Communication pubs.acs.org/jchemeduc
An In-Pharm-ative Educational Poster Anthology Highlighting the Therapeutic Agents That Chronicle Our Medicinal History Elizabeth A. Ilardi, Edon Vitaku, and Jon T. Njardarson* Department of Chemistry & Biochemistry, University of Arizona, Tucson, Arizona 85721, United States S Supporting Information *
ABSTRACT: Disease Focused Posters is a new, free, and readily accessible collection of graphical timelines that arrange the vast number of FDA approved pharmaceuticals according to a specific theme. Capitalizing on the elegance of structural imagery and the innovative functions of organic compounds, each poster (in its simplistic appearance) has the capacity to communicate a wealth of information that appeals to the educational desires of the public, from the nonscientist to the expert.
KEYWORDS: Continuing Education, General Public, Graduate Education/Research, Upper-Division Undergraduate, Organic Chemistry, Inquiry-Based/Discovery Learning, Internet/Web-Based Learning, Applications of Chemistry, Drugs/Pharmaceuticals, Natural Products
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simplistic appearance was envisioned to appeal to a variety of audiences with different educational backgrounds. Each poster is organized into a thematic graphical list of pharmaceuticals with their structures strategically placed as focal points. The drugs are further described by four additional characteristics: initial market name, International Nonproprietary Name (INN),5 color-coded subclass of function, and the date approved by the FDA (Figure 1).6 From this set of information conveniently displayed on one page, it is possible that any viewer can extract additional knowledge of organic architecture and utility without the need of formal instruction. Currently, a variety of posters themed according to the drugs’ association with a particular clinical indication have been produced. These include Anti-Infective, Cardiovascular System, Nervous System, Sensory Organ, Respiratory System, Musculo-Skeletal, GenitoUrinary and Sex Hormone, Endocrine System, Blood and Blood Forming Organs, and Alimentary Tract and Metabolism. Gratifyingly, this project is not limited in the number of thematic montages that can be created. Uniquely defined posters can materialize based upon different parallels that are contained within this anthology. It is probable that the drugs can be reorganized into posters with innovative themes, such as approval year, structural diversity (substituent or core architecture), according to other functional similarities, or even tailored to a viewer’s specific conceptual request. The collection has recently expanded to include two additional posters: Fluorinated Pharmaceuticals and Sulfur Containing
n 1937, the ill preparation of a sulfanilamide medication (“Elixir Sulfanilamide”) that used the toxic substance diethylene glycol (DEG) was responsible for the deaths of more than 100 people in the United States. As a result, the U.S. Food and Drug Administration (FDA) initiated a formal establishment of strict provisions for pharmaceutical companies and products, as well as specific mandates for biological chemicals. Since then, thousands of “new molecular entities” and “new drug applications” have been approved for commercial usage.1 Consequently, inspired by the continued instructive successes of our Top200 pharmaceutical posters2 and the interactive Web-based virtual flashcard database, Chemistry by Design,3 the challenge was to organize this abundance of available new drug information. In conjunction with a selection of early medications used since the 18th century, a novel educational device that would continue to operate as a mode of data mining, as well as a catalyst for discovery, came to life. Although a few drug databases do exist,4 the aim was to develop a comprehensive, yet concise, poster compilation composed of this valuable information. The basis of the design was motivated by the notion that artistic models serve as productive visual aids that both reinforce an objective and provoke the exchange of new ideas. The concept of the Top200 drug posters evolved by employing the powerful graphical language of organic chemistry that spans pharmaceutical history. The collection of posters is intended to serve as a multifaceted vehicle for sparking ideas, enhancing knowledge, and promoting conversations among both nonscientists and the experts. In the development of this project, the necessity of a © XXXX American Chemical Society and Division of Chemical Education, Inc.
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Figure 1. Graphical representation of the Nervous System Drugs from 1880 to 2011 with expanded view of the poster contents.
Pharmaceuticals. Overall, the opportunities for gaining new educational insights are continual. The scope of information that can be mined from each poster, despite its minimalistic appearance, is remarkable. In addition to the five characteristics of representative data, a viewer can ascertain an assortment of qualitative trends, specifically, the many changes that have occurred in drug development over time. From a historical perspective, the posters act as platforms for further exploration into the history behind each pharmaceutical using other sources, such as those invaluable lessons learned from futile drugs like Elixir Sulfanilamide and other recalled medicines. As an archival collection, the evolution of the types of therapeutics that were formulated within different decades is not only a testament to the relevant diseases of each historical time period, but also a significant display of structural and functional advancement. It is evident from the images that drugs can be constituted of varying compositions and architectures, ranging from the simple inorganic potassium chloride to large complex organic natural products, such as paclitaxel. Presently, examination of the data set of all pharmaceuticals revealed that about 20% of all pharmaceuticals contain the element fluorine in addition to C, H, N, O. Several medicines also incorporate sulfur, with some of the earliest examples including antibiotics containing sulfonamides (sulfa-drugs) and β-lactams as imperative constituents for bacterial protection. Aromatics, nucleoside analogues, peptides, heterocycles, cyclopropanes, and cyclobutanes (rarely found in nature), and some violations of the Lipinski Rules are all represented, which appeal to the powerful relationship between structural motif and drug discovery. Figure 2 displays representative structural motifs of pharmaceuticals selected from various posters. The colored descriptors, specifically, the highlighted structure and name of functional group class, however, are not incorporated into the posters available on the Internet. Intriguingly, it is also apparent that many molecular frameworks are multifunctional and have survived the test of time. Examples include the innate values of the penicillin or cephalosporin cores that make up suitable Anti-Infective drugs, the benzodiazepine architecture in drugs associated with the
Figure 2. Representative pharmaceuticals bearing common structural motifs. Note that these examples were selected from various posters in the collection, and each functionality is highlighted and named. Those specific colored descriptions are not included in the posters available on the Internet.
