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Beyond C, H, O, and N! Analysis of the Elemental Composition of U.S. FDA Approved Drug Architectures Miniperspective Brandon R. Smith, Candice M. Eastman, and Jon T. Njardarson* Department of Chemistry and Biochemistry, 1306 E. University Boulevard, University of Arizona, Tucson, Arizona 85721, United States S Supporting Information *
ABSTRACT: The diversity of elements among U.S. Food and Drug Administration (FDA) approved pharmaceuticals is analyzed and reported, with a focus on atoms other than carbon, hydrogen, oxygen, and nitrogen. Our analysis reveals that sulfur, chlorine, fluorine, and phosphorous represent about 90% of elemental substitutions, with sulfur being the fifth most used element followed closely by chlorine, then fluorine and finally phosphorous in the eighth place. The remaining 10% of substitutions are represented by 16 other elements of which bromine, iodine, and iron occur most frequently. The most detailed parts of our analysis are focused on chlorinated drugs as a function of approval date, disease condition, chlorine attachment, and structure. To better aid our chlorine drug analyses, a new poster showcasing the structures of chlorinated pharmaceuticals was created specifically for this study. Phosphorus, bromine, and iodine containing drugs are analyzed closely as well, followed by a discussion about other elements.
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phosphorus, bromine, and iodine. Phosphorus is a clear winner for eighth place followed by a secure ninth place for bromine. Remarkably, all four halogen atoms make it into the top 10, with chlorine and fluorine being the heavy hitters (Cl > F ≫ Br > I).3 Phosphorus’ significance among top ranked elements is not a surprise, although it is notable for how many drugs contain it. The rest of the elements, except for boron, are all metals ranging from simple alkalis to transition metals and lanthanoids.4 Iron, platinum, and cobalt are the three most common transition metals utilized. Apart from C, H, O, and N a total of 20 other elements have made it into approved pharmaceutical structures found in our disease focused posters. We next decided to analyze the distribution and relative impact of these elements across the 12 disease categories (Chart 2).56 Among the three heavy hitting elements (sulfur, chlorine, and fluorine), sulfur occupies either first or second place as the most frequently used atom in all 12 disease categories. Chlorine is not far behind with either top or runner up status in 75% of categories. Fluorine is a distant third place with only one top finish (sensory organ drugs) and two silver medals in the categories of endocrine system and anti-infective drugs, and two shared top two finishes with sulfur in dermatological and oncological drugs. Most sulfur drugs are approved for cardiovascular conditions, while the greatest number of chlorinated and fluorinated drugs can be found
e recently analyzed and reported on the structural diversity of sulfur and fluorine containing pharmaceuticals and their distribution as a function of time and disease.1 As part of this analysis, we created new custom pharmaceutical posters displaying drugs containing these important elements arranged chronologically according to approval date.2 Stimulated by what we learned about the significant roles that sulfur and fluorine play in the makeup of U.S. FDA approved pharmaceuticals, we set out to uncover what other elements had made it into approved drugs. Our database of U.S. FDA approved drugs contains 1994 entries and covers drugs approved through the year 2012. Since our primary focus is on small molecule drugs, it is important to mention that this database is composed of 1086 unique small molecules. This number is arrived at by subtracting approved biologics (146) and peptides (23) and removing duplications resulting from combination drugs (537) or drugs approved for use in multiple therapeutic areas. We began the study by analyzing our 12 disease focused pharmaceutical posters for the elemental composition of drugs. What is immediately evident from Chart 1 is that three elements tower over all others in terms of the number of drugs they are found in. Not surprisingly, sulfur and fluorine are two of these three, but interestingly our analysis reveals that chlorine is much more frequented in drugs than fluorine. With sulfur, chlorine, and fluorine occupying positions 5−7, respectively (behind C, H, O, and N) in terms of their frequency in drugs, the remaining top 10 are occupied by © 2014 American Chemical Society
