Perspective

pubs.acs.org/jmc

Data-Mining for Sulfur and Fluorine: An Evaluation of

Pharmaceuticals To Reveal Opportunities for Drug Design and
Discovery
Miniperspective
Elizabeth A. Ilardi, Edon Vitaku, and Jon T. Njardarson*
Department of Chemistry and Biochemistry, University of Arizona, 1306 E. University Boulevard, Tucson, Arizona 85721, United
States
*
S Supporting Information

ABSTRACT: Among carbon, hydrogen, oxygen, and nitrogen, sulfur and

fluorine are both leading constituents of the pharmaceuticals that comprise our
medicinal history. In efforts to stimulate the minds of both the general public
and expert scientist, statistics were collected from the trends associated with
therapeutics spanning 12 disease categories (a total of 1969 drugs) from our new
graphical montage compilation: disease focused pharmaceuticals posters. Each
poster is a vibrant display of a collection of pharmaceuticals (including structural
image, Food and Drug Administration (FDA) approval date, international
nonproprietary name (INN), initial market name, and a color-coded subclass of
function) organized chronologically and classified according to an association
with a particular clinical indication. Specifically, the evolution and structural
diversity of sulfur and the popular integration of fluorine into drugs introduced
over the past 50 years are evaluated. The presented qualitative conclusions in
this article aim to promote innovative insights into drug development.

P harmaceuticals have a profound effect on the overall well-

being of society. Each year, the pharmaceutical industry
produces a wealth of useful information characterizing the
language of organic chemistry to educate both the nonscientist
and the expert researcher (Table 1a).7 Our database consists of
thematic graphical timelines of the first formulations of drugs
drugs that have been developed. Conveniently, there exists approved by the United States Food and Drug Administration
several drug databases that organize these descriptive proper- introduced over the past century. Currently our collection
ties, including data regarding drug structure, function, consists of 1969 compounds, and newly approved drugs will be
pharmacology, pharmacokinetics, etc.1−3 Unfortunately, some
added annually. All therapeutics are grouped according to an
databases are minimal in scope or are difficult to navigate;
therefore, strategic analyses, such as the evaluation of association with 12 disease categories (Anti-Infectives, Car-
architectural or functional patterns that are present within diovascular, Alimentary Tract and Metabolism, Musculoskeletal
these sets of drugs, have been limited. The identification of System, Oncological, Blood and Blood Forming Organs,
qualitative trends and patterns among all pharmaceuticals, or Endocrine System, Respiratory System, Dermatological, Nerv-
data mining, is a profitable method to highlight new ous System, Sensory Organ, and Genitourinary and Sex
opportunities for drug discovery.4 Statistics regarding functional Hormone).8 Inspired by the educational success of our earlier
group, molecular composition, atom and substitution arrange- Top200 drug posters, each pharmaceutical is represented by its
ments, or target medical condition that characterizes each structure, initial market name, INN, color-coded subclass of
structure can act as guides for the development of new function, and the initial date approved by the FDA.9−12 The
synthetic strategies, formulation of new drugs, and the spartan descriptions enable a nonspecialist to obtain
advancement of chemical education.5 This information can information about organic architecture and utility without the
also aid in identifying deficiencies within pharmacopoeia itself.
need of formal instruction. The database can continuously grow
Images of molecular architectures serve as effective catalysts
that provoke serendipitous discovery. Over the years we have as new drugs are approved annually. Perhaps the most
learned that establishing a detailed knowledge of common profitable facet of this compilation is that it can also perpetually
pharmaceutical structural motifs can reveal areas for the evolve. Uniquely themed posters can materialize based upon
development of new synthetic methodologies.6 Consequently,
our second-generation of graphical montages, the disease Received: September 6, 2013
focused pharmaceutical posters, harnesses the illustrative Published: October 8, 2013

© 2013 American Chemical Society 2832 dx.doi.org/10.1021/jm401375q | J. Med. Chem. 2014, 57, 2832−2842
Journal of Medicinal Chemistry Perspective

Table 1. (a, Left) Percent Composition of Small-Molecule, Combination, and Biological Pharmaceuticals in the 2011 Top200
Brand Name Drugs by U.S. Retail Sales and by Total U.S. Prescriptions, (b, Middle) Percent Composition of Drugs Containing
Sulfur or Fluorine (Excluding Biological Drugs) Using the Same Data Set, and (c, Right) Structures of Sulfur-Containing Drugs
in the Top 20 Drugs by U.S. Retail Sales and by Total U.S. Prescriptions in 2011.

