Future

Review

Medicinal Chemistry

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Polyfluorinated groups in medicinal chemistry

Introduction of novel and diverse functional groups in drug discovery is always seen with hesitancy until good activity and low toxicity characteristics are proven. The introduction of fluorine in drug-like compounds is now a well-accepted strategy in medicinal chemistry. However, polyfluoroalkyl groups, with the exception of trifluoromethyl substituents, are not well explored yet. Our aim is to show to the readers how polyfluorinated groups can be beneficial to the properties of pharmaceutically active compounds by highlighting the structure–activity relationship (SAR) studies that led to the selection of polyfluorinated moieties as key structural features. Despite the fact that the use of higher polyfluoroalkyl/aryl moieties is still in its infancy, we believe that they will soon acquire the same importance of their lower parents.

Introduction of fluorine in order to improve the pharmacological properties of a drug is now well accepted in medicinal chemistry. To demonstrate that this is actually occurring nowadays is the fact that several reviews about the effects of fluorine in drug discovery have already been published [1–3] . Therefore, this aspect will not be discussed in detail in this perspective. However, we feel that a short introduction on the ‘fluorine effect’ would be beneficial for the overall discussion. This manuscript will focus on biologically active molecules with polyfluorinated groups, giving some insights on the biological properties improvement, associated with their introduction when compared with the parent structures. The object of the present discussion will mainly be structures bearing fluoroalkyl groups with more than one fluorine atoms, such as the trifluoromethyl and difluoromethyl groups attached to carbon, sulfur and oxygen atoms, as well as higher polyfluoroalkyl groups such as the C2F5 or greater. In addition, since the pentaflurosulfanyl group (SF5) contains multiple fluorine atoms and improved synthetic methodologies are making this group more and more accessible, we will discuss the use of this novel functionality in drug discovery. Poly-

10.4155/FMC.15.5 © 2015 Future Science Ltd

Marcella Bassetto1, Salvatore Ferla1 & Fabrizio Pertusati*,1 School of Pharmacy & Pharmaceutical Sciences, Cardiff University, Redwood Building, King Edwards VII Avenue, Cardiff, UK *Author for correspondence: [email protected] 1

fluorinated nucleoside and nucleotide drugs will be treated in a separated section. To conclude, though the use of high perfluoroalkyl groups (higher than SF5 and C2F5) in medicinal chemistry is not well investigated yet, in our opinion it could be relevant for the aim of this review to give a brief overview about the use of these groups and where their introduction has been beneficial or detrimental for biological activity. Selected examples, which support the two different theories, will be discussed in the last section. Fluorine effects in organic molecules

Despite the fact that fluorine constitutes the most abundant halogen on earth, only a dozen of fluorinated organic compounds have been identified in nature [4] . The incorporation of fluorine-containing groups into organic molecules often drastically perturbs the chemical, physical and biological properties of the parent compounds, therefore organofluorine structures are receiving increasing attention in the medicinal, pharmaceutical, agricultural and material sciences. The effect of fluorine on lipophilicity of molecules can be diverse depending on the number of fluorine atoms. Often the monofluorination or trifluoromethylation of

Future Med. Chem. (2015) 7(4), 527–546

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ISSN 1756-8919

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Review  Bassetto, Ferla & Pertusati

Key term Pentafluorosulfanyl (SF5): It is the organic derivative of hypervalent sulfur compound SF6 in which one of the fluorine atom is replaced by an organic residue. The most important properties are the high dipolar moment (μ= 3.44D), high Pauling electronegativity (3.62), great lipophilicity (π=1.50) and its great cross sectional area (32.6 Å 2; As reference CF3 has an area of 29.0 Å 2 and that of t-Bu 43.8 Å 2). Its 19F NMR chemical shift is between +84 ±71 ppm (CFCl3).

saturated alkyl groups results in a decreased lipophilicity, because of the relative polarity of these groups imparted by the C-F dipoles. In contrast, fluorination of aromatic rings always increases the lipophilicity of the molecule [5] . The Hansch-Leo hydrophobic parameter π, derived from the octanol/water partition coefficients Px and PH, is the conventional quantitative measure of aromatic substituent effects on lipophilicity [6,7] . The effect of fluorination can be quite large, over two orders of magnitude, on the partition coefficient: some hydrophobic parameters are shown in Table 1. In recent years, there has been a growing interest in the insertion of the trifluoromethyl group (CF3) and in its association with heteroatoms such as trifluoromethoxy (OCF3) or trifluoromethanesulfenyl (SCF3). These functional groups have similar properties to the CF3 group [8–10] . The SCF3 group shows high lipophilicity (π = 1.44), while the trifluoromethanesulfonyl group (SO2CF3) has the strongest electronwithdrawing power (σm = 0.79, σp = 0.93), and the trifluoromethanesulfinyl (SOCF3) exists between the first two (Table 2) . In recent years, fluorine NMR spectroscopy has emerged as an important tool to study the binding properties of drugs in different receptors. Different libraries of fluorinated compounds have been screened for the identification of fragments (as part of a Fragment-Based Drug Discovery) that bind specifically to particular regions of the target receptor. 19F chemical shift, influenced by the local environment around the Table 1. Hydrophobic parameter [πx = log (P x / PH ) (octanol-H2O)] for C6F5X compounds.

528

X

πx 

X

πx 

F

0.14

SCH3

0.61

[5]

Cl

0.71

SCF3

1.44

[5]

OH

− 0.67

CH3CO

0.02

[5]

CH3

0.56

CF3CO

0.55

[5]

CF3

0.88

CH3SO2

−1.63

[5]

OCH3

−0.02

CF3SO2

0.55

[5]

OCF3

1.04

Future Med. Chem. (2015) 7(4)

Ref.

 

fluorine atom, has been used to identify in combination with protein x-ray crystal structure, those ligands that will have a strong binding affinity. Shielded fluorine atoms (those with increased electron density) were usually found in close proximity of hydrogen bond donors meanwhile deshielded fluorine atoms were often found close with hydrophobic protein side chains and with the carbon of carbonyl groups of the protein backbone. These observations led to the definition of the ‘rule of shielding’ [11] . This approach can facilitate the design of drugs with potent and specific interactions with the appropriate receptor. Briefly, according to this rule, shielded fluorine atoms (with 19F shift at high field) are preferentially involved in dipolar interactions or in hydrogen bonding with appropriate parts of the receptor, meanwhile deshielded fluorine (low field shift) always interact with hydrophobic residues, mainly the carbon backbone of the protein. The increased popularity of polyfluoro groups might be due to the fact that the repertoire of synthetic methodologies available today for their introduction into organic molecules is growing at an accelerated rate. In the next section a brief overview of selected synthetic methodologies will be given, in order to facilitate the access to fluorinated and polyfluorinated scaffolds for the interested readership, and to stimulate them into this exciting field of organic synthesis. Synthetic methodologies for the introduction of polyfluorinated groups in drugs & prodrugs Aromatic trifluoromethylation, difluoromethylation & polyfluoroalkylation

Introduction of the trifluoromethyl group into organic substrates is a very well-known practice in organic chemistry. Intensive studies have been performed and nowadays the methods to accomplish this transformation are countless. For this reason only a selection of the most general methodologies will be presented. Aromatic trifluoromethylation can be accomplished according to Figure 1A reactions 1–5 meanwhile polyfluoroalkylation can be achieved via reactions 6 and 7 [12] . Introduction of CF3 group into aliphatic chains can be usually accomplished with the same reagents and methodologies shown in Figure 1A. Despite the great diversity of trifluoromethylation procedures, difluoromethylation of organic substrates has been studied in less detail. However, it can be accomplished on a variety of aromatic and heteroaromatic substrates according to the procedures summarized in Figure 1B. Aromatic trifluoromethanesulfenylation

In the last few years a great deal of interest has been delivered to the introduction of trifluoromethylthio

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Polyfluorinated groups in medicinal chemistry 

Review

Table 2. Substituent constants for selected perfluorogroups. Substituent constants

CF3 

OCF3 

SCF3 

π

0.88

1.04

1.44

σm

0.43

0.38

0.40

σp

0.54

0.35

0.50

(SCF3) functional group into organic substrates with biological interest. On aromatic substrates, two strategies may be applied: (1) direct trifluoromethanesulfenylation of aryl halides, boronic acids and diazonium salts and (2) trifluoromethylation of sulfur-containing compounds (Figure 1C) . Alkyl trifluoromethanesulfenylation

shows the most general strategies used to incorporate the trifluoromethylthio group into aliphatic chains of organic molecules [13] . This transformation can be accomplished by electrophilic, nucleophilic or radical mechanism as well as by functionalization of substrates with C-S bond already in place. Figure 1D

