Chemical Education Today
Research Advances Potential New Drugs: 970 Million and Still Counting; Natural Viagra?; Sugarcoated Quantum Dots for Drug Delivery Angela G. King Department of Chemistry, Wake Forest University, Winston-Salem, North Carolina 27109
[email protected] Many current research projects focus on aspects of molecular medicine. This month's Research Advances highlight the development of a small-molecules database for inspiring new drug design, the scientific assessment of a folk remedy, and the possibility of enhancing drug-delivery mechanisms. Potential New Drugs: 970 Million and Still Counting Like astronomers studying stars in the universe, chemists in Switzerland are reporting the latest results of a survey of the socalled chemical universe where tomorrow's miracle drugs may reside. On the basis of an ongoing count, the scientists conclude that 970 million chemicals are suitable for study as new drugs (1). The study represents the largest publicly available database of virtual molecules ever reported, the researchers say. In the study, Reymond and Blum of the University of Berne point out that the rules of chemical bonding allow elements such as carbon, hydrogen, oxygen, nitrogen, and fluorine to potentially form millions of different molecules. This chemical universe has an enormous potential for drug discovery, particularly for identifying small molecules consisting of 10-50 atoms. Most of today's medicines consist of such small molecules, but until now, scientists had not attempted a comprehensive analysis of the molecules that populate the chemical universe (2, 3). In the report, Reymond and Blum describe development of a new searchable database, GDB-13, that scientists can use in the quest for new drugs (Figure 1). The database consists of all molecules containing up to 13 atoms of carbon, nitrogen, oxygen, sulfur, and chlorine under rules that define chemical stability and synthetic feasibility. The researchers identified more than 970 million possible structures, the vast majority of which have never been produced in the lab. Reymond, Blum, and their colleagues believe that some of these molecules could lead to the design and production of new drugs for fighting disease. Natural Viagra? Move over, Viagra! Researchers in Italy report that an ancient Chinese herbal remedy known as “horny goat weed” shows potential in lab studies as source for new drugs to treat erectile dysfunction (ED). The study provides scientific evidence supporting the herb's well-known folk reputation as a natural aphrodisiac. Mario Dell'Agli and colleagues point out (4, 5) that ED affects an estimated 18 million men in the United States alone. Viagra (sildenafil) and several other prescription drugs are now available for
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Figure 1. Composition of GDB-13. Reprinted with permission from J. Am. Chem. Soc. 2009, 131, 8732-8733. Copyright 2009 American Chemical Society.
ED (6), but studies show that these drugs may cause side effects such as headache, facial flushing, stomach upset, and visual disturbances. To find better treatments, the scientists studied herbal extracts reputed to improve sexual performance, focusing on Tribulus terrestris L., Ferula hermonis, and Epimedium brevicornum Maxim. Scientists assayed the extracts against human cGMP-phosphodiesterase-5 (PDE5), an enzyme that controls blood flow to the penis and whose inhibition results in an erection. Of the extracts tested, only “Epimedii herba” (the common name for the dried aerial parts of E. brevicornum, E. sagittatum Maxim, or E. koreanum Nakai collected in the summer) was active against PDE5. This extract is sold in convenience stores across the country as “horny goat weed”, and its activity is attributed to the presence of icariin (1) in the extract (Figure 2). Chemical modification of icariin yielded compound 2, which potently inhibited PDE5 with an IC50 close to that of sildenafil. Compound 2 offers the potential for fewer side effects than sildenafil because of its increased selectivity for the target enzyme. Sugarcoated Quantum Dots for Drug Delivery Quantum dots (QDs) are nanocrystals that glow when exposed to ultraviolet light. Scientists in Switzerland are reporting
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r 2009 American Chemical Society and Division of Chemical Education, Inc. pubs.acs.org/jchemeduc Vol. 87 No. 1 January 2010 10.1021/ed800024h Published on Web 12/18/2009
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Chemical Education Today
Figure 2. Icariin (1) and a derived compound (2) that inhibited PDE-5 with an IC50 close to that of sildenafil. (Glc is glucose; Rha is rhamnose.) Structures provided by A. King.