Figure 1. Top200 pharmaceutical posters (produced annually) and disease focused pharmaceutical posters (12 primary posters, future montages
produced by demand).

drug similarities, parallels, or patterns contained within this combination drugs in our database. Following an initial
library of pharmaceuticals. tabulation of the sulfur-containing and fluorinated pharmaceut-
The subsequent analysis is intended to provide a practical icals in both of the Top200 brand name drugs by U.S. retail
example of how simple data-mining can transform what may sales in 2011 and Top200 brand name drugs by total U.S.
seem like a daunting amount of information into a springboard prescriptions in 2011, we then evaluated the overall diversity
for inspiration, application, and/or further investigation using and evolution of sulfur and fluorine in pharmaceuticals over
supplementary resources. Of the principal elements that time (Figure 1).
comprise all drugs (carbon, hydrogen, oxygen, or nitrogen), The use of organosulfur compounds as medicinal remedies
sulfur represents the fifth most prevalent element in overall dates back to the ancient Egyptians, who described a sulfuric
architectural representation and biological significance. Sulfur ointment with mild antiseptic effects. Similarly, the mytho-
compounds are in clinical use for variable medical conditions, logical writings of the ancient Greeks depicted injured warriors
such as depression, arthritis, diabetes, cancer, and acquired healing in the sulfur-rich baths of Agamemnon. During the
immune deficiency syndrome (AIDS) since the formal Victorian era in Europe, people often used “brimstone and
establishment of the FDA in the early 20th century.13 treacle” as a laxative and tonic for children.15 In the 1920s,
Moreover, fluorine, the smallest halogen and most electro- “colloidal’” sulfur was regularly administered to patients
negative element, is a key constituent of about 20% of recently suffering from rheumatoid arthritis. Eventually, modern medical
approved pharmaceuticals.14 This Miniperspective investigates applications of sulfur-containing compounds have grown to
select statistics associated with the incidence of sulfur and include antibacterials, anti-inflammatories, dermatologics, and
fluorine in the molecular composition of small-molecule and cancer treatments.13 Considering the age of drug resistance and
2833 dx.doi.org/10.1021/jm401375q | J. Med. Chem. 2014, 57, 2832−2842
Journal of Medicinal Chemistry Perspective

Table 2. (a, Top) Percent Composition of Small-Molecule, Combination, and Biological Pharmaceuticals Introduced by Decade
and (b, Bottom) Percent Composition of Small-Molecule, Combination, and Biological Pharmaceuticals That Comprise Each
of the 12 Representative Disease Categories

