- Email: [email protected]
Technologies to develop new metal medicines
Drug Discovery Today: Technologies
Vol. 16, 2015
Editors-in-Chief Kelvin Lam – Simplex Pharma Advisors, Inc., Boston, MA, USA Henk Timmerman – Vrije Universiteit, The Netherlands DRUG DISCOVERY
TODAY
TECHNOLOGIES
Editorial
Technologies to develop new metal medicines Francois Dufrasne Laboratoire de Chimie Pharmaceutique Organique, Faculte´ de Pharmacie – Universite´ Libre de Bruxelles Campus Plaine CP 205/5, 1050 Brussels, Belgium. Email: ([email protected])
Looking back to history, physicians would say that most of the metal significant uses in medicine belong to the past, with only few compounds marketed. However chemists and bioinorganic researchers would claim that the future of metals in medicine is certainly wide open with a large variety of compounds and applications looming at the horizon. As a matter of proof numerous research groups work in this field, providing new data about the already well demonstrated or the putative roles that some metals or their complexes could play in human therapy. Another way to assess the popularity of this class of compounds is to turn to the metrics. For example, platinum, gold, copper and iron at least have gathered more than 3000 papers about their uses as curative compounds. Besides these most currently studied species, all the transition metals are considered by renowned specialists of this discipline as strongly underestimated as future cures. At a moment when pipelines of the pharmaceutical industries seem to somewhat dry up it is clear that this class of compounds is still a mine that must be explored to discover new biologically active metal-containing compounds. Historically metals were among the first ‘drugs’ used to treat diseases such as rheumatoid arthritis (gold), infections (bismuth, mercury, arsenic, antimony and silver), anemia (iron), diabetes (vanadium) and inflammation (copper). However, the first breakthrough in the rational development of a bioactive metal-containing compound family was initiated by the serendipitous discovery of the anticancer cisplatin by Barnett Rosenberg in 1965. That was the starting point of a real rush to develop tools for the discovery of metallodrugs, mainly against cancer and, later, other diseases. However, this is a rather common opinion among medicinal chemists that this is a relatively easier task to design an organic drug candidate than an organometallic one. Difficulties can be mainly ascribed to the fact that most of the metals are considered to have pleiotropic actions compared to organic drugs. Metals are able to react, interact or bind with numerous chemical groups present in biologically important molecules of which the most representative are certainly thiols of 1740-6749/$ ß 2015 Elsevier Ltd. All rights reserved.
cysteine and glutathione, but also carboxylic acids, phosphates and amines. As a consequence, analytical methods have to be chosen to find out the fate of these compounds in cells or, to a larger extent, in living organisms. Since Rosenberg’s discovery analytical chemistry and biotechnologies have shown continuous improvements in terms of data processing speed, accuracy and detection limit. The present issue proposes articles that highlight four techniques that are especially useful for the development of metallodrugs. In the first paper of the series, Peter Sadler and Taotao Zou present general aspects and recent developments in NMR of metal-containing drug candidates. The authors give a brief summary of the important advantages (clearly the unique possibility of analyzing NMR signals of the metal in complex media devoid of these metals in normal conditions) and drawbacks (mainly the low sensitivity) of this technique. Then, they give us an insight into several successes from the literature but also their own experience, especially with probably the most interesting metals for the moment: ruthenium, rhodium, osmium, iridium, platinum and gold. Finally, they conclude by opening the doors to new NMR methods that are now available to study biologically relevant metal complexes.
Franc¸ois Dufrasne is pharmacist and has Ph.D. in pharmaceutical sciences (Universite´ Libre de Bruxelles, Brussels, Belgium). He is professor (organic and pharmaceutical chemistry) in the universities of Brussels and Mons (Belgium). His main research interests focus on the design and synthesis of metal complexes and organic molecules having potential therapeutic applications against cancer, inflammation and diseases of the central nervous system. He is especially interested in the development of cytotoxic platinum complexes and the study of the relationship between their chirality and their bioactivity.