Received: July 28, 2014 Published: September 25, 2014 9764
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Chart 1. Beyond C, H, O, and N
Chart 2. Relative Frequency of Top “Nonessential” Elements Found in Each Disease Category
cancer, with the exception of oxaliplatin which has also been approved for alimentary tract and metabolism conditions. What is evident from our analysis is that chlorine and phosphorus are the most frequently represented heteroatoms in addition to sulfur and fluorine. With several hundred drugs containing these elements, we concluded that it would be of general interest to dig deeper into this intriguing structure space to learn what patterns might emerge. We decided to first take a closer look at U.S. FDA approved phosphorus containing drugs. After removing structure duplications, we realized that we could display all of them in a single montage (Figure 1). This montage7 allows for rapid recognition of phosphorus substitution patterns as well as structural diversity. For example, all except the phosphine gold complex auranofin contain a pentavalent phosphorus atom of which there is close to an even split between representations of phosphate and phosphonate and their derivatives.8 Only one drug, fosinopril, contains a
among nervous system and oncological drugs. Solidly in fourth place, following S, Cl, and F is phosphorus (P) with its highest rank finish (no. 3) among musculoskeletal drugs and a top 5 finish in every disease category besides sensory organ. Phosphorus shines significantly among oncological and endocrine drugs taking fourth place in both. Brominated drugs make it into the top 5 in five instances, with bromine being noticeably represented in respiratory system, nervous system, and sensory organ drugs. Iodinated drugs are in fifth place in four disease categories: cardiovascular, dermatological, endocrine system, and sensory organ drugs. Four other elements (platinum, iron, magnesium, and boron) make it into the top 5 with representation among alimentary tract and metabolism (magnesium), blood and blood forming organs (iron), musculoskeletal (boron), and oncological (platinum) drugs. Platinum drugs are almost exclusively employed to battle 9765
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Figure 1. Phosphorus containing pharmaceuticals.
atom: cobalt in cyano- and hydroxocobalomin and gold in auranofin (for treatment of rheumatoid arthritis). Particularly curious with respect to their structural simplicity, small molecular weights and reactive functional groups are the natural product antibiotic fosfomycin and the synthetic antiviral foscarnet, which contain α-oxirane and carbonyl groups, respectively. Phosphorus-containing moieties are commonly utilized as prodrug elements. This is exemplified by nucleoside prodrugs9 adefovir dipivixil and tenofovir disopropoxil furmate (approved for the treatment of hepatitis B and human immunodeficiency virus (HIV), respectively), as well as fosphenytoin, amifostine, ceftaroline fosamil, fosinopril, cyclo-
phosphinate group (two carbon attachments). A third of those belonging to the phosphate family are either thio (amifostine) or amino (ceftaroline fosamil, ifosfamide, and cyclophosphamide) derivatives. Half of the phosphonic acid pharmaceuticals belong to a class of drugs called bisphosphonates, which are important for the treatment of osteoporosis. Natural products and natural product phosphorus containing motifs are well represented, ranging in structural complexity from B12 vitamin complexes (cyano- and hydroxocobalomin), vancomycin (telavancin), and cephalosporin derivatives (ceftaroline fosamil) to simpler lipid (surfaxin) and carbohydrate (auranofin) structures. Three of the phosphorus drugs contain a metal 9766
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Figure 2. Poster of chlorine containing pharmaceuticals.