Synthesis of OCFn-containing compounds

Despite the fact that the majority of the anesthetics used today belong to the class of perfluoro ethers, the synthetic methodologies available for their synthesis is not well developed as well as other perfluorocompounds. The synthesis of the lower member of the perfluoroalkoxy groups, namely the trifluoromethyl ethers, can be accomplished by several methods. One of the oldest is the fluorination of trichloroanisole by anhydrous HF or a combination of SbF3 and SbCl5 (Figure 1F-a)  [14] . Other methods involving very toxic reagents were also developed Figure 1F-b [10] . A more accessible strategy for the preparation of these materials is the CF3 transfer to alcohols. The most developed reagents able to accomplish this transformation are the Umemoto and Togni reagent. Umemoto reagent is more suitable for the preparation of aromatic trifluoromethyl ethers (Figure 1F-c) [15] meanwhile the hypervalent iodine (Togni) reagent is more suitable for the preparation of aliphatic trifluoromethyl ethers when used in presence of zinc triflate (Figure 1F-d)  [16] . When phenol is treated with Togni reagent the desired trifluoromethyl ether is obtained in mixture with products of aromatic trifluomethylation (Figure 1F-d). In principle, fluoroalkyl transfer operated by the same reagents can be used to prepare higher perfluoroalkyl ethers. However, examples of these transformations have yet to be appear in the literature. Higher aromatic perfluoroalkyl ether can be prepared by direct fluorination (with elemental fluorine) of the corresponding fluorovinyl ether as highlighted in Figure 1F-e  [17] . An excellent review on the preparation and application of trifluoromethyl ether has also

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SOCF3 

SO2CF3 

SF5 

0.55

1.50

Ref. [9]

0.63

0.79

0.61

[9]

0.68

0.93

0.68

[9]

published recently and the reader is referred to this paper for further synthetic details [18] . Synthesis of pentafluorosulfanyl-containing compounds

Chemists have known the pentafluorosulfanyl (SF5) group for a long time. The intrinsic difficulty of its introduction (due to the harsh conditions needed) into a variety of substrates has always precluded the investigation of its use in medicinal and material chemistry. However, the last few years have witnessed an increased use of this functional group, especially in material chemistry, due to the appearance of novel and safe methodologies, which give access to this very interesting functional group [19–21] . Furthermore, more and more building blocks having the SF5 group already incorporated into aromatic ring are now commercially available. As a consequence, SF5 group became increasingly popular among medicinal chemists, with SF5 containing compounds showing already a promising potential as drug-like scaffolds. A selection of the easiest synthetic pathways used to introduce this functional group in organic functionalities is shown in Figure 1E [22–24] . In the following sections the different polyfluorinated groups that are of relevant interest in medicinal chemistry will be taken into consideration. Examples of biologically active molecules, containing each of them will be given, in order to highlight the effects that these groups have on the biological properties of the compounds. Trifluoro-, difluoro- & monofluoromethylcontaining compounds In this section, biologically active compounds bearing an aromatic CF3 and/or CF2H group will be described first, followed by those having the same fluorinated moieties attached to a heteroatom like O and S. C-CF3-containing compounds

CF3 group is the most common among the polyfluoroalkyl substituents, and many newly approved drugs show the increasing presence of this group in their structures [25] . Tafenoquine

8-Aminoquinolines (8-AQ) such as Primaquine 1 (Figure 2) are an important class of antiparasitic agents,

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Review  Bassetto, Ferla & Pertusati with broad utility and excellent efficacy, but also with limitations due to hematological toxicities, primarily methemoglobinemia and hemolysis. Research for safer alternatives ended up with Tafenoquine 2, a new 8-aminoquinoline developed by GlaxoSmithKline in collaboration with Medicines for Malaria Venture that is currently on Phase III clinical trials for the treatment of malaria. Its biological action is similar to 1, but with a better safety profile (Figure 2A) [26] . As a clear example of how polyfluoroalkyl groups can be beneficial to the properties of a drug, it is sufficient to say that in these structures, the replacement of the aromatic CF3 group with a dichloroaryl group led to compound 3 (NPC1161C) with increased mortality in mice and reduced enzymatic stability (Figure 2A) [27] .

against different types of cancer [28] . It was initially developed from a vascular endothelial growth factor receptor inhibitor, compound 4, which due to an off-target inhibition of carbonic anhydrase (CA) and its limited water solubility, did not progress behind Phase II in the clinic (Figure 2B) . Replacement of the original sulfonamide with a cyclopropyl sulfoximine led to a reduced CA inhibition, to an improved aqueous solubility and a decent antiproliferative activity. More relevant to our discussion, the introduction of the trifluoromethyl group was the key step toward high potency and an improved antitumor activity. Aprepitant

Neurokinin 1 (NK1) antagonists are a recent class of therapeutics that has antidepressant, anxiolytic and antiemetic properties. Aprepitant 8 (Emend, Figure 2C) was the first drug available on the market for the treatment of vomiting and nausea caused by chemotherapy regimen [29] . It exerts its action by blocking the neuro-

Roniciclib

The trifluoromethyl pyrimidine Roniciclib 5 (Figure 2B) is a very potent paninhibitor of cyclin-dependent kinases (CDKs), currently in Phase II clinical trials Cl

Br

Cl

Het 2

TMSCF3 CuI, KF 3 CF3SO2Cl Ru(Phen)3Cl2, hà t-BuONO, then TMSCF3, AgF 4 B(OH)2

SCF3 +

N

R = EDG, X=H

Cu Rf N

TMSCF3 R KF, cat. Pd(II) 7 cat. ligand Rf = CF3, CF2CF3 Rf DMF, 50–100°C CF3 1. t-BuOM (M = Na, K) Het DMF, rt, 1h CuCl CuC2F5 R PhMe, 3 h 2. C2F5COOEt 6 50 °C, 1–2 h 5 X CF3SO2Na t-BuOOH B(OH)2 Het

1

SCF3 CuSCF3 or Hg(SCF3)2/Cu

X

(Bpy)CuSCF3]

R R = H, Alk, EWD... X = Cl, Br, I

R

CF2H

I

2)

CF2H Het

H

Zn(SO2CF2H)2 t-BuOOH CF3COOH

CF2H

Het

CH2Cl2-H2O, 24 h, rt

Het

PhSO2CF2I, Rh(Bpy)3Cl2.5H2O, K2HPO4 CH2Cl2-H2O, 24 h, rt

R

R

R

R

R- + XSCF3 RX + -SCF3 R1 RH +

3)

CF2R visible light xanthone Selectfluor CH3CN, 24 h, rt

CH2R

CF2R AgNO3, Na2S2O8, Selectfluor CH3CN-H2O, 3–10h, 80°C

TMSCF3/S8 10 mol% CuSCN R 20 mol% Phen R = H, Alk, EWG... X = B(OH)2/BF3K t-BuONO/CuSCF3

R = H, Alk, EWG... X = NH2

CF2H

1. CuI, CsF, Et3SiCF2COOEt 2. hydrolysis 3. decarboxylation

CuI, CsF, TMSCF3 NMP, 120°C

SCF3

Me4NSCF3 or

SCF3

R X = B(OH)2, Br

1)

EDG ClSCF3 or CF3CO2SCF3

R2 R1 R2

R3

E+ or NutrifluoromethaneE+ or Nusulfenylation RSH + XCF3 trifluoromethylation RS- + XCF3 RSX + XCF3

+ . SCF3 R4 R3 R4

+ XCF3

RS- + . CF3 RSSR + . CF3

radical

radical R-S-CF3

addition

functionalisation

S

CF3

Figure 1. Selected methodologies for the introduction of aromatic and heteroaromatic substrates. (A) CF3 and C2F5, groups into aromatic and heteroaromatic rings; (B) CF2H group into aromatic compounds; (C) SCF3 group into aromatic and heteroaromatic rings; (D) SCF3 group in aliphatic chain; (E) SF5 group in aromatic and heteroaromatic rings; (F) Selection of synthetic methodologies for the introduction of OCFn group in organic substrates. 