http://dx.doi.org/10.1016/j.ddtec.2015.10.001
31
Drug Discovery Today: Technologies | Editorial
In a second article, another very important technique is described by Hannah Holtkamp and Christian G. Hartinger: capillary electrophoresis (CE). It is interesting to compare the use of CE and NMR that are clearly complementary methods. Indeed if NMR has a clear advantage because it allows performing structural analysis, CE is much more sensitive (especially capillary electrophoresis or CEC) and leads to separation of the metallic species into an electric field thanks to their charge. As a matter of proof, the authors present several examples of applications of CEC in analyzing complex mixtures of adducts of metals with different molecules. They also show future improvements of this technique by its coupling to other analytical tools such as laser-induced fluorescence and mass spectrometry (MS), with a closer look at electrospray ionization and inductively coupled plasma mass spectrometry (ICP-MS), the latter being especially suitable for metal analysis. The link between the contribution of Hannah Holtkamp and Christian G. Hartinger and the next paper is mass spectrometry. This method is certainly the most popular in drug development since it is both accurate and sensitive, and it can be coupled to separation tools. It also gives the researcher an insight into the structure of the compounds. However what are its abilities in metallodrug development? M. Sooriyaar¨ rgen Gailer answer this question in achchi, T.T. Morris and Ju the third paper in which they expose the use of this technique in metal species analysis in blood to explore this aspect of
32
www.drugdiscoverytoday.com
Vol. 16, 2015
pharmacokinetics. They present very practical methods, and analyze the critical points of the experimental design to implement, from sample preparation to experimental and analytical conditions. They also showcase practical applications of this tool. Finally we end this survey with a very new technique presented by a team led by Jacinto Sa`: resonant X-ray emission spectroscopy (RXES). This method, maybe better known by inorganic chemists working in fundamental sciences, has been used successfully to analyze the speciation of cisplatin in water in situ and, more recently, in the analysis of the expected reactivity of Pt complexes stereoisomers. It gives a precise idea of the geometry and the electronic density of the metal center, allowing some correlations with its ability to bond other molecules. Jacinto Sa` and his coauthors describe the potential of this brand new tool in metallodrug development. Potential new therapeutic entities possessing a metal core are waiting behind the drug market’s door and there are so many promising compounds still to be discovered. The present issue of Drug Discovery Today: Technologies will give you a general survey of the most relevant analytical techniques that can be used to develop metal-containing molecules. We hope that you will enjoy the reading of these papers written by world renowned specialists. Best regards, Francois Dufrasne
Vol. 16, 2015
Editors-in-Chief Kelvin Lam – Simplex Pharma Advisors, Inc., Boston, MA, USA Henk Timmerman – Vrije Universiteit, The Netherlands DRUG DISCOVERY
TODAY
TECHNOLOGIES
Editorial
Technologies to develop new metal medicines Francois Dufrasne Laboratoire de Chimie Pharmaceutique Organique, Faculte´ de Pharmacie – Universite´ Libre de Bruxelles Campus Plaine CP 205/5, 1050 Brussels, Belgium. Email: ([email protected])
Looking back to history, physicians would say that most of the metal significant uses in medicine belong to the past, with only few compounds marketed. However chemists and bioinorganic researchers would claim that the future of metals in medicine is certainly wide open with a large variety of compounds and applications looming at the horizon. As a matter of proof numerous research groups work in this field, providing new data about the already well demonstrated or the putative roles that some metals or their complexes could play in human therapy. Another way to assess the popularity of this class of compounds is to turn to the metrics. For example, platinum, gold, copper and iron at least have gathered more than 3000 papers about their uses as curative compounds. Besides these most currently studied species, all the transition metals are considered by renowned specialists of this discipline as strongly underestimated as future cures. At a moment when pipelines of the pharmaceutical industries seem to somewhat dry up it is clear that this class of compounds is still a mine that must be explored to discover new biologically active metal-containing compounds. Historically metals were among the first ‘drugs’ used to treat diseases such as rheumatoid arthritis (gold), infections (bismuth, mercury, arsenic, antimony and silver), anemia (iron), diabetes (vanadium) and inflammation (copper). However, the first breakthrough in the rational development of a bioactive metal-containing compound family was initiated by the serendipitous discovery of the anticancer cisplatin by Barnett Rosenberg in 1965. That was the starting point of a real rush to develop tools for the discovery of metallodrugs, mainly against cancer and, later, other diseases. However, this is a rather common opinion among medicinal chemists that this is a relatively easier task to design an organic drug candidate than an organometallic one. Difficulties can be mainly ascribed to the fact that most of the metals are considered to have pleiotropic actions compared to organic drugs. Metals are able to react, interact or bind with numerous chemical groups present in biologically important molecules of which the most representative are certainly thiols of 1740-6749/$ ß 2015 Elsevier Ltd. All rights reserved.
