The fascinating story of olefin (or alkene) metathesis (eq
1) began almost five decades ago, when Anderson and
Merckling reported the first carbon-carbon double-bond
rearrangement reaction in the titanium-catalyzed polymerization of norbornene. Nine years later, Banks and Bailey reported “a new disproportionation reaction . . . in which olefins are converted to homologues of shorter and longer carbon chains...”. In 1967, Calderon and co-workers named this metal-catalyzed redistribution of carbon-carbon double bonds olefin metathesis, from the Greek word “μeτάθeση”, which means change of position. These contributions have since served as the foundation for an amazing research field, and olefin metathesis currently represents a powerful transformation in chemical synthesis, attracting a vast amount of interest both in industry and academia.

https://core.ac.uk/download/pdf/4884240.pdf

Ruthenium-based heterocyclic carbene-coordinated olefin metathesis catalysts.

Fragment-based methods have made substantial contributions to drug discovery in the past 20 years, particularly for challenging targets. Erlanson and colleagues discuss progress in the field, key aspects such as the design of fragment libraries and the choice of screening technique, and how current challenges in fragment-based drug discovery might be overcome.

Twenty years on: the impact of fragments on drug discovery.

The decomposition of a series of ruthenium metathesis catalysts has been examined using methylidene species as model complexes. All of the phosphine-containing methylidene complexes decomposed to generate methylphosphonium salts, and their decomposition routes followed first-order kinetics. The formation of these salts in high conversion, coupled with the observed kinetic behavior for this reaction, suggests that the major decomposition pathway involves nucleophilic attack of a dissociated phosphine on the methylidene carbon. This mechanism also is consistent with decomposition observed in the presence of ethylene as a model olefin substrate. The decomposition of phosphine-free catalyst (H_2IMes)(Cl)_2Ru CH(2-C_6H_4-O-i-Pr) (H_2IMes = 1,3-dimesityl-4,5-dihydroimidazol-2-ylidene) with ethylene was found to generate unidentified ruthenium hydride species. The novel ruthenium complex (H_2IMes)(pyridine)_3(Cl)_2Ru, which was generated during the synthetic attempts to prepare the highly unstable pyridine-based methylidene complex (H_2IMes)(pyridine)_2(Cl)_2Ru CH_2, is also reported.

Decomposition of Ruthenium Olefin Metathesis Catalysts

Ring-closing metathesis (RCM) of dienes is one of the most important methodologies now in use for the assembly of cyclic organic compounds. First employed by Villemin and by Tsuji nearly three decades ago,1,2 the reaction has risen to astonishing prominence in organic synthesis over the past decade, owing largely to the development of easily handled catalysts that enable controlled reaction.3 RCM represents a key step in many synthetic sequences: recent reviews describe its use in, inter alia, construction of synthetically valuable building blocks such as heterocyclic rings containing phosphorus,4 sulfur,4 oxygen,5 or nitrogen,5,6 including aromatic heterocycles;7 spirocyclic,8,9 cyclophane,8 and polycyclic compounds;8,9 and compounds of biological and medicinal relevance such as peptidomimetics,10,11 carbohydrate derivatives,11-14 alkaloids,11,15-19 bioactive cyclic molecules,20,21 and polycyclic ethers,22 including macrocyclic aza-crown ethers23 and topologically interesting molecules and “molecular machines”.24,25 While the common rings of 5-7 members have historically been dominant, owing in part to their greater ease of access, important advances have been made in the synthesis of medium20,26-30 and macrocyclic16,17,23,27,31-35 targets. One aspect of this review will examine the increased tendency of many medium and large rings to participate in equilibrium metathesis, and the resulting implications for selectivity and yields.

Equilibrium ring-closing metathesis.

Less than a decade ago, it was shown that bromodomains, acetyl lysine 'reader' modules found in proteins with varied functions, were highly tractable small-molecule targets. This is an unusual property for protein-protein or protein-peptide interaction domains, and it prompted a wave of chemical probe discovery to understand the biological potential of new agents that targeted bromodomains. The original examples, inhibitors of the bromodomain and extra-terminal (BET) class of bromodomains, showed enticing anti-inflammatory and anticancer activities, and several compounds have since advanced to human clinical trials. Here, we review the current state of BET inhibitor biology in relation to clinical development, and we discuss the next wave of bromodomain inhibitors with clinical potential in oncology and non-oncology indications. The lessons learned from BET inhibitor programmes should affect efforts to develop drugs that target non-BET bromodomains and other epigenetic readers.

Bromodomains: a new target class for drug development

Nuclear magnetic resonance (NMR) spectroscopy has evolved into a powerful tool for fragment-based drug discovery over the last two decades. While NMR has been traditionally used to elucidate the three-dimensional structures and dynamics of biomacromolecules and their interactions, it can also be a very valuable tool for the reliable identification of small molecules that bind to proteins and for hit-to-lead optimization. Here, we describe the use of NMR spectroscopy as a method for fragment-based drug discovery and how to most effectively utilize this approach for discovering novel therapeutics based on our experience.

Fragment-based drug discovery using NMR spectroscopy.

Cellular and genetic evidence suggest that inhibition of ATAD2 could be a useful strategy to treat several types of cancer. To discover small-molecule inhibitors of the bromodomain of ATAD2, we used a fragment-based approach. Fragment hits were identified using NMR spectroscopy, and ATAD2 was crystallized with three of the hits identified in the fragment screen.

http://pubs.acs.org/doi/pdf/10.1021/jm501035j

Mary J. Harner

Papers

Fragment-based drug discovery using NMR spectroscopy.

Fragment-based screening of the bromodomain of ATAD2.

Ruthenium Alkylidenes: Fast Initiators for Olefin Metathesis