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Polyfluorinated groups in medicinal chemistry 

SF5 a)

COOH

F 5S

COOH exo17% endo 51%

110°C, 10 h

HN N

CH2N2

b) F5S

Et2O, 0 °C, 80min

Cl

SF5

SF5 +

NOH

c) F S 5

+ COOH

+ 1,2

F5S Cl 40°C, 3–4 h

Ar

37%

Ar SF5

SF4Cl ZnF2

KF/Cl2

d) R

R

SF5

O N 1,2

Ar = Ph, p-C6H4F

S S

H2N N

51%

Cl

Et3N

Review

or HF

R

R

OH OCH3

OCF3

OCCl3

a)

PCl5, Cl2

HF or

heat

SbF3 + SbCl5

OH

Cl Cl NaOH

b)

c)

O

+ O

I

R NaH. 18-crown-6 DMF, r.t. to 70°C

d) OCF3

Cl

F3C

1. Cl2 (75%) 2. SbF3 + SbCl5

PhOH

OCF3

O O

S S

F3C

I

O

C5H11OH

O CF3 +

+

CF3 C5H11OCF3

Zn(OTf)2

O

O

71%

OCF3

OCF CF2

e)

OC2F5

F2

DIPEA

X

CF3

X = H (24%) X = NO2 (60%)

X

Figure 1. Selected methodologies for the introduction of aromatic and heteroaromatic substrates (cont.). (A) CF3 and C2F5, groups into aromatic and heteroaromatic rings; (B) CF2H group into aromatic compounds; (C) SCF3 group into aromatic and heteroaromatic rings; (D) SCF3 group in aliphatic chain; (E) SF5 group in aromatic and heteroaromatic rings; (F) Selection of synthetic methodologies for the introduction of OCFn group in organic substrates. 

kinin-1 (NK-1) receptor. This molecule, derived from a series of optimizations, began from the structure of CP-96345 (6, Figure 2C), initially developed by Pfizer. Although showing good activity and selectivity against other receptors, 6 became recognized as an antagonist of the L-type calcium channel, leading to cardiovascular side effects. Since the affinity for this channel was due to the basicity of the nitrogen heterocycle (quinuclidine ring), decreased nitrogen basicity was the key requirement for further development of the compound. Replacing quinuclidine (pKa ~10) with the less basic piperidine (pKa ~ 8.3), the diphenylmethyl groups with a phenyl ring and the benzylamine with bistrifluoromethyl benzyl ether, led to the development by Merck of compound 7 (L733060, Figure 2C), which shows better penetration in the central nervous system due to the presence of a 3,5-bis-(trifluoromethyl)phenyl group. Introduction of an electron-withdrawing group into the nitrogen-containing ring further decreased the nitrogen basicity as well as the affinity for the L-channel, while maintaining the biological activity in the nanomolar range. Replacing the piperidine ring with N-1,2,4-triazole-morpholine retained activity while

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reducing the affinity for the L-channel. Although the bis-trifluoromethyl-benzyl ether contributed to the reduction in basicity of the morpholine ring, it was necessary to replace one of the benzylic hydrogen with a methyl group in order to increase the metabolic Key terms Cyclin-dependent kinases: A family of protein kinases known for their role in regulating the cell cycle. Other functions of these enzymes are the processing of mRNA and the differentiation of nerve cells. T CDKs phosphorylate their substrates (cyclines) on serines and threonines residues, so they are serine-threonine kinases. If it is possible to selectively interrupt the cell cycle regulation in cancer cells by interfering with CDK action, the cell will die. Neurokinin 1 receptor: The neurokinin 1 receptor (NK1R) is a receptor found both in the central and peripheral nervous system. It belongs to the tachykinin receptor subfamily of G protein-coupled receptor (GPCRs). The natural ligand for this receptor is a neuro-undecapeptide, (belonging to the tachykinin superfamily), a substance that functions as a neurotransmitter and as a neuromodulator. The peptide is released from the terminals of specific sensory nerves, and it is associated with inflammatory processes and pain.

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A A

H N

O

NH2

H2N

N

H N

O

N

O

H2N CF3

H N

O

Cl

N

O

Cl

O

1 Primaquine B B

Br

N

2 Tafenoquine

3 NPC1161C

CF3

H N

O

OH

N

N

HClHN

OH

N

HN NH2 S 4

O

S

O

O 5 Roniciclib

C C O

F

O

CF3 O

N

N H 7

L-733060 IC50 = 0.9 nM Ca2 + binding IC50 = 760 nM

Enhance in vivo activity and improve metabolism increase NK1 binding affinity reduce basicity and affinity for Ca2 + L-channels reduce oxidative cleavage in vivo

O

N

6

CF3

F3C

CF3

NH

CP-96345

NH

HN

N

HN 8

O

Aprepitant

Figure 2. Bologically active compounds bearing CF3 groups. (A) 8-quinoline derivatives as antimalarial drugs; (B) roniciclib and its precursor compound 4; (C) structural development of Aprepitant (8).

cleavage of the carbon–oxygen bond. Introduction of a fluorine atom in the para position of the phenyl ring was finally necessary to block oxidative metabolism of the drug. Aprepitant development is summarized in Figure 2C . Sitagliptin

The incretin hormone GLP-1 is secreted by the gastrointestinal tract to reduce sugar levels in blood by stimulation of insulin production. GLP-1 is rapidly degraded, in vivo, by the action of dipeptidyl peptidases (DPPs). Therefore, inhibitors of DPP-IV are valuable drug candidates for the development of antidiabetic compounds; among them, Sitagliptin 15 (Merck) was the first approved by the FDA in 2006 for the treatment of Type 2 diabetes mellitus [30] . Also in this case it is interesting to report the structure–activity relationship (SAR) studies on this structure, in order to highlight the influence of polyfluoro groups in the optimization of their antidiabetic potency (Table 3) .

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The lead compound 9 (R 2 = H) has been found to possess an IC50 value of 455 μM (Table 4) . An improvement in activity was observed by replacing the hydrogen (R 2 = H) with an ethyl group (R 2 = Et) in the triazole ring (compound 9 vs compound 10). A significant increase in the bioavailability was then obtained by replacing the ethyl group with the trifluoromethyl group (compound 11), with concomitant increase in DDP-IV inhibitory activity. The presence of the CF3 group in the triazole ring is fundamental for activity due to its electrostatic interaction with the side chains of arginine and serine residues of DPP-IV. Removal of this group causes a four-time reduction in potency (compouns 9 and 13). The use of higher fluorinated analogues like the pentafluorethyl substituent (14) was not beneficial to potency or to parameters, especially if compared with the CF3 group. However, the C2F5 was still associated with a bioavailability improvement (compound 13 vs 14). Finally, the position of the three fluorine atoms in the aromatic ring is important for the whole properties of the molecule [30] . Sitagliptin is

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Polyfluorinated groups in medicinal chemistry 

Review

Table 3. COX-2 inhibitors structure–activity relationship studies. R2

R1 N N

X

SO2NH2

General structure of COX-2 inhibitors Cpd

R1 

R 2 

X

COX-1 IC50 (μM)

COX-2 IC50 (μM)

16

CF3

H

F

 

 

[31]

17

CF3

H

H

55.1

0.032

[31]

18

CF2H

H

H

33.7

0.13

[31]

19

CFH2

H

H

>100

0.20

[31]

20

H

H

F

>100

>100

[31]

Celecoxib (21)

CF3

H

Me

15.0

0.040

[31]

22

CF2H

H

Me

12.5

0.013

[31]

23

CH3

H

H

>100

62.8

[31]

24

CF3

Cl

Cl

0.065

0.0053

[31]

25

H

Cl

H

31

0.049

[31]

26

H

Br

Cl

8.71

0.031

[31]

27

CH3

 

Cl

0.58

0.028

[31]

28

CH2OH

 

Cl

0.17

0.34

[31]

29

CO2CH3

 

Cl

0.41

0.16

[31]

30

CONH2

 

Cl

8.8

1.09

[31]

extremely selective for the DDP-IV, as demonstrated by its inactivity against other similar enzymes like DPPVIII, DDP-IX, whose inhibition is associated with acute toxicity in preclinical studies. It is clear from the above example that further SAR studies are necessary to evaluate the influence of longer polyfluoroalkyl substitutes on drug properties. It emerges that the influence of an additional CF2 group is not easily predictable, at least at this stage, and that further studies are necessary to gain deep knowledge of its properties and its capability to modify the overall properties of the parent compounds. On the contrary, Sitagliptin is another clear example of the successful application of monofluoro and trifluoromethyl groups in drug discovery. Celecoxib

Modern nonsteroidal anti-inflammatory drugs work by inhibiting the cyclooxygenase (COX) family of enzymes. Among them, Celecoxib is a selective COX-2 inhibitor used to treat osteoarthritis, rheumatoid arthritis, ankylosing spondylitis, acute pain in adults and juvenile rheumatoid arthritis in patients 2 years or older [31] .

