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New synthetic technologies
Drug Discovery Today: Technologies
Vol. 10, No. 1 2013
Editors-in-Chief Kelvin Lam – Simplex Pharma Advisors, Inc., Arlington, MA, USA Henk Timmerman – Vrije Universiteit, The Netherlands DRUG DISCOVERY
TODAY
TECHNOLOGIES
New synthetic chemistry for medicinal chemistry
EDITORIAL
New synthetic technologies Floris Rutjes Radboud University Nijmegen, Institute for Molecules and Materials, Heyendaalseweg 135, 6525 AJ Nijmegen, The Netherlands. Email: ([email protected])
Since ancient history, small molecule drugs have been used in the treatment of diseases. For ages people took those drugs using extracts of herbs and leaves based on tradition and experience from their ancestors. Once scientists started to realize that small molecules were the actual active constituents, more focused efforts to identify new small molecule medicines started. In particular in the second half of the 20th century the dedicated search for small molecule drugs by the pharmaceutical industry took an enormous flight. And although currently the impact of biologicals and peptidebased drugs is increasing, small molecule drugs still dominate the market. One of the key technologies required in the small molecule drug development trajectory is synthetic organic chemistry. This trajectory starts with high-throughput screening of large collections of small molecules, followed by optimization of confirmed hits that have been identified in the process. Development candidates have to be scaled up and if they reach the final stages, also have to be produced in large quantities. From a synthetic perspective, while constructing compound libraries, one requires synthetic methods to create maximum molecular diversity to cover as much of the chemical space as possible. In later stages, synthetic procedures to install particular functional groups are important so that properties of molecules can be modulated to reach the best pharmacokinetic profile. Finally, initially developed synthetic pathways may be entirely discarded once production volumes need to be synthesized and higher yielding or more cost effective routes might have to be developed. All these aspects require a continuous development of new, more efficient and more sustainable synthetic technologies. This issue of Drug Discovery Today: Technologies provides an overview of recent developments in synthetic organic chemistry, which are relevant with respect to the drug discovery process as a whole. 1740-6749/$ ß 2012 Elsevier Ltd. All rights reserved.
Floris Rutjes (1966) received his PhD under supervision of Prof. Nico Speckamp at the University of Amsterdam in 1993. After two years of post-doctoral research in the group of Prof. K.C. Nicolaou at The Scripps Research Institute, he was appointed assistant professor at the University of Amsterdam. In 1999, he became full professor in Synthetic Organic Chemistry at Radboud University Nijmegen and in 2007 also Director of the Educational Institute for Molecular Sciences. His research interests comprise new catalytic methods and their application in the synthesis of bioactive molecules and natural products, new molecular diagnostic tools for application in life sciences and synthesis in microreactors. He is co-founder of the companies Chiralix and Future Chemistry and received several awards including the Unilever Research Prize (1988), the Gold Medal of the Royal Netherlands Chemical Society (KNCV, 2002), the AstraZeneca Award for Research in Organic Chemistry (2003) and the award of most entrepreneurial scientist of the Netherlands (2008).