phosphamide, ifosfamid, cyanocobalamin, and hydroxycobalamin. There are four disease categories where phosphorus atoms most commonly occur. Those are oncological, anti-infectives, musculoskeletal, and endocrine drugs with 20, 14, 7, and 7 members, respectively. It is worth noting that 14 of the 20 phosphorus containing oncological drugs are marketed and governmentally allowed chemotherapy combination drugs despite not being formally approved as combinations by the FDA.10 When analyzed as a function of time, one learns that 56% of phosphorus containing drugs were approved in the 20year period of 1990−2009. A closer look at the 233 approved chlorine containing drugs reveals a total of 167 unique small molecules (Figure 2). Following in the footsteps of our earlier analyses, for which we created custom sulfur and fluorine focused pharmaceuticals posters, a similar chlorine focused poster was created.11 This new poster is presented as a grid showcasing all the unique chlorine containing drugs in a chronological order with international nonproprietary name (INN), structure, a colorcoded disease category, and year of approval displayed in a minimalist format with the aim of presenting each of the organic architectures as prominently as possible. In analyzing the composition of chlorinated drugs, we chose to first look at their distribution as a function of approval date and disease states for which they were approved for (Chart 3). The disease categories containing the greatest numbers of chlorinated drugs are nervous system (18%), cardiovascular (17%), oncological (14%), and dermatological (10%). Though the chlorine atom in these drugs is not necessarily part of the drug’s pharmacophore, it is often used to tune other parameters such as lipophillicity. Additionally, for drugs whose site of action is the central nervous system, halogenation has been shown to improve blood−brain barrier permeability.3a The greatest numbers of chlorinated pharmaceuticals were approved in the 1980s (17%), 1990s (16%), and 2000s (19%) with a sharp decline in the most recent decade (10%). These approval
Chart 3. Approval Date and Disease Condition Distribution of Chlorinated Pharmaceuticals
numbers are well correlated with an unusually high number of cardiovascular drugs being approved in that same 3 decade span. In the 4 decades since the 1950s, new chlorinated pharmaceuticals were most commonly nervous system drugs, while since the 1990s most are cardiovascular and, most recently, oncological drugs. Other noteworthy spikes are an unusually high number of chlorinated dermatological and oncological drugs being approved in the 1980s and 2000s, respectively. The first two U.S. FDA approved chlorine containing organic pharmaceuticals were chloramphenicol (1949, anti-infective) and hexachlorophene (1949, dermatological). In the following decade (1950s), 26 chlorinated pharmaceuticals were approved, most of which were nervous system drugs (11, 42%). There are a total of 167 unique chlorinated drug structures among the 233 approved chlorine containing pharmaceuticals. 9767
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Chart 4. Percent of Chlorine Atoms and Their Distribution per Chlorinated Drug
Chart 5. Distribution of Chlorine Atom Attachments
We next turned our attention to analyzing what types of carbon atoms the chlorines were attached to. We chose to focus our attention on the hybridization (sp2 vs sp3)12 of the carbon atoms connected to the chlorine atoms as well as whether these carbon atoms were part of a chain or a ring (acyclic vs cyclic). Given the recent discussions and arguments being made for the low frequency of sp3-hybridzation in approved drugs, we were interested in learning what the hybridization statistics for chlorine containing drugs were.13 The data presented in Chart 5 reveal that 83% of chlorine atoms are attached to sp2hybridized carbon atom, 15% to sp3-hybridized ones, and the remaining 2% are either chloride alkali salts or chlorine transition metal ligands. Chlorine incorporation into sp2hybridized rings towers over all other forms of attachment. This may be due to chlorine’s prominent role in Topliss schemes for optimization of phenyl ring substitution in drug design,14 which have been widely utilized by medicinal chemists over the past 40 years. In a comparison of C−Cl hybridization
Of these, the vast majority (73%) contain a single chlorine atom (Chart 4). The rest contain primarily two chlorine atoms (23%), with only a handful of drugs containing three (2.6%), four (1.4%), or six (0.5%) chlorine atoms. Interestingly, no approved pharmaceuticals contain five chlorine atoms. The data in Chart 4 reveal that 98.7% of these chlorine atoms are monosubstituted (CCl), while only four (1.3%) are disubstituted (CCl2) with not a single approved drug containing a CCl3 group. This is in stark contrast with fluorine, wherein a significant number of drugs contain a CF3 group. The four pharmaceuticals that contain a CCl2 group are chloramphenicol, methoxyflurane, mitotane, and trichlormethiazide approved in 1949, 1960, 1970, and 1988, respectively. In all four cases, the dichloride functional group is at the end of a chain (CHCl2) and never within a carbon chain (CCl2). There is one additional drug that contains a geminal dichloride, which is cisplatin wherein two chlorides are attached to a platinum atom. 9768
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Chart 6. C−Cl sp3 vs sp2 Hybridization Distribution as a Function of Disease Category
Figure 3. Distribution of chlorine substituted aromatic and heteroaromatic rings.
