Correction: The growing applications of click chemistry.

Correction for 'The growing applications of click chemistry' by John E. Moses et al., Chem. Soc. Rev., 2007, 36, 1249-1262.

Modular synthesis of functional libraries by accelerated SuFEx click chemistry.

Accelerated SuFEx Click Chemistry (ASCC) is a powerful method for coupling aryl and alkyl alcohols with SuFEx-compatible functional groups. With its hallmark favorable kinetics and exceptional product yields, ASCC streamlines the synthetic workflow, simplifies the purification process, and is ideally suited for discovering functional molecules. We showcase the versatility and practicality of the ASCC reaction as a tool for the late-stage derivatization of bioactive molecules and in the array synthesis of sulfonate-linked, high-potency, microtubule targeting agents (MTAs) that exhibit nanomolar anticancer activity against multidrug-resistant cancer cell lines. These findings underscore ASCC's promise as a robust platform for drug discovery.

The Certainty of a Few Good Reactions.

The impact of click chemistry was recently recognized with the 2022 Nobel Prize in Chemistry. The breadth of areas where click chemistry has accelerated discovery is prodigal. In one of the most written about subjects in chemistry over recent years, this short perspective zones in on a small fragment of what we, the authors, consider are some of the most critical developments in synthetic chemistry, which have expanded access to the click chemistry toolbox. In addition, we touch upon areas within medicinal chemistry and novel approaches to drug discovery enabled by click chemistry, where we believe there is untapped potential for biological function to be found and exploited.

Efficient conversion of aromatic amines into azides: a one-pot synthesis of triazole linkages.

[reaction: see text] An efficient and improved procedure for the preparation of aromatic azides and their application in the Cu(I)-catalyzed azide-alkyne 1,3-dipolar cycloaddition ("click reaction") is described. The synthesis of aromatic azides from the corresponding amines is accomplished under mild conditions with tert-butyl nitrite and azidotrimethylsilane. 1,4-Disubstituted 1,2,3-triazoles were obtained in excellent yields from a variety of aromatic amines without the need for isolation of the azide intermediates.

Targeting glycolysis: a fragment based approach towards bifunctional inhibitors of hLDH-5.

hLDH-5 has emerged as a promising target for anti-glycolytic cancer chemotherapy. Here we report a first generation of bifunctional inhibitors, which show promising activity against hLDH-5.

G-quadruplex compounds and cis-platin act synergistically to inhibit cancer cell growth in vitro and in vivo.

The ability of two structurally diverse telomeric G-quadruplex-binding compounds to synergise the action of cis-platin has been investigated in two cancer cell lines. One compound is a trisubstituted acridine compound AS1410, a close analogue of BRACO-19, and the other is a non-polycyclic compound synthesised using click chemistry and containing two triazole rings. Both compounds produce growth arrest at sub-cytotoxic concentrations in the two cell lines (MCF7 and A549), with behaviour consistent with telomere targeting mechanisms. Synergistic behaviour was observed in both cell lines with both compounds in combination with cis-platin, but only when the ratio of AS1410:cis-platin is >1. In vivo tumour xenograft studies with the A549 lung cancer model and the trisubstituted acridine compound AS1410 showed only a modest anti-tumour effect when administered alone, but produced rapid and highly significant decreases in tumour volume when administered in combination with cis-platin.

Targeting telomerase and telomeres: a click chemistry approach towards highly selective G-quadruplex ligands.

Maintenance of telomeres--specialized complexes that protect the ends of chromosomes, is undertaken by the enzyme complex telomerase, which is a key factor that is activated in more than 80% of cancer cells, but is absent in most normal cells. Targeting telomere maintenance mechanisms could potentially halt tumour growth across a broad spectrum of cancer types, with little cytotoxic effect outside cancer cells. Here, we describe in detail a new class of G-quadruplex binding ligands synthesized using a click chemistry approach. These ligands comprise a 1,3-di(1,2,3-triazol-4-yl)benzene pharmacophore, and display high levels of selectivity for interaction with G-quadruplex DNA vs. duplex DNA. The ability of these ligands to inhibit the enzymatic activity of telomerase correlates with their ability to stabilize quadruplex DNA, and with estimates of affinity calculated by molecular modeling.

The growing applications of click chemistry.

Click chemistry, the subject of this tutorial review, is a modular synthetic approach towards the assembly of new molecular entities. This powerful strategy relies mainly upon the construction of carbon-heteroatom bonds using spring-loaded reactants. Its growing number of applications are found in nearly all areas of modern chemistry from drug discovery to materials science. The copper(I)-catalysed 1,2,3-triazole forming reaction between azides and terminal alkynes has become the gold standard of click chemistry due to its reliability, specificity and biocompatibility.

Stabilization of G-quadruplex DNA by highly selective ligands via click chemistry.

A series of G-quadruplex stabilizing compounds have been prepared via click chemistry employing the Cu(I)-catalyzed Huisgen reaction. These compounds were shown to bind tightly to G-quadruplex DNA even in the presence of competing high concentrations of duplex DNA. Furthermore, a modified TRAP assay has shown that some of these compounds also inhibit telomerase at low micromolar concentration.