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Ref.

The development of Celecoxib began with the observation that the spatial orientation of the aromatic rings on the heterocyclic moiety was a critical parameter for the blockage of COX-2. SC-58125 (16) was used for the first SAR studies. Key modifications were the replacement of the methylsulfone with the corresponding sulfonamide and modifications of the Key terms Dipeptidyl peptidase-4: An antigenic enzyme expressed on the surface of most cell types associated with immune regulation, signal transduction and apoptosis. It is an intrinsic membrane glycoprotein and a serine peptidase that cleaves X-proline dipeptides from the N-terminus of polypeptides. The substrates of CD26/DPP-IV are proline (or alanine)-containing peptides and include growth factors, chemokines, as well as vasoactive peptides. Cyclooxygenase (COX): Cyclooxygenase (COX), or (Prostaglandin-endoperoxide synthase) is an enzyme that is responsible for formation of important biological mediators called prostanoids, such as prostaglandins, prostacyclin and thromboxane. Inhibition of COX can deliver relief from the symptoms of inflammation and pain. Nonsteroidal anti-inflammatory drugs (NSAID) were designed to target this enzyme.

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Review  Bassetto, Ferla & Pertusati

Table 4. Structure and biological properties for DPP-4 inhibitors. NH2

O N

N

R1

N

N R2

General structure of DPP-IV inhibitors Cpd

R1 

R 2 

DPP-IV IC50 CLp ml/ (μM) min/kg

t1/2 (h)

F (%)

Ref.

9

3,4-di-F

H

455

10

3,4-di-F

Et

231

45

2.7

2

[30]

11

3,4-di-F

CF3

128

51

1.8

44

[30]

12

2,5-di-F

CF3

27

43

1.6

51

[30]

13

2,4,5-tri-F

H

67

40

1.0

3

[30]

14

2,4,5-tri-F

C 2 F5

71

58

2.3

61

[30]

Sitagliptin (15)

2,4,5-tri-F

CF3

18

60

1.2

76

[30]

[30]

CLp: Plasma clearance; F: Biovalability; IC50 : Concentration of compound exhibiting 50% DPP-IV inhibition; t1/2: Half life.

5-phenyl ring for the pharmacokinetic characteristics of the drug (Table 3) . These studies were done keeping the pyrazole ring constant with both CF3 and CF2H groups intact. Trifluoromethyl and difluoromethyl substituents provided superior performance in both potency and selectivity when compared with other groups: these data are summarized in Table 3. Structures with Cl, Br, or CN in position 4 of the pyrazole ring showed high potency against COX-2, and removal of the CF3 group with these substitutions led to an improvement in selectivity (compounds 25–26 vs 24). Chlorine substitution on the 5-Ph gave increased potency, but its replacement with a methyl group shortened the half-life of the drug to 3–6 h. The same effect was observed by replacing the CF3 group with CF2H. Celecoxib was finally selected for its overall biological performance. OCF3-, OC2F5 -, OCF2H- & OC2F4H- containing compounds

In the following section, the drugs bearing the trifluoro- and difluoromethyl groups directly connected to an oxygen atom will be presented. The comparison of the effect of these groups with the corresponding ones without heteroatom or with a hydrocarbon spacer will be also discussed. Proton pump inhibitors

The SAR studies that led to the discovery of Omeprazole represent an excellent example to highlight the importance of polyfluoro groups in drug discovery. It serves also to highlight the influence of alkyl spacers on

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Future Med. Chem. (2015) 7(4)

the modulation of the effect of fluoro-groups on drug properties. The first proton pump-inhibiting drug Omeprazole was released on the market by the AB Hassle Company, and it was used for the treatment of dyspepsia, peptic ulcer disease, gastroesophageal reflux disease, laryngopharyngeal reflux and Zollinger–Ellison syndrome  [32] . Its first fluorinated analogue to reach the market was Lansoprazole (32, Table 5)  [33] . The introduction of a fluoroalkyl group into the original scaffold greatly improved both pharmacological and physicochemical properties (Table 5) . Introduction of longer polyfluoroalkyl groups was detrimental for the antisecretory and antiulcer activity of the molecules, although compounds 33 and 34 still have comparable of better activity with respect to the nonfluorinated analogue omeprazole [33] . Introduction of a methyl group in either R1 and or R 3 causes a slight decrease in the antiulcer activity. Polyfluorinated analogues administered at dose of 2000 mg/Kg in mice caused no toxic effect to the animals: this constitutes a general advantage of perfluorogroups over the normal alkyl ones. Further development of proton pump inhibitors (PPIs) led to the discovery of Pantoprazole, which represents an example of the usage of the difluoromethyl group. Addition of a trifluoromethyl group to the benzimidazole moiety led to a series of very active compounds with varying solution-stability. In general, fluoro substituents were found to block metabolism at the point where they were attached. The insertion of a more balanced fluoroalkoxy substituent, instead of the

future science group

Polyfluorinated groups in medicinal chemistry 

Review

Table 5. Effect of polyfluoroalkyl groups on the pharmacological activity of Lansoprazole-like structures. R1 R4

H N

R3 N

S N

OR2

O

General structure of PP inhibitors Cpd

R1 

R 2 

R3 

R4 

Antisecretory activity ED50 (mg/kg) † 

Antiulcer activity ID50 (mg/kg) * 

Ref.

Omeprazole (31)

H

CH3

CH3

OCH3

3.3

6.3

[33]

Lansoprazole (32)

CH3

CH2CF3

H

H

1.6

0.9

[33]

33

H

CH2CH3

H

H

34

H

CH2C2F5

H

F

35

H

CH2C2F4H

H

Pantoprazole(36)

OCH3

CH3

H

5.1*

[33]

2.7

0.8

[33]

H

3.5

1000

 

[38]

40

Cl

-CH2CH2-

 

772

 

[38]

41

Cl

CH3

c-pentyl

4.3

 

[38]

42

Cl

CF2H

c-pentyl

11

 

[38]

43

Cl

CF2H

CF2H

11

 

[38]

44

CO2H

CF2H

CF2H

24

77

[38]

45

CH2CO2H

CF2H

CF2H

53

58

[38]

46

CONH2

CF2H

CF2H

8.6

1.0

[38]

47

CH2OH

CF2H

CF2H

44

0.47

[38]

48

(CH3)CHOH

CF2H

CF2H

45

0.51

[38]

49

(CH3)2COH

CF2H

CF2H

9.6

0.36

[38]

L-791943 (50)

(CF3)2COH

CF2H

CF2H

4.2

0.67

[38]

Starting from the benzoic acid derivative 44, it was discovered that neutral substituents with not excessive polarity such as an amide group confer a great potency [30] . A simple hydroxymethtyl group was also able to increase the potency in a HWB test (46). Despite this activity improvement, the pharmacokinetic profile did not improve to a great extent. The bulkiness of the carbinol moiety was also an important parameter: the increased size of this group (compounds 48 and 49) led to a remarkable improvement in the GST and HWB activities. Unfortunately, the half-lives of these compounds was still too short (about 1–2 h). Attempting to improve the metabolic stability, the alkyl carbinol moiety was replaced with bis-trifluoromethyl carbinol, which led to the discovery of L-791943. This compound

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Future Med. Chem. (2015) 7(4)

O

Ref.

displayed good activity coupled with good metabolic stability. Moreover, the potential for causing emesis, one of the major drawbacks of typical PDE4 inhibitors, was also assessed. Ferrets could be dosed orally with up to 30 mg/kg of L-791943 (50), with plasma concentrations reaching 14 mM without causing emesis [38] . S(O)nCFpHx in biologically active compounds Aromatic and heterocyclic polyfluoroalkyl sulfides are another class of compounds, which is finding increasing application for the preparation of pharmaceutical products and represents an important feature in the general development of organo-fluorine chemistry over the last twenty years.