C9 (steroid numbering) while alclometasone contains a secondary chloride at C7. Evaluating the C−Cl sp2/sp3-hybridization drug distribution as a function of disease category is equally interesting (Chart 6).15 Chlorinated oncological drugs stand out in this data set, with significantly more drugs containing chlorines connected to sp3-hybridized (26) vs sp2-hybridized (15) carbon atoms. This number is even more remarkable, as it represents 40% of all such sp3-hybridized drugs,16 with dermatological, respiratory, and sensory drug categories being the closest three in representation with 18%, 12%, and 9%, respectively. In contrast, drugs containing a chlorine atom connected to a sp2-hybridized carbon atom are well represented across all 12 disease categories, with most found among cardiovascular (21%) and nervous system (21%) and fewest for musculoskeletal (4%) and
trends as a function of ring vs chain, the trends are quite stark with 99% of chlorine substituted sp2-hybridized carbon atoms being part of a ring while 86% of chlorine substituted sp3hybridized carbon atoms belong to a chain. The structures of these few outliers are shown below. The five drugs that contain a vinyl chloride group are ethchlorvynol, chlorotrianisene, clomifene, cefaclor, and loracarbef. The other five, which have a sp3-hybridized chlorine atom that is part of a ring, are beclomethasone, clocortolone, alclometasone, mometasone, and pimecrolimus approved in 1976, 1977, 1982, 1987, and 2001, respectively. Pimecrolimus is an asomycin type natural product derivative of FK-506, while the other four are all steroidal derivatives of which three (beclomethasone, clocortolone, and mometasone) are decorated with a tertiary chloride at 9769
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Figure 4. Highly reactive chlorinated drugs: nitrogen mustards.
Figure 5. Bromine containing U.S. FDA approved pharmaceuticals.
chloropurine (cladribine and clofarabine), two are pyridines with chlorines in meta-positions (eszopicolone and roflumilast), and the remaining two chlorinated heterocycles are 4chloroimidazole (losartan) and 3-chloro-2,6-diaminopyrazine (amiloride). In the case of the synthetic purine analogues (cladribine and clofarabine) the halogen substitution is critical to the drug’s mode of action; the halogenated purine is incorporated into the genome but disrupts DNA replication and repair.3a Recent research has revealed that halogen bonding is critical to substrate binding in halopurines and many other chlorinated drugs.3d If there is one family of pharmaceuticals wherein chlorine plays a central reactive role, it is nitrogen mustards. The history and origins of nitrogen mustards as chemical warfare and later as chemotherapeutic agents have been well documented.17 Within our database of U.S. FDA approved drugs we identified eight unique pharmaceuticals containing the reactive fragment of nitrogen mustard drugs (β-monochloro or dichloro amino groups). These eight oncological drugs are displayed in Figure
sensory organ (4%) drugs. Only eight approved chlorinated drugs (shown in Figure 7) contain a chlorine atom as part of a stereocenter, of which four are anti-inflammatory corticosteroids (clocortolone, beclometasone, alclometasone, and mometasone), three are anesthetics (halothane, enflurane, and forane), and one is an anti-infective (clindamycin). Of these eight, five are chiral (steroids and clindamycin) and five contain a secondary C−Cl stereocenter (anesthetics, clindamycin, and aclometasone). Since the vast majority of C(sp2)−Cl groups are attached to an aromatic ring, we wondered what the breakdown was with respect to phenyl vs heteroaromatic substituted chlorines. Our analysis reveals that there is not much of a distribution, with 95% of aromatic chlorine containing rings being phenyl. The 11 approved drugs containing heteroaromatic chlorine atoms are represented by eight unique chemical structures (Figure 3), of which five are six-membered rings and three are five-membered rings. Two of these contain a 2-chlorothiophene (rivaroxaban and tioconazole), two are decorated with a 6-amino-29770
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Figure 6. Iodine and platinum containing U.S. FDA approved pharmaceuticals.