the continual need for the development of medicinal therapies, Noteworthy advances in the development of fluorinated
existing sulfur-containing compounds may provide leads to drugs as anesthetics, blood substitutes, antivirals, antifungals,
forthcoming pharmaceuticals. fluorinated steroids, anti-inflammatories, central nervous system
The medicinal impact of organosulfur compounds is (CNS) medications, and anticancer therapies have been
extraordinary. Inspection of the structures of compounds accomplished within the past 10 years.17 However, to date,
within both of the Top200 brand name drugs by U.S. retail the representation of fluorine is markedly less, existing in only
sales (RS) in 2011 and Top200 brand name drugs by total U.S. 15% of the top 20 drugs, particularly, as a fluorinated aromatic:
prescriptions (P) in 2011 revealed that 24.8% and 22.5% of Lipitor (atorvastatin, no. 1 RS, no. 5 P), Crestor (no. 8 RS, no.
drugs (excluding biological drugs) contain this heteroatom.16 In 10 P), and Lexapro (escitalopram, no. 18 RS, no. 16 P).
Conclusively, the percentage of sulfur-containing drugs exceeds
addition, 40% and 25% of the top 20 drugs by RS and P,
fluorinated compounds in both surveys.
respectively, including Plavix (clopidogrel, no. 2 RS, no. 7 P, Historically, small-molecule compounds range in architec-
thiophene), NexIUM (esomeprazole, no. 3 RS, no. 11 P, tures from simple organic acyclics and heterocyclics to complex
sulfinyl), Seroquel (quetiapine, no. 6 RS, thiazepine), Singulair peptides, carbohydrates, and natural products (Table 2).18
(montelukast, no. 7 RS, no. 8 P, thioether), Crestor However, the first biological drug, a biosynthetic “human”
(rosuvastatin, no. 8 RS, no. 10 P, sulfonamide), Cymbalta insulin trade-named Humulin, was developed by Genentech
(duloxetine, no. 9 RS, thiophene), Actos (pioglitazone, no. 13 and manufactured/marketed by Eli Lilly and Company. Since
RS, thiazolidinedione), Zyprexa, (olanzapine, no. 16 RS, its approval for therapeutic use in 1982, most of the
thiophene), and amoxicillin (no. 20 P, β-lactam) contain sulfur. biopharmaceutical products derived from natural sources have
2834 dx.doi.org/10.1021/jm401375q | J. Med. Chem. 2014, 57, 2832−2842
Journal of Medicinal Chemistry Perspective

Table 3. (a, Left) Percent Composition of Sulfur-Containing and Fluorinated Pharmaceuticals per Decade within 12
Representative Disease Categoriesa and (b, Right) Fluorinated Pharmaceuticals Poster

a
The number above each bar reflects the combined total number of drugs approved during each decade (excluding biological drugs and oncological
combination therapies).

Table 4. Percent Composition of Sulfur-Containing and Fluorinated Pharmaceuticals That Comprise Each of the 12
Representative Disease Categoriesa

a
The number above each bar reflects the total number of drugs in each category (excluding biological drugs).

grown to include proteins, nucleic acids (deoxyribonucleic acid nitrogen) through the present. Generally, advantages to the
(DNA), ribonucleic acid (RNA), or antisense oligonucleo- carbon−fluorine bond include its metabolic stability and the
tides), and living microorganisms (viruses and bacteria).19 fact that fluorine acts as a bioisostere of the hydrogen atom.
Upon the basis of the results in Table 2, biologics, such as The incorporation of fluorine generally increases a molecule’s
synthetic insulin analogues, encompass a considerable percent- lipophilicity, facilitating bioavailability (as in minimizing the
age of drugs for the treatment of conditions dealing with blood potential cytochrome P450 enzymatic oxidation of proximate
and blood forming organs. Indeed, the 146 representative functionalities), which in turn maximizes medicinal benefits at a
biologics (out of 1969 drugs) featured in the posters provide a lower dosage.26 However, there is also a subset of molecules
significant medicinal impact within other disease therapies where the introduction of fluorine can actually increase the
including rheumatology, oncology, cardiology, dermatology,
hydrophilicity of molecules, in which many of these had a
gastroenterology, and neurology. Although many contain sulfur,
fluorine atom within 3 Å of an O atom.27 Currently, over 225
primarily in the form of disulfides and amino acids,20 the focus
of the following analysis will concern the range of sulfur motifs fluorinated small-molecule and combination pharmaceuticals
within small-molecule and combination drugs that have been have been FDA approved exhibiting widespread biological
introduced since the early 1900s. activity since 1955. The rise of fluorinated agents may be on the
As evident by Table 3, the frequency of new fluorinated horizon; nevertheless, sulfur continues to sustain its status as a
drugs has been gradually rising since their first appearance in leading biologically relevant structural component. The
the 1950s.21−26 However, sulfur continues to maintain its status structural constraints of fluorine, as in the limitations associated
as the dominating heteroatom integrated into the set of 362 with valency, severely limit the development of varied drug
sulfur-containing FDA approved drugs (besides oxygen or candidates.28,29
2835 dx.doi.org/10.1021/jm401375q | J. Med. Chem. 2014, 57, 2832−2842
Journal of Medicinal Chemistry Perspective

Figure 2. Structural diversity of sulfur-containing and fluorinated functional groups that describe the molecular architecture of the pharmaceuticals
within 12 representative disease categories.

