Ribosome-Templated Azide–Alkyne Cycloadditions: Synthesis of Potent Macrolide Antibiotics by In Situ Click Chemistry

Abstract

Over half of all antibiotics target the bacterial ribosome-Nature's complex, 2.5 MDa nanomachine responsible for decoding mRNA and synthesizing proteins. Macrolide antibiotics, exemplified by erythromycin, bind the 50S subunit with nM affinity and inhibit protein synthesis by blocking the passage of nascent oligopeptides. Solithromycin (1), a third-generation semisynthetic macrolide discovered by combinatorial copper-catalyzed click chemistry, was synthesized in situ by incubating either E. coli 70S ribosomes or 50S subunits with macrolidefunctionalized azide 2 and 3-ethynylaniline (3) precursors. The ribosome-templated in situ click method was expanded from a binary reaction (i.e., one azide and one alkyne) to a sixcomponent reaction (i.e., azide 2 and five alkynes) and ultimately to a sixteen-component reaction (i.e., azide 2 and fifteen alkynes). The extent of triazole formation correlated with ribosome affinity for the anti (1,4)-regioisomers as revealed by measured K d values. Computational analysis using the Site-Identification by Ligand Competitive Saturation (SILCS) approach indicated that the relative affinity of the ligands was associated with the alteration of macrolactone+desosamine- HHS Public Access

Self-triggered click reaction in an Alzheimer's disease model:in situbifunctional drug synthesis catalyzed by neurotoxic copper accumulated in amyloid-β plaques

“…[4][5][6] Due to its high efficiency, fast kinetics, and mild reaction conditions, the Cu(I)-catalyzed azide-alkyne cycloaddition (CuAAC) reaction has received special attention in many biochemical applications such as bioconjugation, [7][8][9][10][11] biosensing, [12][13][14] and drug synthesis. 15,16 Many kinds of Cu sources are efficient for CuAAC bioorthogonal reactions. Besides typical Cu(I) complexes and the reduction of Cu(II) complexes, 17 various Cu-containing nanoparticles (NPs) are increasingly used for CuAAC reactions, including Cu, Cu 2 O and CuO NPs, 18,19 Cuimmobilized inorganic and polymer NPs, [20][21][22] as well as Cudoped semiconductor NPs.…”

The Lock is the Key: Development of Novel Drugs through Receptor Based Combinatorial Chemistry

“…More recently, Glassford et al have expanded the templation potential of the in situ click chemistry to E. coli 70S ribosomes or their 50S subunits and thus synthesized potent macrolide antibiotics that target bacterial ribosome. 144 Also, the in situ click chemistry approach has been applied to explore the conformational space of the ligand binding site of a M. tuberculoisis transcriptional repressor EthR which regulates the transcription of monooxygenase EthA and thus controls the sensitivity of M. tuberculoisis to an- tibiotic ethionamide. The in situ formed inhibitor, displayed 10-fold higher activity than the starting azide, and induced a significant conformational change of the ligand-binding domain of EthR.…”

A Biocompatible Heterogeneous MOF–Cu Catalyst for In Vivo Drug Synthesis in Targeted Subcellular Organelles

“…[5] Another important application of click reactions is in pharmaceutical science. [7] Therefore,p roblems associated with the toxicity,d elivery,a nd localization of the synthesized active drug molecules are inevitable. [6] However,m ost drug synthesis through click chemistry is carried out on the basis of a"two-step" model.…”