Figure 7. “One-hit wonders”.
structures (Figure 5).18 The first brominated pharmaceutical to be approved was the anesthetic halothane in 1956. Halothane is part of a large family of halogenated anesthetic drugs, which are primarily decorated with fluorines or chlorines with halothane being the only one in the family containing a bromine atom. The antihistamine agent brompheniramine was approved the following year (1957), and it belongs to a larger class of antihistamine drugs that share common structural features. Two additional brominated members of this class were approved in the 1970s (dexbrompheniramine) and 1980s (bromodiphenhydramine) of which one is the active single enantiomer of brompheniramine. Pipobroman is an early anticancer agent containing two reactive primary β-bromoamide groups. Nicergoline and bromocriptine, approved for treating among other things dementia and Parkinson’s, respectively, both contain similar ergot alkaloid cores with vastly different side chains. Nicergoline acts on the α1 adrenergic receptor, while bromocriptine acts on the dopamine D2 receptor. Remoxipride, approved for the treatment of schizophrenia, also acts on the dopamine D2 receptor. Bretylium is an ammonium salt that is no longer available. The remaining six brominated pharmaceuticals are remarkable
4 along with a cardiovascular drug (phenoxybenzamine) containing the same reactive fragment. Remarkably, new members are still being approved for this class of drugs, with bendamustine entering the market only a few years ago (2008), 50 years after the first mustard chemotherapy drug was approved (chlorambucil). With respect to the β-chloroamino fragment, five of the eight contain two such fragments connected to a common nitrogen atom of which three are electron rich anilines (chlorambucil, melphalan, and bendamustine) while cyclophosphamide and estramustine are alkylamines decorated with electron withdrawing groups. The other three mustard drugs (lomustine, carmustine, and ifosfamide) are notable for being decorated with functional groups rarely utilized in drugs such as a nitroso and a cyclic aminophosphate. Lomustine and carmustine both share a common urea core, which in the later approved ifosfamide has been replaced by a phosphate group. Lomustine and phenoxybenazmine are the only approved mustard drugs containing a single β-chloroamino group. Bromine is the ninth most commonly utilized element in drug architectures. The 22 approved bromine containing drugs (Figure 1) are represented by 14 unique brominated chemical 9771
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contain rare elements. These include gadolinium,26 gallium, indium, iodine, molybdenum, radium, rubidium, samarium, strontium, technetium, thallium, xenon, and yttrium.27 Also overlooked in our analysis are the many consumer products that contain FDA approved metals such as deodorants, sunscreens, and skin care products. In conclusion, it is fascinating and instructive to learn about the exact frequency, distribution, and diverse ways in which elements other than C, H, O, and N have been incorporated in U.S. FDA approved pharmaceuticals. It is our hope that this analysis serves as a useful reference source and an inspiration for pharmaceutical researchers to incorporate less commonly used elements into their screening collections. Furthermore, we hope the synthetic organic chemistry community uses these analyses as catalysts for devising new and improved ways to synthesize commonly used as well as underrepresented and nonexistent drug architectures with more exotic atoms.