future science group

Polyfluorinated groups in medicinal chemistry 

One of the driving forces for the introduction of polyfluoroalkyl sulphide groups is the high lipophilic properties of polyfluoroalkylthio groups (the greatest Hansch constant π = 1.44, belongs to SCF3 group) [39] , which increases the ability of such molecules to cross lipid membranes and therefore creates opportunities for the modification of known and new drugs. Some examples of bioactive compounds containing SCF3, SOCF3 and SO2CF3 groups will be discussed in further detail in this section.

tiated in the United States in patients with metastatic castrate refractory prostate cancer. The trial is expected to be completed by April 2016 to move to the next levels. Navitoclax development is summarized in Figure 3. The development process started with the discovery of the first lead compound 51, which was found to bind to a transmembrane protein Bcl-xL (B-cell lymphoma-extra large) with an inhibition constant (Ki) of 36 nM [41] . This property was significantly diminished in the presence of serum, because of its great affinity for human serum albumin (HAS) domain III [42] . The peripheral positions of compound 51 were optimized in compound 52, which showed higher selectivity for Bcl-xL with a Ki of 0.8 nM. In order to improve the binding, a lipophilic biphenyl group was introduced into the piperazine ring, allowing a deeper access into the binding pocket on the protein surface of Bcl-xL/inhibitor complexes. This modification led to the discovery of ABT-737 (53) (FL5.12/ Bcl-2: EC50 = 7.7 nM; FL5.12/ Bcl-XL: EC50 = 30 nM; H146/10%HS: EC50 = 87 nM) [43] . However, ABT-737 was not orally bioavailable (F = 6%), due

Navitoclax

Navitoclax (ABT-263; RG-7433) (55) was developed by AbbVie for the potential oral treatment of cancers such as lymphoid malignancies, small-cell lung cancer and solid tumors [40] . This compound belongs to a type of small-molecule inhibitors of Bcl-2 family proteins (Bcl-2/Bcl-xL/Bcl-W ) and causes complete tumor regressions in small-cell lung cancer and ALL xenograft models, with improved physiochemical and pharmaceutical properties in comparison with its parent molecules. In April 2013, Phase II clinical trials were iniNO2 H N S O2

O

NO2

NO2 H N

H N H N

O

S

S O2

Review

S

H N

O

N

S O2

H N S

N

N

N

N 51

F

53 ABT-737

52

Cl CF3 H N

O

S O2

H N S

F3CO2S N

H N

O

S O2

H N S

N O

N N

N N

Cl

54

Cl

55 ABT-263 Navitoclax

Figure 3. Development of Navitoclax from compound 51.

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Review  Bassetto, Ferla & Pertusati to its low aqueous solubility, poor absorption (permeability) and inadequate metabolic characteristics [44] . The simple replacement of the nitro group in ABT747 with a trifluoromethyl group in compound 54 imparted a 16-fold increase in systemic exposure with 24% oral bioavailability. Nevertheless, compound 55 showed a significant loss of potency (H146/10%HS: EC50 = 2.46 uM). This loss in potency was attributed to the less electron-withdrawing property of the CF3 group in comparison with the original nitro group. This assumption led to the idea to introduce a strongly electron-withdrawing trifluoromethanesulfonyl group, which proved to be the essential modification to give the desired biological response. Further optimization included the replacement of one of the phenyls in the biphenyl fragment by a gem-dimethylcyclohexene group, and the N,N-dimethylamino function by a morpholine ring. These final steps led to the discovery of Navitoclax (FL5.12/Bcl- 2: EC50 = 5.9 nM; FL5.12/Bcl-XL: EC50 = 4.2 nM; H146/10%HS: EC50 = 86.7 nM). The presence of a bulky and electronegative group appears to be beneficial to the biological activity of the parent scaffold. It is our opinion that further improvement may be achieved by switching the CF3 group with the bigger and more electronegative such for example SF5 moiety.

Dihydroorotate dehydrogenase inhibitors

Dihydroorotate dehydrogenase (DHODH) catalyzes the fourth step in the de novo pyrimidine biosynthesis in particular the conversion of dihydroorotate to orotic acid. Its inhibition would lead to pyrimidine nucleotide depletion and inhibition of DNA and RNA synthesis and cell proliferation. A DHODH inhibitor would have potential therapeutic benefits in disorders involving aberrant cell proliferation such as arthritis. The biological activities of a series of compounds derived from Leflunomide (56) active metabolite, compound 57 (Table 7), were measured after oral administration in both rat and mouse delayed type hypersensitivity (DTH) models. For compounds showing DTH activity in both species, an approximate half-life in mouse and rat was also determined. Compounds were later tested in the inhibition of DHODH, and the correlation between their in vivo DTH activity and their in vitro DHODH potency was studied [45] . Aromatic substituents were investigated for structure–activity relationships (Table 7, only the most potent derivatives are shown) and also to investigate the metabolism of various functional groups. The best substituents are lipophilic and weak hydrogen bond acceptors, such as the SCF3 group. Compounds 58, 59 and 60 were found to be the most potent, with the best overall pharmacological profile for combined rat

Table 7. Activity and pharmacokinetic properties for the most potent antiarthritis compounds derived from Leuflunomide 56.  CF3

CF3

HN

HN

O

R

O

HN OH

NC

O OH

NC

N O 56 Leflunomide

57

58–63

Structures of Leflunomide (56), its metabolite 57 and general structure of DHODH inhibitors Cpd

R

 

 

Leflunomide (56)

DTH (%)† 

t1/2 (h) 

Mouse

Rat

Mouse

Rat

84

78

30

9

57

DHODH IC50 (nM) ‡  Mouse

Ref.

Rat

  [45]

69

13

[45]

58

CN

73

47

6

5

42

53

[45]

59

SCF3

39

58

6

2

100

5

[45]

60

NO2

64

90

8

4

50

21

[45]

61

SOCF3

25

75

3

3

417

16

[45]

62

SO2CF3

43

66

14

14

89

3

[45]

63

OCF3

85

78

42

22

173

5

[45]

% Inhibition (1mg/kg). IC50 (nM).

† ‡

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Future Med. Chem. (2015) 7(4)

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Polyfluorinated groups in medicinal chemistry 

and mouse DTH activity and modified kinetic properties, when compared with leflunomide. In the case of compounds 58 and 60 no metabolites could be observed in either rat or mouse plasma by HPLC. However, 59 showed two metabolites in HPLC, which were identified by as 61 and 62, with 62 displaying itself potent DTH activity and long kinetics. The presence of an SCF3 group in position 4 makes compound 59 one of the most potent in rat DTH (58% inhibition at 1 mg/kg). This compound also becomes one of the most potent in vitro rat DHODH enzyme inhibitor (IC50 5 nM). Pentafluorosulfanyl (SF5) group in biologically active compounds The pentafluorosulfanyl (SF5) group is an organic derivative of the hypervalent molecule sulfur hexafluoride (SF6). In the last decade the organic chemistry of the SF5 group has been extensively investigated, leading to a large and ready availability of building blocks and reagents bearing this substituent [46,47] . Several studies on SF5 properties have already been published reporting its chemical and hydrolytically stability [47,48] , the steric demand and symmetry (volume of SF5 is slightly less than t-butyl and greater than CF3)  [49] , the electron-withdrawing effect [21,50] , the electronegativity (SF5 = 3.65, CF3 = 3.36), and the nontoxicity of its degradation products [51] . These unique properties make the pentafluorosulfanyl group an attractive substituent in medicinal chemistry applications and confirm that the SF5 is not only a simple CF3 analogue. As a consequence of that, the use of SF5 in biological molecules (either as a replacement of a CF3 group or added denovo) is increasing, leading to an improved biological activity in either case. Nowadays, due to the relative novelty of this group, there are no drugs in the market showing this structural feature. However, several examples of biologically active molecules have been recently reported in literature. Examples of bioactive compounds containing the SF5 group will be discussed in this section. Sodium proton exchangers inhibitors