Table 5. Percent Composition of Occurrences of Each Sulfur-Containing Functional Group (410 Instances in 369 Total Drugs)
That Describe Sulfur-Containing Pharmaceuticals within the 12 Representative Disease Categories (Excluding Biological
Drugs)

Of the 12 disease categories surveyed (Table 4), sulfur is to treat a variety of diseases. Still, the same fluorinated scaffold
more heavily represented, prevailing in 10/12 groups, and has been established for dermatological treatments, which is
comprises >50% more drugs than fluorine in the Anti-Infectives conceivably a factor that contributes to the equal distribution of
catagory and >60% in Cardiovascular and Musculoskeletal both sulfur and fluorine in this category. However, studies have
categories. While sulfur clearly has the advantage of forming
confirmed the development of many adverse effects of inhaled
more structurally diverse bonds, fluorinated compounds surpass
corticosteroids or application of fluorinated therapies to the
organosulfurs by nearly 30% for sensory organ therapies.
Perhaps this dominance can be attributed to the evolution of face, including glaucoma.30,31 Therefore, even though a drug
analogues of synthetic fluorinated steroids, corticosteroids, and scaffold may seem to recur throughout history, evidence of
prostanoids derived from their C−H precursors developed as unfavorable side effects reflects the continual need for skeletal
extremely potent ophthalmological and otological agents used improvement. Although it appears that the distribution of sulfur
2836 dx.doi.org/10.1021/jm401375q | J. Med. Chem. 2014, 57, 2832−2842
Journal of Medicinal Chemistry Perspective

Table 6. Percent Composition of the Top Sulfur-Containing Functional Groups That Comprise Newly FDA Approved Drugs
per Decadea

a
The number on the top of each bar indicates the total number of sulfur functional groups in each category.