for the diversity of disease conditions they are used to treat, such as open-angle glaucoma (brimonidine), inflammation (bromfenac), HIV (etravirine), thyroid cancer (vandetanib), and multidrug resistant tuberculosis (bedaquiline). With respect to bromine substitution patterns, 12 of the 14 unique structures contain a bromine atom attached to aromatic groups with the remaining two being part of primary (pipobroman) or secondary (halothane) alkyl chains. There are only six drug structures that include iodine (Figure 6),19 of which four contain an aromatic ring with two iodine atoms substituted meta to each other. Liothyronine and levothyroxine are synthetic versions of the naturally occurring thyroid hormones triiodothyronine (T3) and thyroxine (T4) that are used when the body does not form enough of the natural hormones. Interestingly, the enantiomer (dextrothyroxine) of levothyroxine was approved as a cholesterol lowering agent but was discontinued because of significant side effects. The other drug containing more than one iodine atom is amiodarone, which is an antiarrhythmic medication. Idoxuridine, which is an iodinated deoxyuridine used for treatment of herpes simplex keratitis, is one of the first antiviral drugs to be approved by the U.S. FDA. Finally, haloprogin is most fascinating, as it is the only approved drug containing a 1haloalkyne fragment. Haloprogin is an antifungal medication used to treat conditions such as athlete’s foot. Platinum appeared as one of the most commonly employed metal in drugs (Chart 1). A closer look reveals that the 12 approved platinum drugs20 comprise only three unique platinum complexes (cisplatin, carboplatin, and oxaliplatin). Having discussed the frequency, distribution, and structures of the most commonly used heteroatoms among pharmaceuticals, we were curious to take a closer look at the “pioneering” elements that as of today have only made it into one approved drug each.21 Shown in Figure 7 are the nine U.S. FDA approved pharmaceuticals containing those pioneering elements, namely, aluminum, selenium, lithium, potassium, arsenic, magnesium, gallium, gold, and boron. The oldest of these drugs are potassium chloride, which has been in use the longest, and the antifungal agent selenium disulfide. The 1980s saw the introduction of two additional elements in the form of sucralfate and auranofin, which contain the metals aluminum and gold,22 respectively. In the following decade, lithium carbonate23 and gallium(III) nitrate were approved. The two most recently approved drugs in this special category are arsenic trioxide and bortezomib, which are used to treat leukemia and multiple myeloma, respectively.24 It is worth noting that prior to the establishment of the FDA the arsenic containing drug arsphenamine (salvarsan) was widely used for treating syphilis. Only four of these eight drugs are attached to complex organic architectures. Sucralfate and auranofin both contain a glucose group that is either peracetylated or persulfated. Sucralfate contains multiple aluminum atoms, with each sulfate group being connected to an aluminum trihydroxide group, while auranofin has a single gold atom attached to the carbohydrate via an anomeric thioglycoside linkage. Bortezomib, a remarkable recent drug architecture containing a chiral boronic acid group, is the first proteasome inhibitor to be approved for human use.25 While our analysis attempts to highlight all the uncommon elements featured in pharmaceutical drugs, one area that was not analyzed because of its breadth is radiopharmaceuticals. These compounds are worth recognition in this context, as many FDA approved radiopharmaceuticals and contrast agents
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ASSOCIATED CONTENT
S Supporting Information *
A line graph depicting number of approved drugs for top elements (S, Cl, F, P, Br, and I) as a function of the disease condition; a chart of chlorinated pharmaceuticals. This material is available free of charge via the Internet at http://pubs.acs.org.
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AUTHOR INFORMATION
Corresponding Author
*Phone: 520-626-0754. E-mail:
[email protected]. Author Contributions
The manuscript was written through contributions of all authors. All authors have given approval to the final version of the manuscript. Notes
The authors declare no competing financial interest. Biographies Brandon R. Smith received a B.S. from The Pennsylvania State University in December of 2010. Brandon entered the graduate program in chemistry at The University of Arizona in August 2012, and in January of 2013 he joined the research group of Professor Njardarson. Candice M. Eastman is an undergraduate at the University of Arizona pursuing a B.S. in Nutritional Science with minors in Chemistry and Philosophy. She hopes to later attend Pharmacy School and graduate with her Pharm.D. Jon T. Njardarson received his Ph.D. at Yale University, CT, in 2001 with Professor John L. Wood. Following postdoctoral training with Professor Samuel J. Danishefsky at The Memorial Sloan-Kettering Cancer Center, NY, he started his independent career in 2004 at Cornell University, NY. In 2010, Professor Njardarson moved his research group to The University of Arizona.
