Vsevolod V. Rostovtsev

Bio: Vsevolod V. Rostovtsev is an academic researcher from Scripps Research Institute. The author has contributed to research in topics: Cycloaddition & Filtration (mathematics). The author has an hindex of 3, co-authored 4 publications receiving 11056 citations.

Copper(I)-catalyzed synthesis of azoles. DFT study predicts unprecedented reactivity and intermediates.

Abstract: Huisgen's 1,3-dipolar cycloadditions become nonconcerted when copper(I) acetylides react with azides and nitrile oxides, providing ready access to 1,4-disubstituted 1,2,3-triazoles and 3,4-disubstituted isoxazoles, respectively. The process is highly reliable and exhibits an unusually wide scope with respect to both components. Computational studies revealed a stepwise mechanism involving unprecedented metallacycle intermediates, which appear to be common for a variety of dipoles.

Copper(I)-Catalyzed Synthesis of Azoles. DFT Study Predicts Unprecedented Reactivity and Intermediates.

Abstract: Huisgen's 1,3-dipolar cycloadditions become nonconcerted when copper(I) acetylides react with azides and nitrile oxides, providing ready access to 1,4-disubstituted 1,2,3-triazoles and 3,4-disubstituted isoxazoles, respectively. The process is highly reliable and exhibits an unusually wide scope with respect to both components. Computational studies revealed a stepwise mechanism involving unprecedented metallacycle intermediates, which appear to be common for a variety of dipoles.

In situ click chemistry generation of cyclooxygenase-2 inhibitors

Abstract: Cyclooxygenase-2 isozyme is a promising anti-inflammatory drug target, and overexpression of this enzyme is also associated with several cancers and neurodegenerative diseases. The amino-acid sequence and structural similarity between inducible cyclooxygenase-2 and housekeeping cyclooxygenase-1 isoforms present a significant challenge to design selective cyclooxygenase-2 inhibitors. Herein, we describe the use of the cyclooxygenase-2 active site as a reaction vessel for the in situ generation of its own highly specific inhibitors. Multi-component competitive-binding studies confirmed that the cyclooxygenase-2 isozyme can judiciously select most appropriate chemical building blocks from a pool of chemicals to build its own highly potent inhibitor. Herein, with the use of kinetic target-guided synthesis, also termed as in situ click chemistry, we describe the discovery of two highly potent and selective cyclooxygenase-2 isozyme inhibitors. The in vivo anti-inflammatory activity of these two novel small molecules is significantly higher than that of widely used selective cyclooxygenase-2 inhibitors. Traditional inflammation and pain relief drugs target both cyclooxygenase 1 and 2 (COX-1 and COX-2), causing severe side effects. Here, the authors use in situ click chemistry to develop COX-2 specific inhibitors with high in vivo anti-inflammatory activity.

Cu-catalyzed azide-alkyne cycloaddition.

Abstract: The Huisgen 1,3-dipolar cycloaddition reaction of organic azides and alkynes has gained considerable attention in recent years due to the introduction in 2001 of Cu(1) catalysis by Tornoe and Meldal, leading to a major improvement in both rate and regioselectivity of the reaction, as realized independently by the Meldal and the Sharpless laboratories. The great success of the Cu(1) catalyzed reaction is rooted in the fact that it is a virtually quantitative, very robust, insensitive, general, and orthogonal ligation reaction, suitable for even biomolecular ligation and in vivo tagging or as a polymerization reaction for synthesis of long linear polymers. The triazole formed is essentially chemically inert to reactive conditions, e.g. oxidation, reduction, and hydrolysis, and has an intermediate polarity with a dipolar moment of ∼5 D. The basis for the unique properties and rate enhancement for triazole formation under Cu(1) catalysis should be found in the high ∆G of the reaction in combination with the low character of polarity of the dipole of the noncatalyzed thermal reaction, which leads to a considerable activation barrier. In order to understand the reaction in detail, it therefore seems important to spend a moment to consider the structural and mechanistic aspects of the catalysis. The reaction is quite insensitive to reaction conditions as long as Cu(1) is present and may be performed in an aqueous or organic environment both in solution and on solid support.

Bioorthogonal Chemistry: Fishing for Selectivity in a Sea of Functionality

Abstract: The study of biomolecules in their native environments is a challenging task because of the vast complexity of cellular systems. Technologies developed in the last few years for the selective modification of biological species in living systems have yielded new insights into cellular processes. Key to these new techniques are bioorthogonal chemical reactions, whose components must react rapidly and selectively with each other under physiological conditions in the presence of the plethora of functionality necessary to sustain life. Herein we describe the bioorthogonal chemical reactions developed to date and how they can be used to study biomolecules.

The growing applications of click chemistry

Abstract: 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.