Nervous System, and the steroid scaffold used for Cardiovascular (and other) complications among many others. Combination drugs were also included, as the importance of structural and functional compatibilities are significant. Furthermore, it is notable the efficiency of the use of biologics (i.e., vaccines, growth hormones, fusion proteins, etc.) to target different parts of the body, as well as their increasing appearance in new drugs developed within the last 20 years. For instance, none appear on the poster displaying the AntiInfective drugs, and only 2 of 292 on the Nervous System poster. Contrarily, biologics have now transpired as a new class of rheumatologic, oncologic, dermatologic, gastroenterologic (and other) therapeutic alternatives for the treatment of many diseases. The emphasis on minimalism as a part of the graphical design philosophy should significantly engage both the novice and professional and has the potential to be an effective educational catalyst for advancing combinatorial chemistry and B
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(7) Prototypes of three of these posters were first presented at the 33rd National ACS Medicinal Chemistry Symposium, Tucson, Arizona, May 19−23, 2012. Our Disease Focused Posters can be found at the Njardarson Research Group Website. http://www.cbc. a ri z o n a . e d u / n j a r d a r s o n / g r o u p / c o n t e nt / d i s e a s e - f o c u s e d pharmaceutical-posters (accessed Aug 2013).
drug discovery. The posters are available on the Internet as PDF files that can be downloaded and printed free of charge.7 The development of an interactive Web application is planned that will continue to celebrate the beauty of organic architecture as well as concisely inform the public of pertinent information associated with each pharmaceutical.
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ASSOCIATED CONTENT
S Supporting Information *
PDF files for Anti-Invective Drugs, Nervous System Drugs, and Cardiovascular Drugs. This material is available via the Internet at http://pubs.acs.org.
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AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS We would like to thank the National Science Foundation for initial support (NSF Grant No. 0848324 and Grant No. CHE1266365) and Daniel J. Mack, Monica A. Fallon, and Erik B. Gerlach for invaluable assistance in putting the posters together.
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REFERENCES
(1) Information regarding the history of the U.S. FDA can be found at U.S. Food and Drug Administration Web Page. http://www.fda. gov/ (accessed Aug 2013). (2) Mcgrath, N. A.; Brichacek, M.; Njardarson, J. T. A Graphical Journey of Innovative Organic Architectures That Have Improved Our Lives. J. Chem. Educ. 2010, 87, 1348−1349. Our Top200 drug posters can be found at the Njardarson Research Group Web site. http:// www.cbc.arizona.edu/njardarson/group/top-pharmaceuticals-poster (accessed Aug 2013). (3) Draghici, C.; Njardarson, J. T. Chemistry By DesignA Web Based Educational Flashcard for Exploring Synthetic Organic Chemistry. J. Chem. Educ. 2012, 89 (8), 1080−1082. Chemistry by Design can be found at Chemistry By Design Web Page. http://www. chemistrybydesign.oia.arizona.edu (accessed Aug 2013). (4) Selected drug databases: (a) Goede, A.; Dunkel, M.; Mester, N.; Frömmel, C.; Preissner, R. SuperDrug: A Conformational Drug Database. Bioinformatics 2005, 21, 1751−1753. (b) Zhu, F.; Shi, Z.; Qin, C.; Tao, L.; Liu, X.; Xu, F.; Zhang, L.; Song, Y.; Liu, X. H.; Zhang, J. X.; Han, B. C.; Zhang, P.; Chen, Y. Z. Therapeutic Target Database Update 2012: A Resource for Facilitating Target-Oriented Drug Discovery. Nucleic Acids Res. 2012, 40, D1128−D1136. (c) WhirlCarrillo, M.; McDonagh, E. M.; Hebert, J. M.; Gong, L.; Sangkuhl, K.; Thorn, C. F.; Altman, R. B.; Klein, T. E. Pharmacogenomics Knowledge for Personalized Medicine. Clin. Pharmacol. Ther. 2012, 92, 414−417. (5) IUPAC Compendium of Chemical Terminology, Gold Book. http://goldbook.iupac.org/index.html (accessed Aug 2013). (6) We collected and confirmed data using several sources including: (a) Knox, C.; Law, V.; Jewison, T.; Liu, P.; Ly, S.; Frolkis, A.; Pon, A.; Banco, K.; Mak, C.; Neveu, V.; Djoumbou, Y.; Eisner, R.; Guo, A. C.; Wishart, D. S. DrugBank 3.0: A Comprehensive Resource For ’Omics’ Research On Drugs. Nucleic Acids Res. 2011, 39, D1035−D1041. (b) Drug Information Online. http://www.drugs.com/ (accessed Aug 2013); (c) CenterWatch: FDA Approved Drugs. http://www. centerwatch.com/drug-information/ (accessed Aug 2013); (d) Approved Drug Products with Therapeutic Equivalence Evaluations (Orange Book), 33rd, ed.; U.S. Department of Health and Human Services, U.S. Food and Drug Administration: Rockville, MD, 2013. C
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