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ACKNOWLEDGMENTS We thank the National Science Foundation (NSF Grant CHE1266365) for financial support of our pharmaceutical poster outreach projects and resulting analysis efforts.
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ABBREVIATIONS USED FDA, Food and Drug Administration; INN, international nonproprietary name; SEN, sensory organ; RES, respiratory; ONC, oncological; NER, nervous system; MSK, musculoskeletal; GUS, genitourinary and sex hormone; END, endocrine 9772
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(17) (a) Saha, P.; Debnath, C.; Bérubé, G. Steroid-Linked Nitrogen Mustards as Potential Anticancer Therapeutics: A Review. J. Steroid Biochem. 2013, 137, 271−300. (b) Bansal, R.; Acharya, P. C. ManMade Cytotoxic Steroids: Exemplary Agents for Cancer Therapy. Chem. Rev. 2014, 114, 6986−7005. (18) Brominated drugs were discussed recently: (a) Qin, J.; Chen, P. Bromine Pharmacokinetics and Pharmacodynamics. Guangdong Weiliang Yuansu Kexue 2011, 18 (10), 1−21. (b) Qin, J.; Chen, P. Bromine in Medicinal Research and Clinical Application. Guangdong Weiliang Yuansu Kexue 2011, 18 (9), 1−31. (c) Wallwey, C.; Li, S.-M. Ergot Alkaloids: Structure Diversity, Biosynthetic Gene Clusters and Functional Proof of Biosynthetic Genes. Nat. Prod. Rep. 2011, 28, 496−510. (19) It is worth noting that several FDA approved contrast agents contain iodine atoms. Since these are not drugs, we did not include them in our analysis. (20) (a) Wang, X.; Guo, Z. Targeting and Delivery of PlatinumBased Anticancer Drugs. Chem. Soc. Rev. 2013, 42, 202−224. (b) Graf, N.; Lippard, S. J. Redox Activation of Metal-Based Prodrugs as a Strategy for Drug Delivery. Adv. Drug Delivery Rev. 2012, 64, 993− 1004. (21) For a recent discussion of obscure elements in pharmaceuticals, consult the following: Sekhon, B. S. Inorganics/Bioinorganics: Biological, Medicinal and Pharmaceutical Uses. J. Pharm. Educ. Res. 2011, 2, 1−20. (22) (a) Bhabak, K. P.; Bhuyan, B. J.; Mugesh, G. Bioinorganic and Medicinal Chemistry: Aspects of Gold(I)−Protein Complexes. Dalton Trans. 2011, 40, 2099−2111. (b) Berners-Price, S. J.; Filipovska, A. Gold Compounds as Therapeutic Agents for Human Diseases. Metallomics 2011, 3, 863−873. (23) Bschor, T. Lithium in the Treatment of Major Depressive Disorder. Drugs 2014, 74, 855−862. (24) In July 2014 a second boron containing pharmaceutical, tavaborole, received FDA approval as a topical antifungal. (25) Smoum, R.; Rubinstein, A.; Dembitsky, V. M.; Srebnik, M. Boron Containing Compounds as Protease Inhibitors. Chem. Rev. 2012, 112, 4156−4220. (26) Newman, D. J.; Cragg, G. M. Natural Products as Sources of New Drugs over the 30 Years from 1981 to 2010. J. Nat. Prod. 2012, 75, 311−335. (27) Cardinal Health. FDA-Approved Radiopharmaceuticals and Formulary. http://www.cardinal.com/us/en/ nuclearmedicinecompliance/fdaapproved (accessed July 18, 2014).