One recent trend that is witnessed in lead discovery, is the steady increase of chiral, often heterocyclic structures in compound collections, thereby extending coverage of the chemical space provided by planar, aromatic scaffolds. The synthesis of non-chiral heterocyclic structures is a central theme in the first article by Shen and Graham. Among the transition metals that over the years have been employed in the synthesis of such ring systems, for a long time gold has remained relatively unexplored. This changed during the past decade, in which gold-catalyzed transformations have proven their value in providing efficient access to a wide range of heterocycles, including pharmacophores that are relevant for
http://dx.doi.org/10.1016/j.ddtec.2012.10.005
e1
Drug Discovery Today: Technologies | New synthetic chemistry for medicinal chemistry
medicinal chemistry. In particular the mechanistic divergence and the excellent functional group tolerance make that the number of applications is still rapidly increasing, including the synthesis of biologically active molecules and a drug candidate. In the article by Ruijter and Orru, the relevance of multicomponent reactions for the synthesis of druglike structures and actual drugs is reviewed. The strength of multi-component reactions resides in the fact that multiple bonds are formed in a single process, so that with relative ease large arrays of different compounds can be synthesized. The concept of making multiple bonds in one pot also contributes to the green character of such processes due to a strong reduction of workup steps and functional group interconversions. With the advent of chirality in drugs, the availability of asymmetric synthesis methods to produce single enantiomers has become an important issue. The article by Madduri, Harutyunyan and Minnaard provides a comprehensive overview of recent developments in the field of asymmetric catalysis to create highly challenging enantiopure tertiary alcohols by enantioselective addition of organometallic nucleophiles onto ketones, guided by chiral ligands. In the same field of asymmetric catalysis, organocatalysis has emerged as a new and viable approach to catalyze a range of different reactions. In addition to transition metals and enzymes, small organic molecules can efficiently catalyze the formation of new, often CC-bonds, which are generally
e2
www.drugdiscoverytoday.com
Vol. 10, No. 1 2013
formed in an asymmetric manner. The article by Mahrwald provides a concise overview of developments in this field so far. Important developments and pharmaceutically relevant applications of biocatalysis methods are highlighted by Simon, Mutti and Kroutil. Advantages of using enzymes lie in the fact that reactions can be carried out in water, under mild conditions, in absence of protecting groups. Furthermore, enzymes can be highly substrate specific and generally exert a high control over the regio- and stereoselectivity of the reaction. The article by Van Berkel and Van Delft reviews metal-free bioconjugation strategies based on so-called ‘click-reactions’. These are fast and irreversible reactions between specific functional groups, which do not react with anything else in a cellular environment. Applications in the field of chemical biology are provided, but also the potential in modulating biopharmaceuticals by site-specific modification is included. Finally, Yoshida and co-workers describe recent developments in continuous flow synthesis, focused on potential applications in pharmaceutical research. In process chemistry, the awareness of the advantages of flow chemistry (e.g. in terms of safety in case of hazardous reagents or intermediates) has led to an increasing number of industrial applications. This article, however, clearly shows that flow chemistry may also be a viable tool for the generation of small molecule compound libraries.
Vol. 10, No. 1 2013
Editors-in-Chief Kelvin Lam – Simplex Pharma Advisors, Inc., Arlington, MA, USA Henk Timmerman – Vrije Universiteit, The Netherlands DRUG DISCOVERY
TODAY
TECHNOLOGIES
New synthetic chemistry for medicinal chemistry
EDITORIAL
New synthetic technologies Floris Rutjes Radboud University Nijmegen, Institute for Molecules and Materials, Heyendaalseweg 135, 6525 AJ Nijmegen, The Netherlands. Email: ([email protected])
Since ancient history, small molecule drugs have been used in the treatment of diseases. For ages people took those drugs using extracts of herbs and leaves based on tradition and experience from their ancestors. Once scientists started to realize that small molecules were the actual active constituents, more focused efforts to identify new small molecule medicines started. In particular in the second half of the 20th century the dedicated search for small molecule drugs by the pharmaceutical industry took an enormous flight. And although currently the impact of biologicals and peptidebased drugs is increasing, small molecule drugs still dominate the market. One of the key technologies required in the small molecule drug development trajectory is synthetic organic chemistry. This trajectory starts with high-throughput screening of large collections of small molecules, followed by optimization of confirmed hits that have been identified in the process. Development candidates have to be scaled up and if they reach the final stages, also have to be produced in large quantities. From a synthetic perspective, while constructing compound libraries, one requires synthetic methods to create maximum molecular diversity to cover as much of the chemical space as possible. In later stages, synthetic procedures to install particular functional groups are important so that properties of molecules can be modulated to reach the best pharmacokinetic profile. Finally, initially developed synthetic pathways may be entirely discarded once production volumes need to be synthesized and higher yielding or more cost effective routes might have to be developed. All these aspects require a continuous development of new, more efficient and more sustainable synthetic technologies. This issue of Drug Discovery Today: Technologies provides an overview of recent developments in synthetic organic chemistry, which are relevant with respect to the drug discovery process as a whole. 1740-6749/$ ß 2012 Elsevier Ltd. All rights reserved.
