nature.[4±11] The use of an enzyme target to select building blocks and synthesize its own inhibitor is a relatively unexplored option. This approach depends on the simultaneous binding of two ligands, decorated with complementary reactive groups, to adjacent sites on the protein; their co-localization is then likely to accelerate the reaction that connects them.[12] When the catalysis of such bond formation is blocked by product inhibition, the higher affinity products[12±14] then serve as lead compounds. This and similar approaches that have been adopted by a number of investigators employ one of five types of connecting reactions: formation of hydrazone or Schiff base adducts, disulfide bond formation, alkylation of free thiols or amines, epoxide ring-opening, or olefin metathesis.[5, 6, 8, 11, 15±19] Most closely related to the work described herein is the generation of carbonic anhydrase inhibitors by using the SN2 reaction of a thiol with an -chloroketone in the presence of the enzyme target.[16] Most of the above strategies share the limitation that the reactive groups on the ligand probes (building blocks), being either electrophiles or nucleophiles, are likely to react in undesired ways within biochemical systems. An alternative is offered by the TMcream of the crop∫ among TMclick reactions∫[20]–the Huisgen 1,3-dipolar cycloaddition of azides and acetylenes to give 1,2,3-triazoles [Eq. (1)].[21±23] This water-

In situ click chemistry

Abstract: IN THE "CLICK CHEMISTRY" STRATEGY DEVELOPED RECENTly at Scripps Research Institute, reactive molecular building blocks are designed to "click" together selectively and covalently. The Scripps resea...