and fluorine is comparable in a few categories, the global range ties against a wide range of bacteria. It was determined that the
of structure and function of sulfur compounds is far superior. sulfanilamide portion of the molecule was responsible for this
Elemental sulfur is nontoxic and essential for life. The human biological effect, acting as a bioisostere of carboxylic acid
body consists of nearly 0.25% sulfur, which is a crucial groups. Sulfanilamide inhibited the action of the physiological
component of many biological processes.32 As a third row substance p-aminobenzoic acid (PABA) (required by bacteria
element with the capacity to expand its valence shell to form to synthesize folic acid), inspiring the theory for the mechanism
more than four covalent bonds and to assume oxidation states of action of drugs that is based on substance antagonism.38 In
ranging from −2 to +6, sulfur can form a variety of molecular the years following, manufacturers continued to produce
arrangements, making it one of the most chemically versatile of thousands of sulfa drug analogues, eventually leading to the
the early elements.33 A survey of the structures in our data set toxic preparation of “elixir sulfanilamide”, a medical disaster
determined that the architectures of sulfur-containing drugs can that poisoned and killed over 100 people with diethylene glycol,
be classified into 10 different categories of various permutations which was the cause of death. This event sparked the passage of
of organosulfur derivatives including sulfonamide, sulfone, the Federal Food, Drug, and Cosmetic Act, which gave
sulfinyl, thioester, thioether, thiophene, thiazole, β-lactam, authority to the FDA to oversee the safety of drugs and
thiazepine/thiazine, and thiadiazole, illustrated in Figure 2.34 production.39 Since sulfanilamide, more than 150 different
Drugs consisting of minimally represented structural compo- derivatives have appeared on the market, chemically modified
nents were characterized according to two additional functional
to achieve more effective antibacterial activity, wider spectrum
group classes, miscellaneous acyclic and miscellaneous cyclic.
of microorganisms affected, or more prolonged action.
Not surprisingly, over 10% of all compounds contain more than
Sulfonamides also have an extensive biological profile, known
one, or more than one type, of the listed functionalities.
Contrarily, fluorine is chemically restricted to bonding to exhibit antibacterial, hypoglycemic, diuretic, anticarbonic
predominantly35,36 with carbon, so the multiplicity of com- anhydrase, antithyroid, anti-inflammatory, antihypertensive,
pounds that can be generated is somewhat restricted. anticonvulsant, and anticancer properties. These compounds
The impact of the development of sulfur therapeutics was are relatively inexpensive to produce and are still used in many
instrumental to the evolution of the pharmaceutical industry. parts of the world to treat fungal diseases in combination with
Undoubtedly, several valuable lessons have been learned from other drugs synergistically.38 On the other hand, it is no secret
both the successes and failures of pioneering drugs, as well as that several sulfonamide drug combinations or individual drugs
from the paths leading to their production. Table 5 reflects the have been said to cause immune mediated allergic reac-
recurrence of a specific functional group in the set of sulfur- tions.40,41 However, reactions such as hypersensitivity or severe
containing drugs. Notably, over 25% of compounds contain a skin rashes are now associated with the presence of an aniline
sulfonamide substituent, present nearly 29% of the time. “Sulfa structure and have been incorrectly associated with solely
drugs”, or synthetic substances derived from sulfanilamide (p- sulfonamide-containing drugs.42,43 In some cases, a person can
aminobenzenesulfonamide), emerged as effective treatments for be desensitized to these adverse responses using a gradient
bacterial infections and diabetes through the 1940s.37 In 1932, dosage.44 Currently, sulfa drugs are receiving renewed interest
Gerhard J. P. Domagk discovered that a prodrug derived from for the treatment of infections caused by bacteria resistant to
sulfanilamide, trade-named Protonsil, had antagonistic proper- other antibiotics.45
2837 dx.doi.org/10.1021/jm401375q | J. Med. Chem. 2014, 57, 2832−2842
Journal of Medicinal Chemistry Perspective

Table 7. Percent Composition of the Majority of Sulfur-Containing Functional Groups That Comprise Pharmaceuticals in Each
of the 12 Representative Disease Categoriesa

a
The number above each bar reflects the total number of sulfur-containing drugs in each category (excluding biological drugs).