Floris Rutjes (1966) received his PhD under supervision of Prof. Nico Speckamp at the University of Amsterdam in 1993. After two years of post-doctoral research in the group of Prof. K.C. Nicolaou at The Scripps Research Institute, he was appointed assistant professor at the University of Amsterdam. In 1999, he became full professor in Synthetic Organic Chemistry at Radboud University Nijmegen and in 2007 also Director of the Educational Institute for Molecular Sciences. His research interests comprise new catalytic methods and their application in the synthesis of bioactive molecules and natural products, new molecular diagnostic tools for application in life sciences and synthesis in microreactors. He is co-founder of the companies Chiralix and Future Chemistry and received several awards including the Unilever Research Prize (1988), the Gold Medal of the Royal Netherlands Chemical Society (KNCV, 2002), the AstraZeneca Award for Research in Organic Chemistry (2003) and the award of most entrepreneurial scientist of the Netherlands (2008).
One recent trend that is witnessed in lead discovery, is the steady increase of chiral, often heterocyclic structures in compound collections, thereby extending coverage of the chemical space provided by planar, aromatic scaffolds. The synthesis of non-chiral heterocyclic structures is a central theme in the first article by Shen and Graham. Among the transition metals that over the years have been employed in the synthesis of such ring systems, for a long time gold has remained relatively unexplored. This changed during the past decade, in which gold-catalyzed transformations have proven their value in providing efficient access to a wide range of heterocycles, including pharmacophores that are relevant for
http://dx.doi.org/10.1016/j.ddtec.2012.10.005
e1
Drug Discovery Today: Technologies | New synthetic chemistry for medicinal chemistry
medicinal chemistry. In particular the mechanistic divergence and the excellent functional group tolerance make that the number of applications is still rapidly increasing, including the synthesis of biologically active molecules and a drug candidate. In the article by Ruijter and Orru, the relevance of multicomponent reactions for the synthesis of druglike structures and actual drugs is reviewed. The strength of multi-component reactions resides in the fact that multiple bonds are formed in a single process, so that with relative ease large arrays of different compounds can be synthesized. The concept of making multiple bonds in one pot also contributes to the green character of such processes due to a strong reduction of workup steps and functional group interconversions. With the advent of chirality in drugs, the availability of asymmetric synthesis methods to produce single enantiomers has become an important issue. The article by Madduri, Harutyunyan and Minnaard provides a comprehensive overview of recent developments in the field of asymmetric catalysis to create highly challenging enantiopure tertiary alcohols by enantioselective addition of organometallic nucleophiles onto ketones, guided by chiral ligands. In the same field of asymmetric catalysis, organocatalysis has emerged as a new and viable approach to catalyze a range of different reactions. In addition to transition metals and enzymes, small organic molecules can efficiently catalyze the formation of new, often CC-bonds, which are generally
e2
www.drugdiscoverytoday.com
Vol. 10, No. 1 2013
formed in an asymmetric manner. The article by Mahrwald provides a concise overview of developments in this field so far. Important developments and pharmaceutically relevant applications of biocatalysis methods are highlighted by Simon, Mutti and Kroutil. Advantages of using enzymes lie in the fact that reactions can be carried out in water, under mild conditions, in absence of protecting groups. Furthermore, enzymes can be highly substrate specific and generally exert a high control over the regio- and stereoselectivity of the reaction. The article by Van Berkel and Van Delft reviews metal-free bioconjugation strategies based on so-called ‘click-reactions’. These are fast and irreversible reactions between specific functional groups, which do not react with anything else in a cellular environment. Applications in the field of chemical biology are provided, but also the potential in modulating biopharmaceuticals by site-specific modification is included. Finally, Yoshida and co-workers describe recent developments in continuous flow synthesis, focused on potential applications in pharmaceutical research. In process chemistry, the awareness of the advantages of flow chemistry (e.g. in terms of safety in case of hazardous reagents or intermediates) has led to an increasing number of industrial applications. This article, however, clearly shows that flow chemistry may also be a viable tool for the generation of small molecule compound libraries.