an advance that could help tap the much-heralded potential of QDs for the treatment of cancer and other diseases. The scientists are publishing the first study showing that giving QDs an icing-like cap of certain carbohydrates makes them accumulate in the liver but not in other parts of the body (7, 8). The researchers suggest that such selective targeting could be used to deliver anticancer drugs to one organ without causing the body-wide side effects that occur with existing cancer drugs. QDs, which are about 1/5000th the width of a human hair, are inorganic probes that display narrow, size-dependent luminescence with broad absorption spectra (9-11). QD colloidal cores are cytotoxic, so in vivo or in vitro applications require coating the core with a biocompatible material such as polyethylene glycol (PEG). PEG also increases water solubility and can serve as a short tether to attach carbohydrates to the QDs. Because the QD surface can be functionalized with DNA, protein, and small molecules, QDs have been used in solar cells, medical diagnostic imaging, and electronics. Scientists believe these particles also show promise for drug delivery in treating cancer and other diseases. However, until recently, researchers had not found an ideal way to target these dots to specific tissues or organs in order to maximize their effectiveness and limit toxicity. A new report by Peter H. Seeberger and colleagues at the Max Planck Institute of Colloids and Interfaces describes development of a new type of QD coated with sugar molecules attracted to receptors in specific tissues and organs (Figure 3). Certain liver cells expose the asialoglycoprotein receptor (ASGP-R), which binds specifically to galactosyl-terminal glycoproteins. Further work revealed that HepG2 (liver) cells preferentially took up Gal-capped QDs over PEGylated QDs by receptor-mediated endocytosis. In a study with laboratory mice, the scientists coated QDs with either D-mannose or D-galactosamine, both sugars that accumulate selectively in the liver (Figure 4). The sugarcoated dots became 3 times more concentrated in the mice livers than the regular dots did, demonstrating the former's higher specificity. The researchers say that this offers great potential for using the carbohydrate-capped QDs for in vivo targeting. Literature Cited 1. Blum, L. C.; Reymond, J.-L. 970 Million Druglike Small Molecules for Virtual Screening in the Chemical Universe Database GDB-13. J. Am. Chem. Soc. 2009, 131, 8732–8733. 2. J. Chem. Educ. 2008, 85, 1598 describes other research involving database work that includes analysis of existing molecules' shapes.
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Vol. 87 No. 1 January 2010
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Figure 3. Quantum dots and sugars used in this study (n = 45-50). Reprinted with permission from J. Am. Chem. Soc. 2009, 131, 21102112. Copyright 2009 American Chemical Society.
Figure 4. Quantum dots capped with D-mannose, D-galactose, and D-galactosamine have been synthesized. The stable, high quantum yield fluorescence of QDs was exploited to study specific carbohydrate-protein interactions in vitro and in vivo. Copyright 2009 American Chemical Society.
3. This Journal has previously reported on a project for undergraduates that combines drug design and in silico testing. See J. Chem. Educ. 2005, 82, 890. 4. Dell'Agli, M.; Galli, G. V.; Dal Cero, E.; Belluti, F.; Matera, R.; Zironi, E.; Pagliuca, G.; Bosisio, E. Potent Inhibition of Human Phosphodiesterase-5 by Icariin Derivatives. J. Nat. Prod. 2008, 71, 1513–1517. 5. More information on Bosisio's work is available online. See http://www. protease.net.au/index.php?id=23&pid=140 (accessed Nov 2009). 6. A brief history of the work leading to the development of Viagra is found at http://biotechpharmaceuticals.suite101.com/article.cfm/ the_discovery_of_viagra (accessed Nov 2009). 7. Kikkeri, R.; Lepenies, B.; Adibekian, A.; Laurino, P.; Seeberger, P. H. In Vitro Imaging and in Vivo Liver Targeting with Carbohydrate Capped Quantum Dots. J. Am. Chem. Soc. 2009, 131, 2110–2112. 8. More information on Seeberger's work is available online. See http://www. mpikg.mpg.de/Biomolekulare_Systeme/index.html (accessed Nov 2009). 9. Quantum dots are featured in a slideshow on bioimaging available online at http://www.sciencemag.org/feature/data/bioimaging/ ssintro.html (accessed Nov 2009). 10. This Journal has recently published experiments using quantum dots in three undergraduate lab projects. See 2008, 85, 842; 2007, 84, 1301; and 2005, 82, 1700. 11. Excellent background material and visualizations that start with “What is a quantum dot?” and range to large and ongoing research projects are available online at http://cobweb.ecn.purdue.edu/ ~gekco/topics/quantumdots/index.html (accessed Nov 2009).
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r 2009 American Chemical Society and Division of Chemical Education, Inc.