Penicillins (penams), cephalosporins (cephems), and mono- integrated into drugs that have yet to be marketed. In
bactams constitute the broad class of β-lactam antibiotics, the particular, the incorporation of the sulfonamide RSO2NHR′
second most prevalent sulfur scaffold (10.5% representation). is a strategic approach to designing compounds with limited
In 1929, Alexander Fleming first isolated penicillin from the CNS penetration.45 Recently, isothioureas and related com-
fungal strain when he observed that bacterial cultures of pounds have been found to be inhibitors of the aspartyl
Staphylococcus in his laboratory were killed by a mold protease β-secretase, which is known to play a role in
contaminant, Penicillium notatum. The discovery of penicillin Alzheimer’s disease.53 The chemically stable sulfoximine
was a breakthrough in modern medicinal chemistry, leading to functionality retains many favorable medicinal properties but
efficient mass production ($0.55/dose in 1946). In 1944, the has been significantly overlooked as a feature of potential
determination of penicillin’s crystal structure, the β-lactam ring clinical candidates.54 In addition, the strongly electron-with-
fused to a five-membered thiazolidine ring, by Dorothy drawing and chemically inert pentafluorosulfanyl (SF5)
Hodgkin paved the way for the development of enhanced substituent possesses a greater lipophilicity than CF3 and is
antibiotics through structural modification.46−48 Today, amox- metabolically stable.36,37,55,56 Further investigation of such
icillin is still one of the most widely prescribed β-lactam minimally explored discoveries in sulfur (or fluorine) chemistry
antibiotics since it initially entered the market in 1972. Twenty can only enhance drug design and development.
years later, it was developed into a thriving combination drug From a historical perspective, sulfonamides have been a
treatment for drug-resistant bacteria including clavulanic acid, leading constituent in new drugs since the first appearance in
trade-named Augmentin (approved 1996). Furthermore, the 1930s, occupying six different decades over the past 100
cephalosporin analogues containing a β-lactam ring fused to a years (Table 6). Introduced in 1959, hydrochlorothiazide, a
six-membered dihydrothiazine ring exhibit more potent sulfonamide-based diuretic is a component of nearly 7% of all
antibacterial properties. Since the medicinal launch of cefalotin small-molecule and combination drugs, has been derivatized
in 1964, six generations of these agents have been synthesized into several multifunctional analogs, and remains a successful
for clinical use.49 Monobactams, like aztreonam (Azactam, additive used today.57 Interestingly, the prominence of β-
approved 1986), are often used in the treatment of lactams has declined, while pharmaceuticals containing
meningitis.50 thiazoles are resurfacing since the 1940s and 1950s. Over the
Thiazoles and thioethers are equally represented (both 8.8%) past 30 years, thioethers and thiophenes have also emerged as
as the third most exemplified constituent. Commercially key functional group substituents.
significant thiazoles include many nonsteroidal anti-inflamma- Evidently, the inclusion of sulfur into new drugs became
tory drugs (NSAIDs) like the widely prescribed Mobic increasingly popular prior to the 2000s. During the 1990s,
(meloxicam) and are known to exhibit chemotherapeutic sulfur-containing drugs for the treatment of half of the disease
effects.51 Pharmacologically, thioethers are linked to sulfinyls categories (Dermatological, Endocrine System, Genitourinary
and sulfones by their redox interconversion and exhibit and Sex Hormones, Nervous System, Respiratory System, and
extensive biological activities.52 Sensory Organ) reached an all-time high. Similarly, sulfur-
Several underrepresented sulfur-containing moieties have containing drugs in the Anti-Infectives and Cardiovascular
emerged as promising structural components that can be categories peaked in the 1980s. On the other hand, the
2838 dx.doi.org/10.1021/jm401375q | J. Med. Chem. 2014, 57, 2832−2842
Journal of Medicinal Chemistry Perspective

Figure 3. (A) Representative sulfur pharmaceuticals introduced during each decade over the past century. (B) Evolution of sulfur and fluorine
pharmaceuticals. (C) Past and present sulfur−fluorine overlap.

frequency of compounds in the Alimentary Tract and thiazines follow accordingly in quantity and functional
Metabolism category and the Blood and Blood Forming capability, most prevalently in Nervous System (31.7%) and
Organ category was greatest in the 2000s. Additionally, sulfur Respiratory System (20.0%) compounds. Although the β-
incorporation into products of the Musculoskeletal and lactam is the second most represented moiety in the total
Oncological category is becoming more common in recent number of sulfur-containing pharmaceuticals, it seems that they
years. are most functionally useful as Anti-Infectives and Respiratory
The overall frequency of sulfur substituent and representa- System drugs. Sulfinyl groups are significant in Alimentary
tion within each disease category is fairly synchronous. Tract and Metabolism (21.4%) and Musculoskeletal (17.4%)
Predictably, sulfonamides are a primary structural feature
drugs, including many that are also Top200 drugs. Thiadiazoles
incorporated into 11/12 disease categories, with the only
are most common in Sensory Organ (16.7%) drugs; however,
exception being the Respiratory System (Table 7). They also
dominate half of them, in particular, Cardiovascular (75.4%), they maintain a widespread biological activity profile.58,59 The
Sensory Organ (41.7%), Blood and Blood Forming Organ sulfone is an underrepresented functional group, but a
(35.3%), Musculoskeletal (34.8%), Alimentary Tract and therapeutic example exists in 50% of disease categories. The
Metabolism (31.0%), and Endocrine System (28.6%) drugs. least exemplified functionality, the thioester, is present in the
Overall, thiophenes are the second most versatile architectural many analogues of fluticasone, a potent Respiratory System
constituent (8/12 categories), although they are lower in drug. In particular, thioesters are inherently reactive as acylating
occurrence as opposed to thiazoles and thioethers, represented agents and are potential metabolites of carboxylic acids in vivo
in 5/12 and 4/12 categories, respectively. Thiazepines/ which can be converted to acyl-coenzyme A esters.60
2839 dx.doi.org/10.1021/jm401375q | J. Med. Chem. 2014, 57, 2832−2842
Journal of Medicinal Chemistry Perspective