cysteine and glutathione, but also carboxylic acids, phosphates and amines. As a consequence, analytical methods have to be chosen to find out the fate of these compounds in cells or, to a larger extent, in living organisms. Since Rosenberg’s discovery analytical chemistry and biotechnologies have shown continuous improvements in terms of data processing speed, accuracy and detection limit. The present issue proposes articles that highlight four techniques that are especially useful for the development of metallodrugs. In the first paper of the series, Peter Sadler and Taotao Zou present general aspects and recent developments in NMR of metal-containing drug candidates. The authors give a brief summary of the important advantages (clearly the unique possibility of analyzing NMR signals of the metal in complex media devoid of these metals in normal conditions) and drawbacks (mainly the low sensitivity) of this technique. Then, they give us an insight into several successes from the literature but also their own experience, especially with probably the most interesting metals for the moment: ruthenium, rhodium, osmium, iridium, platinum and gold. Finally, they conclude by opening the doors to new NMR methods that are now available to study biologically relevant metal complexes.
Franc¸ois Dufrasne is pharmacist and has Ph.D. in pharmaceutical sciences (Universite´ Libre de Bruxelles, Brussels, Belgium). He is professor (organic and pharmaceutical chemistry) in the universities of Brussels and Mons (Belgium). His main research interests focus on the design and synthesis of metal complexes and organic molecules having potential therapeutic applications against cancer, inflammation and diseases of the central nervous system. He is especially interested in the development of cytotoxic platinum complexes and the study of the relationship between their chirality and their bioactivity.
http://dx.doi.org/10.1016/j.ddtec.2015.10.001
31
Drug Discovery Today: Technologies | Editorial
In a second article, another very important technique is described by Hannah Holtkamp and Christian G. Hartinger: capillary electrophoresis (CE). It is interesting to compare the use of CE and NMR that are clearly complementary methods. Indeed if NMR has a clear advantage because it allows performing structural analysis, CE is much more sensitive (especially capillary electrophoresis or CEC) and leads to separation of the metallic species into an electric field thanks to their charge. As a matter of proof, the authors present several examples of applications of CEC in analyzing complex mixtures of adducts of metals with different molecules. They also show future improvements of this technique by its coupling to other analytical tools such as laser-induced fluorescence and mass spectrometry (MS), with a closer look at electrospray ionization and inductively coupled plasma mass spectrometry (ICP-MS), the latter being especially suitable for metal analysis. The link between the contribution of Hannah Holtkamp and Christian G. Hartinger and the next paper is mass spectrometry. This method is certainly the most popular in drug development since it is both accurate and sensitive, and it can be coupled to separation tools. It also gives the researcher an insight into the structure of the compounds. However what are its abilities in metallodrug development? M. Sooriyaar¨ rgen Gailer answer this question in achchi, T.T. Morris and Ju the third paper in which they expose the use of this technique in metal species analysis in blood to explore this aspect of
32
www.drugdiscoverytoday.com
Vol. 16, 2015
pharmacokinetics. They present very practical methods, and analyze the critical points of the experimental design to implement, from sample preparation to experimental and analytical conditions. They also showcase practical applications of this tool. Finally we end this survey with a very new technique presented by a team led by Jacinto Sa`: resonant X-ray emission spectroscopy (RXES). This method, maybe better known by inorganic chemists working in fundamental sciences, has been used successfully to analyze the speciation of cisplatin in water in situ and, more recently, in the analysis of the expected reactivity of Pt complexes stereoisomers. It gives a precise idea of the geometry and the electronic density of the metal center, allowing some correlations with its ability to bond other molecules. Jacinto Sa` and his coauthors describe the potential of this brand new tool in metallodrug development. Potential new therapeutic entities possessing a metal core are waiting behind the drug market’s door and there are so many promising compounds still to be discovered. The present issue of Drug Discovery Today: Technologies will give you a general survey of the most relevant analytical techniques that can be used to develop metal-containing molecules. We hope that you will enjoy the reading of these papers written by world renowned specialists. Best regards, Francois Dufrasne