Sodium proton exchangers (NHEs) constitute a large family of integral membrane protein transporters that are responsible for the counter-transport of protons and sodium ions across lipid bilayers. Although NHE activation is essential for the restoration of physiological pH, hyperactivation of NHE (NHE1 isoform) during ischemia and reperfusion episodes disrupts the intracellular ion balance, leading to cardiac dysfunction and damage [52] . NHE1 inhibitors protect the cardiac tissue during heart attack, organ transplant and cancer chemotherapy. Benzoylguanidine HOE 694 (64) is a

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Review

Na+/H+ exchanger inhibitor, which shows cardioprotective and antiarhythmic effects in ischemia and reperfusion  [53] . Structure–activity studies demonstrated that the guanidinium portion is fundamental for the activity, since it mimics the sodium ion to block the membrane transport, whereas insertion of lipophilic and bulky groups at 4-position of the benzene ring might enhance the activity [49] . Therefore, the pentaflurosulfanyl group was inserted in position 4 obtaining a first generation of derivatives, where compound 65 (Figure 4A) showed an improved activity in the NEH1 inhibition in fibroblasts (IC50 = 14.5 nM) [54] . In order to increase the bulk in position 4, a second generation of compounds were developed and among them compound 66, bearing a pentafluorosulfanylphenoxy group in 4, showed a sevenfold improvement in activity when compared with compound 65 (IC50 = 1.9 nM) [55] . In both generations, the insertion of an SF5 group, in addition to increase the NHE inhibitory activity, improved bioavailability and in vivo half-life. Trypanothione reductase inhibitors

Parasites belonging to trypanosomatid family (Trypanosoma brucei, Trypanosoma cruzi, various species of Leishmania, etc.) are the cause of three human diseases: sleeping sickness, Chagas’ disease and leishmaniasis. Trypanothione reductase (TR) is a flavoenzyme, which is the key enzyme of the trypano-thione-based antioxidant defense system of these parasites. TR has an essential role in the parasite survival and therefore it has become an increasingly popular target [56] . Among all the TR inhibitors developed, the diaryl sulphide-based compounds (67) were the most explored [57] . Starting from these structures Stump et al. designed and synthetized a series of related diarylamines (68–73), bearing either a SF5 or a CF3 or a C(CH3)3 group [58] . Compounds 71–73 were tested against the T. cruzi TR and surprisingly the SF5 derivative (73) showed the same competitive inhibition constant (K ic = 28 μM) of the CF3 compound (K ic = 24 μM) and almost a fourfold improvement when compared with compound 73 (K ic = 84 μM). Moreover, the presence of the SF5 substituent changed the inhibition mode from purely competitive for compound 71 to mixed competitive-uncompetitive for 72. These results were rationalized through molecular modeling studies and the changes in binding affinity are thought to be a consequence of steric and electronic properties of the CF3, SF5 and C(CH3)3. In fact, the bulky t-butyl group prevents an efficient occupation of the binding site (loss of important interactions) leading to a higher K ic for compound 73. The CF3 moiety is smaller and allows compound 71 to better accommodate the TR active site. Although the volume of the

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Review  Bassetto, Ferla & Pertusati

SF5 N 4

F5S N

H3CO2S O

NH2

N

NH2

O

64

NH2

N

H3CO2S

65

66

S Cl

O

NH2

N

NH

+ N

NH HN

NH2

+ N

N

R

O

NH2

Cl

R

NH

Cl

HN Cl

R

67a-c R= 4-t-Bu, 4,5-Cl, Ph,4-OCH2Ph

F 68: R = CF3 69: R = SF5 70: R = C(CH3)3

F 71: R = CF3 72: R = SF5 73: R = C(CH3)3

Figure 4. Improved activity in the NEH1 inhibition in fibroblasts. (A) HOE 694 derivatives; (B) trypanothione reductase inhibitors. 

SF5 is slightly less than t-butyl and greater than CF3, compound 72 showed a similar binding affinity to its CF3 analogue, and according with the authors this is due to the strong electron-withdrawing nature of the pentafluorosulfanyl group, which might strengthen the interaction of 72 with the electron-rich residues of the active site. Compounds 68–73 (Figure 4B) were also tested against the Plasmodium falciparum. All the tested compounds were found active with an IC50 value of 1.5 μM and interestingly the presence of the SF5 increased the selectivity against the parasite, considerably reducing the cytotoxicity values on myoblast cells. Moreover, the SF5 derivatives showed better membrane permeability. Fluorinated nucleosides Nucleosides represent a very important group of molecules in the pharmaceutical chemistry field, due to their pharmacological properties as both anticancer and antiviral agents. Fluorine-containing nucleosides analogues have drawn special attention because of the many unique properties of fluorinated substituent already discussed in the previous sections. Some highly active fluorinated nucleosides have been synthesized and are approved for use in cancer and viral treatment. For example gemcitabine, a deoxycytidine analogue modified with two fluorine atoms at position 2’, has been approved to treat solid tumors [59] . Fluorine atoms and fluorinated groups can be present in nucleosides either in the nucleobase and/or in

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Future Med. Chem. (2015) 7(4)

the sugar. The following section will focus on the presence of polyfluorinated groups in biologically active nucleosides, both in the base and the sugar moieties, and on the effect that these groups have on biological properties. Sugar & phosphate modifications Bis-(Difluoromethylene)triphosphoric acid nucleotide analogs

As a mean to obtain nonhydrolyzable nucleotide analogs, the natural triphosphate group can be modified with a bis-CF2 substitution, which shows the correct polarity to mimic a triphosphate and represents the smallest possible steric perturbation to the natural group. Figure 5A shows both fluorinated DNA and RNA nucleotide analogs. DNA analogs 74a-d can be used as probes to evaluate the mechanism of polymerase action, to explore stereoelectronic effect on active site interactions and to illustrate small differences in the catalytic activity of different enzymes [60] . The synthesis of the hydrolytically stable RNA analogues 75a-d has been recently reported [61] . These compounds could be used to study the active sites of several enzymes, along with their biological functions and mechanisms. 2’-Trifluoromethylthio ribonucleic acids

Different fluorinated RNA derivatives are currently explored as NMR probes for the understanding of

future science group

Review

Polyfluorinated groups in medicinal chemistry 

RNA folding and ligand interactions by 19F NMR spectroscopy [62] . The synthesis of the 2’-SCF3 pyrimidine nucleoside containing oligoribonucleotides 76a and 76b (Figure 5B), has been recently reported [63] . Differently from other 2’ modifications such as OCH3, OCF3 or F, which increase or not alter double helix stability, the presence of a SCF3 substituent in position 2’ of oligoribonucleotides seems to have a strong destabilizing impact on the thermodynamic stability of RNA folds when located in a Watson-Crick base paired helix, due to a remarked intrinsic preference for the C2’-endo conformation of 2’-SCF3 modified nucleosides. It has been already reported that nucleosides with strong destabilizing effects on Watson-Crick pairing such as seconucleosides can significantly reduce off-target effects of siRNA [64] ; this evidence suggests that nucleosides with a 2’-SCF3 modification could be further developed for oligonucleotide therapeutics. OH

HO

OH

F

OH O P

P O P F O O O

O

HO

Base

Fluorinated methylthioadenosine analogs as antimalarial agents

Different fluorinated intermediates of the methionine salvage pathway have been designed as inhibitors to target chloroquine-resistant strains of P. falciparum: the adenosine and ribose analogs 77a-e shown in Figure 5C were found to inhibit P. falciparum growth with IC50 values in the low micromolar range [65] . Nucleobase modifications

Different fluorinated modifications on nucleobases have been reported in the past for investigational and biological purposes; herein the attention will be focused on the effect of perfluorinated base-modifications on the biological activity of nucleosides. Fluorinated 1-deazapurines

1-Deazapurines (imidazo[4,5-b]pyridines) are an important class of heterocyclic compounds that

F OH OH O O P P P F O O O

OH

OH 75a-d

74a-d

Base = Adenine, Guanine, Thymine, Cytidine

N

O

HO

N

N

O

R2

N

N

HO O

in vivo

OH

OH

OH

77a: R = CF2H 77b: R = CF3 77c: R = CH2CF2H 77d: R = CH2CF3 77e: R = CH2CH2F

IC50 = 35 µM IC50 = 18 µM IC50 = 25 µM IC50 = 85 µM IC50 = 43 µM

OH

N

OH

N

R2

N HO

OH

F 3C

OH

Tubercidin (79)