Acyclic and cyclic sulfur constituents describe 17.3% of chemistry perspective, the number of unearthed opportunities
pharmaceuticals. Particularly, sulfonic acid derivatives, for to develop new methodologies using this medicinal anthology
example, the heparin analogues,61 are in highest frequency as inspiration is both advantageous and imminent. In the future,
within the miscellaneous-acyclic group, primarily existing as a we aim to continue to evolve new transformations using sulfur
constituent in drugs within 10/12 disease categories (excluding as the central element.6,74 Currently, a new sulfur-themed
Nervous System and Dermatological drugs). In the late 1990s, pharmaceutical poster has been added to our collection and is
thiazolidinediones, the most represented of the miscellaneous- available on the Internet.7
cyclic group, were introduced into drugs as components of In conclusion, we presented a concise analysis of the
antidiabetic agents for Alimentary Tract and Metabolism and presence of sulfur and fluorine within an extensive set of
Endocrine System treatments.62,63 marketed drugs (1969, total) spanning 100+ years of our
The beauty of organic structural imagery often probes medicinal history. The statistics regarding the percent
curiosity. Upon visual inspection of our extensive data set, it is composition and functional group representation of both
no surprise that many functionally and architecturally elements in reference to decade and disease category reflect just
captivating pharmaceutical agents incorporate a form of sulfur one demonstration of the magnitude of correlations, whether
(Figure 3A). For example, thiopental, a general anesthetic drug, positive or negative, that can be derived from this data set. The
is nearly 80 years old and still in use. In fact, a quick emphasis on minimalism as a part of our graphical design
investigation of this compound (using supplementary sources) philosophy significantly contributed to the overall ease of our
reveals that it holds a place on The World Health statistical assembly. It is notable that people of different
Organization’s “Lists of Essential Medicines”, a list of the educational backgrounds can effortlessly perform this data-
basic medical requirements to establish a fundamental health- mining technique to varying degrees, appealing to the scholastic
care system.64 It is intriguing that a small sulfinyl compound desires of both the general public and the expert. The
like dimethyl sulfoxide (DMSO) (Rimso-50, approved 1978) information contained within this poster collection can also
has an extensive medicinal utility scope still in use.65 incite supplementary exploration using alternative sources.
Interestingly, a rare gold thiolate complex trade-named Ridaura Future investigations will inevitably expose new avenues for the
(auranofin) initially entered the market in 1986 to treat advancement of life sciences including combinatorial chemistry
rheumatoid arthritis.66 The dermatological Altabax (retapamu- and drug design.
lin, approved 2007) was the first drug of a new class of modern
antibiotics to be approved for human use since the discovery of
its parent-compound pleuromutilin in 1950.67 Recently, Teflaro
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*
ASSOCIATED CONTENT
S Supporting Information
(ceftaroline, approved 2010), an advanced generation cepha- Tables listing the initial market name, INN, function, rank, and
losporin prodrug incorporating several forms of sulfur sulfur and fluorine functional group presence for the Top200
(isothiazole, β-lactam, thioether, and thiazole in conjunction drugs by U.S. Retail Sales and Total Prescriptions in 2011;
with a phosphamic acid, oxime, and a pyridine ring), was tables listing the initial market name, FDA approval year,
approved for the treatment of pneumonia and bacterial skin subclass of function, and sulfur and fluorine functional group
infections.68,69 type for 1969 pharmaceuticals (FDA approved from the 1900
The posters also enable any viewer to observe the evolution through 2012) in 12 disease categories, where drugs are
of structure and function of drugs over time. For example, categorized according to (1) small-molecule, combination, and
antipsychotic treatments of schizophrenia have evolved from biological drugs, (2) sulfur and fluorine functional group
promazine,70 consisting of a thiazine adduct, into the inclusion presence, and (3) sulfur functional group by decade and by
of a more complex isothiazole containing motif, Latuda disease category. This material is available free of charge via the
(lurasidone).71 Similarly, the previously popular volatile Internet at http://pubs.acs.org.