system; DER, dermatological; CAR, cardiovascular; BBO, blood and blood forming organ; AIN, anti-infective; ALM, alimentary tract and metabolism; HIV, human immunodeficiency virus
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REFERENCES
(1) Ilardi, E. A.; Vitaku, E.; Njardarson, J. T. Data-Mining for Sulfur and Fluorine: An Evaluation of Pharmaceuticals to Reveal Opportunities for Drug Design and Discovery. J. Med. Chem. 2014, 57, 2832−2842. (2) The Njardarson Group. Disease Focused Pharmaceutical Posters. http://cbc.arizona.edu/njardarson/group/content/disease-focusedpharmaceutical-posters. (3) (a) Kosjek, T.; Heath, E. Halogenated Heterocycles as Pharmaceuticals. In Halogenated Heterocycles; Iskra, J., Ed.; Springer: Berlin, 2012; Vol. 27, pp 219−246. (b) Hernandes, M. Z.; Cavalcanti, S. M. T.; Moreira, D. R. M.; de Azevedo, D. W.; Leite, A. C. L. Halogen Atoms in the Modern Medicinal Chemistry: Hints for the Drug Design. Curr. Drug Targets 2010, 11, 303−314. (c) Parisini, E.; Metrangolo, P.; Pilati, T.; Resnati, G.; Terraneo, G. Halogen Bonding in Halocarbon−Protein Complexes: A Structural Survey. Chem. Soc. Rev. 2011, 40, 2267−2278. (d) Wilcken, R.; Zimmermann, M. O.; Lange, A.; Joerger, A. C.; Boeckler, F. M. Principles and Applications of Halogen Bonding in Medicinal Chemistry and Chemical Biology. J. Med. Chem. 2012, 56, 1363−1388. (4) Metals present as a salt counterion are specifically excluded from this analysis. (5) These 12 graphs display the total number of FDA approved drugs containing elements of interest within each disease category. It is important to note that drugs that are approved for multiple diseases are counted and displayed accordingly in these graphs. (6) A line graph displaying the data in Chart 2 is found in the Supporting Information. The rate of elemental substitution per disease category is displayed for sulfur, chlorine, fluorine, phosphorus, bromine, and iodine. (7) We have created a similar montage as a way to display the new drugs approved by the U.S. FDA in 2011: Njardarson, J. T. Pharmaceutical Structure Montages as Catalysts for Design and Discovery. Future Med. Chem. 2012, 4, 951−954. (8) Elliott, T. S.; Slowey, A.; Ye, Y.; Conway, S. J. The Use of Phosphate Bioisosteres in Medicinal Chemistry and Chemical Biology. MedChemComm 2012, 3, 735−751. (9) In December 2013 the phosphoramidate prodrug sofosburiv received FDA approval for treatment of hepatitis C. (10) According to the National Cancer Institute (http://www.cancer. gov), these chemotherapy regimens do not have an official FDA approval; however, each individual molecular component is FDA approved. (11) This new chlorine focused pharmaceutical poster can be downloaded freely as a PDF file from a designated Web page: http:// cbc.arizona.edu/njardarson/group/content/disease-focusedpharmaceutical-posters. (12) There are no approved drugs containing chlorine atoms attached to sp-hybridized carbon atoms. (13) Clemons, P. A.; Bodycombe, N. E.; Carrinski, H. A.; Wilson, J. A.; Shamji, A. F.; Wagner, B. K.; Koehler, A. N.; Schreiber, S. L. Small Molecules of Different Origins Have Distinct Distributions of Structural Complexity That Correlate with Protein-Binding Profiles. Proc. Natl. Acad. Sci. U.S. A. 2010, 107, 18787−18792. (14) (a) Topliss, J. G. Utilization of Operational Schemes for Analog Synthesis in Drug Design. J. Med. Chem. 1972, 15, 1006−1011. and (b) Topliss, J. G. A Manual Method for Applying the Hansch Approach to Drug Design. J. Med. Chem. 1977, 20, 463−469. (15) Numbers are calculated based on all drugs, including nonapproved oncologicals. (16) It is worth noting that this number is somewhat skewed, as it counts ifosfamide as sp3-chlorinated drug component 13 times because of its common use in combination therapies. 9773
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