R1

CF3

OH

O

N

R

80a: R = C(CH3)3 80b: R = Ph 80c: R = NH2

HO

O

OH 81

N

OH

N

R2

NH

N

N N

N H

N H

78a: R1 = CF3, R2 = CF3 78b: R1 = CF3, R2 = CH3 78c: R1 = CF3, R2 = Ph 78c: R1 = CF2Cl, R2 = CH3

F3C

N

OH N

O

O N

O

N H

R1

OH

OH

H2N

HO

OH

N H2O

RNA

Base = Uracil, Cytidine 76a-b

F3C

N

SCF3

O

O P OH

OH OH

R1

N O

Base

O

Base

O

O

Base = Adenine, Guanine, Uracil, Cytidine

H2N

R S

RNA OH O P

O

N

O

R2

82 R1 = H, CH3, Ph R2 =

N H

O

83 OR

OH

CH2F

CH2F

OH CF3

OH C2F5

Figure 5. Fluorinated DNA and RNA nucleotide analogs. (A) DNA and RNA nucleotide analogs; (B) 2’-Trifluoromethylthio oligoribonucleotides; (C) structure and activity of fluorinated 5-methylthioadenosine analogs; (D) fluorinated 1-deazapurines as potential inhibitors of ADA; (E) structures and activities for fluorinated 7-deazapurines; (F) structures of fluoroalkylated acyclic nucleosides.

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Review  Bassetto, Ferla & Pertusati exhibit a wide range of biological activities and pharmacological properties. Fluorinated 1-deazapurines are phosphodiesterase inhibitors and inhibitors of aurora kinase [66,67] . A series of fluorinated 1-deazapurines substituted at position C-6 by fluorine-containing groups has been synthesized following a mechanism-based design of compounds interfering with adenosine deaminase (ADA) [68] . Several deaminases represent drug targets for the design and synthesis of potent drugs for the treatment of various diseases, such as HIV and cancers. Nucleosides prepared in this study (78a-f) are reported in Figure 5D. They would mimic the transition state of the ADA enzymatic action, most likely the hydrated intermediate. The CF3 group, due to its electron withdrawing properties, would facilitate hydration at the C-6 or C-2 position of the purine ring, mimicking this way the transition state of adenosine hydrolytic deamination. The biological evaluation of these structures has yet to become available to the public. Trifluoromethylated 7-deazapurines

Adenosine analogue nucleosides are a fundamental part of medicinal chemistry. Tubercidin is a well-known adenosine analogue evaluated as anti-cancer agent, whose application in medical practice is limited due to high toxicity. With the target to develop less toxic synthetic analogues, a series of fluorinated nucleosides based on the pyrrolo[2,3-d]pyrimidine (7-deazapurine) motif has been recently reported [69] . The structures designed and synthesized show the presence a CF3 group as well as a variety of C2 substituents in the heterocyclic part, including alkyl, aryl, SMe, Cl, N3 and NH2 moieties. Cytotoxicity studies for these compounds were performed in HeLa S3 and Hep G2 cancer cell lines. The effect of C2 substitutions was explored, and compound 81 was identified as lead candidate (Figure 5E, Table 8) . In contrast with Tubercidin, cell viability remained high, after incubation with compound 81, suggesting that this structural modification might lower the Table 8. Structures and activities for fluorinated 7-deazapurines.

542

Cpd

HeLa S3 IC50 (μM)

Hep G2 IC50 (μM)

Ref.

80a

7.7 ±1.0

11.2 ±1.0

[69]

80b

5.6 ±0.8

[69]

80c

4.6 ±0.8

[69]

81

0.090 ±0.049

±

[69]

Tubercidin (79)

±

±

[69]

Future Med. Chem. (2015) 7(4)

cytotoxicity, while maintaining the antiproliferative properties associated to this scaffold. Fluorinated acyclic nucleosides

Most of the antiviral compounds currently used in the treatment of HSV (herpes simplex virus), VZV (varicella zoster virus) and CMV (cytomegalovirus) belong to the family of acyclic nucleoside analogues. Among these agents, aciclovir and ganciclovir were reported to be efficient antiviral agents with low host toxicity [70] . Also penciclovir, a carba analogue of ganciclovir, was found to be a more potent and highly selective antiviral agent against HSV and VZV [71] . This ciclovirs have stimulated extensive research in the synthesis of new acyclic analogues mimicking the sugar portion of naturally occurring nucleosides, and several fluorinated modifications have been carried out in the past to improve their activities or to evaluate them as tracers for noninvasive positron emission tomography (PET) imaging  [72–74] . For example, a set of nonconventional C-6 fluoroalkylated pyrimidine acyclic nucleoside mimetics 82a-l and 83a-l were prepared as model compounds for the development of tracer molecules in PET (Figure 5F) [75] . When compounds 82al and 83a-l were evaluated for their antiviral and cytostatic activities, some of them showed a slight activity against CMV, VZV and Coxsackie B4 virus, and showed no cytotoxic effect. Perfluoroalkyl groups containing compounds In a study reported by Cranch et al.  [76] , perfluoroaldehyde and perfluorocarboxylic acid compounds were tested for their potential effect on the endocrine glands (testes and thymus) and on the NCS. The difference in activity among the prepared series was linked to the length of the fluorinated chain with a decrease in activity found replacing the CF3 group with the higher C2F5 and a total loss of activity for the longer C3F7 derivative. Trivedi et al. [77] reported a nonthiazolidinedione perfluoro anilides 84 a-j (Figure 6) as oral antidiabetic compounds. All the new perfluoro anilides normalized the plasma glucose and insulin levels in postprandial obese mice after 2 days of oral administration and did not alter the glucose, insulin and free fatty acid levels in control mice. Interestingly, the potency in the series was related to the length of the perfluorinated chain with the largest decrease in glucose and insulin obtained for the C7F15, C8HF16 and C8F17 lateral chain. Shorter perfluorinated chains (e.g. C6F13) give lower glucose and insulin blood level decrease whereas longer chains (e.g., C10HF20) did not significantly improve the glucose-lowering activity and did not attenuate the hyperinsulinemia. Moreover, perfluoro anilides with longer chains (C7F15, C8HF16)

future science group

Polyfluorinated groups in medicinal chemistry 

Review

O R

HN NH

84a–j

N

N

R = CF3, C2F5, C3F7, C4F9, C6F13, C7F15, C8HF16, C8H17, C9F19, C10HF20

O

O S

Ciglitazone (85)

NH O

Figure 6. Perfluoalkylated compounds of relevant interest in medicinal chemistry.

showed better effect on plasma glucose and insulin on insulin-resistant diabetic mouse if compared with the standard ciglitazone (85) or with shorter chain perfluoro anilides derivatives. As reported above, the literature regarding high perfluoroalkyl groups reports conflicting opinions on their advantages and on their safety (possible bioaccumulation), making more difficult the identification of the optimal size/length for a perfluoroalkyl group to improve the biological activity of a compound. As a consequence, the perfluoroalkyl groups field needs deeper and further investigation in order to better clarify the potential role of these groups in medicinal chemistry. Conclusion & future perspective In the present perspective we presented evidences directed to demonstrate to the readership how the use of polyfluoroalkyl groups in medicinal chemistry represents today a mature topic. However, despite the success of the trifluoromethyl group, which is incorporated in several blockbuster drugs, we feel that a great number of studies can be done in this exciting field

toward the exploration of diverse perfluoro groups. As stated in the early part of this manuscript, the great plethora of synthetic methodologies available today for the introduction of polyfluoroalkyl- aryl groups into a great variety of organic structures will, in our opinion, increase the amount of polyfluorinated drugs, prodrugs or drug-like molecules with improved properties in terms of activity and pharmacokinetic profiles. It is our belief that medicinal chemists, in general are reluctant to explore new functional groups, should instead try to incorporate higher polyfluoroalkyl groups into their parent structures. Whenever a bulky, electronegative group is needed, a polyfluoroalkyl group might indeed suite the need. Furthermore, the highly polarizable nature of the carbon–sulfur bond may directly influence reactivity in a manner different from the one associated with the trifluoromethyl group. Personally, we also would like to encourage the exploration of the pentafluorsulfanyl group. In this regard, we are pleased to see that on professional social networks there is a fervid discussion on the utility of the pentafluorosulfanyl, especially when compared with pentafluorethyl

Executive summary Background • Fluorine in organic/medicinal chemistry has been exploited at almost full potential only recently. Several blockbuster drugs nowadays contain fluorine in their scaffold and always new fluorine containing drugs are continuously designed and synthesized. • Scaffolds with trifluoro- and difluoromethyl groups have recently became more and more popular in drug design because it has been demonstrated that these group can be extremely useful in modulating drugs properties. However, polyfluoroalkyl/aryl-containing drugs are much less explored. • Strategies for the introduction of polyfluoroalkyl/aryl group were scarce in the past.