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anesthetic haloethane has since been replaced by the highly
fluorinated Ultane (sevoflurane) (Figure 3B).72 AUTHOR INFORMATION
In 1959, two pyscholeptic Nervous System compounds,
fluphenazine and trifluoperazine, were the first approved drugs Corresponding Author
to incorporate both a form of sulfur and fluorine within their *Phone: 607-227-9347. E-mail: [email protected].
molecular skeletons. Presently, the sulfur−fluorine overlap has Author Contributions
expanded to 36 small-molecule and combination pharmaceut- The manuscript was written through contributions of all
icals spanning 10 disease categories (apart from Sensory Organ authors. All authors have given approval to the final version of
category and Genitourinary and Sex Hormones category). With the manuscript.
the exception of the miscellaneous-acyclic and thiadiazole Notes
compounds, all forms of sulfur are represented in conjunction The authors declare no competing financial interest.
with fluorinated motifs. Although no discernible patterns reveal Biographies
functional group compatibility trends between sulfur and
fluorine motifs, trifluorinated aromatics exist in the highest Elizabeth A. Ilardi received a B.S. in Chemistry at The College of
frequency in combination with the majority of sulfur moieties. William and Mary, VA, and a Ph.D. in Organic Chemistry under the
In 2012, Xtandi (enzalutamide) was FDA approved for the supervision of Dr. Armen Zakarian at University of California, Santa
treatment of castration-resistant prostate cancer, capitalizing on Barbara. Inspired by her passion for science, she chose to continue
the dual functionality of sulfur (thioamide) and fluorine postdoctoral research in Organic Synthesis at The University of
(fluorinated aromatic) for its biological efficacy (Figure 3C).73 Arizona.
Considering the overall functional competence of drugs, Edon Vitaku completed a B.S. in Chemistry at Idaho State University
there is no doubt that sulfur will continue to be a leading in 2010. He is currently a Ph.D. candidate at the University of Arizona.
constituent of novel pharmaceuticals. From a synthetic The focus of his research studies includes the development of novel

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Journal of Medicinal Chemistry Perspective

oxidative dearomatization strategies to be applied towards the (16) Data reflecting the top 200 rankings was collected from http://
synthesis of natural products. www.pharmacytimes.com/publications/issue/2012/July2012/Top-
200-Drugs-of-2011 (2012).
Jon T. Njardarson received his Ph.D. at Yale University, CT, in 2001 (17) Filler, R.; Saha, R. Fluorine in Medicinal Chemistry: A Century
with Professor John L. Wood. Following postdoctoral training with of Progress and a 60-Year Retrospective of Selected Highlights. Future
Professor Samuel J. Danishefsky at The Memorial Sloan-Kettering Med. Chem. 2009, 1, 771−791.
Cancer Center, NY, he started his independent career in 2004 at (18) For information on the use of biological drugs in the
Cornell University, NY. In 2010, Professor Njardarson moved his pharmaceutical industry, see the following: Evens, R. P, Ed. Drug
research group to The University of Arizona. and Biological Development: From Molecule to Product and Beyond;

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Springer Science + Business Media, LLC: New York, NY, 2007.
ACKNOWLEDGMENTS (19) Greenstein, B.; Brook, D. A. Biological Therapeutics;
Pharmaceutical Press: London, U.K., 2011.
We thank the National Science Foundation (NSF Grant (20) For a recent review of sulfur-containing amino acids in
CHE1266365) for research support.

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