Use of polyfluoroalkyl groups • Synthetic fluorine chemistry is nowadays a very prolific branch of organic chemistry and polyfluorinated compounds are now widely available to medicinal chemists. • Pentafluorosulfanyl (SF5) and SCF3 groups are now accessible and are used more often in drug-like scaffolds. Their unique properties have shown to be quite interesting from a medicinal chemistry point of view. • Higher polyfluoroalkyl groups such as C 2F5 or higher have not been explored in great extent as their lower counterpart (CF3, CF2H). • The effects of these group on the pharmacological properties has been sometimes promising and sometimes not. However, much more studies would be required to better understand the effects of these groups.

Conclusion • Polyfluorinated groups have demonstrated a great potential in several area of medicinal chemistry. • The vast selection of synthetic methodologies will make their use more and more common in the future. • New polyfluorinated groups such as SF5, SCF3, have shown very promising results when introduced in drugs scaffold. Their increased availability will surely expand their use in medicinal chemistry. • However, studies toward the assessment of potential toxicity of higher perfluoroalkyl groups are essential.

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Review  Bassetto, Ferla & Pertusati analogues [78] . Due to its unique chemical characteristics and stability properties, our view in this debate is in favor of the use of the SF5 in drug discovery. Financial & competing interests disclosure The authors have no relevant affiliations or financial involvement with any organization or entity with a financial

interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. No writing assistance was utilized in the production of this manuscript. Synthesis, Properties, and Application as a Real CF+ Species Reagent J. Org. Chem. 72, 6905–6917 (2007).

References Papers of special note have been highlighted as: • of interest; •• of considerable interest

544

1

Meanwell N A. Synopsis of some recent tactical application of bioisosteres in drug design. J. Med. Chem. 54(8), 2529–2591 (2010).

2

Wang J, Sánchez-Roselló M, Aceña J L, Al. E. Fluorine in pharmaceutical industry fluorine-containing drugs introduced to the market in the last decade 2001–2011. Chem. Rev. 114(4), 2432–2506 (2014).

•

Gives a complete and exhaustive review of the fluorinecontaining drugs introduced to the market in the last decade.

3

Purser S, Moore PR, Swallow S, Gouverneur V. Fluorine in medicinal chemistry. Chem. Soc. Rev. 37, 320–330 (2008).

4

O’hagan D, Harper DB. Fluorine-containing natural products. J. Fluor. Chem. 100(1–2), 127–133 (1999).

5

Smart B E. Fluorine substituent effects on bioactivity. J. Fluor. Chem. 109(1), 3–11 (2001).

6

Hansch C, Leo A. Exploring QSAR. Fundamentals And Applications In Chemistry And Biology. American Chemical Society, Washington, DC, (1995).

7

Hansch C, Leo A, Hoekman D. Exploring QSAR. Hydrophobic, Electronic And Steric Constants. ACS Professional Reference Book, American Chemical Society, Washington, DC, (1995).

8

Leo A, Hansch C, Elkins D. Partition coefficients and their uses. Chem. Rev. 71(6), 525–616 (1971).

9

Hansch C, Leo A, Unger SH, Kim KH, Nikaitani D, Lien EJ. Aromatic substituent constants for structure activity correlations. J. Med. Chem. 16(11), 1207–1216 (1973).

10

Hansch C, Leo A, Taft RW. A survey of Hammett substituent constants and resonance and field parameters. Chem. Rev. 91(2), 165–195 (1991).

11

Dalvit C, Vulpetti A. Intermolecular and intramolecular hydrogen bonds involving fluorine atoms implications for recognition, selectivity, and chemical properties. ChemMedChem 7(2), 262–272 (2012).

12

Zhu W, Wang J, Wang S et al. Recent advances in the trifluoromethylation methodology and new CF3-containing drugs. J. Fluor. Chem. 167(0), 37–54 (2014).

13

Tlili A, Billard T. Formation of C-SCF3 bonds through direct trifluoromethylthiolation. Angew. Chem. Int. Ed. 52(27), 6818–6819 (2013).

14

Yagupol’skii LM. Dokl. Akad. Nauk SSSR 105, 100–102 (1955).

15

Umemoto T, Adachi K, Ishihara S. CF3-Oxonium Salts, O-(Trifluoromethyl)dibenzofuranium Salts: In situ

Future Med. Chem. (2015) 7(4)

16

Koller R, Stanek K, Stolz D, Aardoom R, Niedermann K, Togni A. Zinc Mediated Formation of Trifluoromethyl Ethers from Alcohols and Hypervalent Iodine Trifluoromethylation Reagents. Angew. Chem. Int. Ed. 48, 4332–4336 (2009).

17

Feiring AE, Rozen S, Wonchoba ER. Synthesis of arylperfluoroalkyl ethers by direct fluorination. J. Fluor. Chem. 34(1998), (1998).

18

Leroux FR, Manteau B, Vors JP, Pazenok S. Trifluoromethyl ethers – synthesis and properties of an unusual substituent. Beil. J. Org. Chem. 15(2008), (2008).

19

T.U: US7592491B2 (2010).

20

Frischmuth A, Unsinn A, Groll K, Stadtmüller H, Knochel P. Preparations and reactions of SF5-substituted aryl and heteroaryl derivatives via Mg and Zn organometallics. Chem. Eur. J. 18(33), 10234–10238 (2012).

21

Bowden BD, Comina PJ, Greenhall MP, Kariuki BM, Loveday A, Philp D. A new method for the synthesis of aromatic sulfurpentafluorides and studies of the stability of the sulfur pentafluoride group in common synthetic transformations. Tetrahedron 56(21), 3399–3408 (2000).

•

Reveals important strategies for the preparation of aromatic sulfur pentafluorides.

22

Brel VK. Synthesis and Diels-Alder reactions of dienophiles with pentafluoro-λ6-sulfanyl (SF5) moiety. Synthesis 2, 339–343 (2006).

23

Brel VK. Synthesis of 4,5-Dihydroisoxazoles connected by short spacers to the pentafluoro-λ6-sulfanyl group. Synthesis (16), 2665–2267 (2006).

24

Savoie PR, Welch JT. Preparation and Utility of Organic Pentafluorosulfanyl-Containing Compounds Chem. Rev. DOI: 10. 1021/cr500336u (2014).

•

During the preparation of our manuscript an excellent review covering all synthetic methods used to introduce the SF5 group has been published.

25

Wishart DS, Knox C, Guo AC, Al. E. DrugBank: a knowledgebase for drugs, drug actions and drug targets. Nucleic Acid Res. 36, D901–D906 (2007).

26

Crockett M, Kain KC. Tafenoquine: a promising new antimalarial agent. Expert Opin. Inv. Drugs 16, 705–715 (2007).

27

Dhammika N, Ager A LJ, Bartlett M, Al. E. Antiparasitic activities and toxicities of individual enantiomers of the 8-aminoquinoline 8-[(4-amino-1-methylbutyl)amino]6-methoxy-4-methyl-5-[3,4-dichlorophenoxy]quinoline succinate Antimicrob. Agents Chemother 6, 2130–2137 (2008).

future science group

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28

29

30

Lucking U, Jautelat R, Kruger M et al. The lab oddity prevails discovery of pan-CDK inhibitor R -S-cyclopropyl-S4-{[4-{[1R,2R -2-hydroxy-1-methylpropyl]oxy}-5trifluoromethyl pyrimidin-2-yl]amino}phenyl sulfoximide BAY-1000394 for the treatment of cancer. ChemMedChem 8(7), 1067–1085 (2013). Watanabe Y, Asai H, Ishii T, Al. E. Pharmacological characterization of T-2328, 2-fluoro-4 ‘-methoxy-3’-2S,3S2-phenyl-3-piperidinyl amino methyll 1,1’-biphenyl4-carbonitrile dihydrochloride, as a brain-penetrating antagonist of tachykinin NK1 receptor. J. Pharmacol. Sci. 106(1), 121–127 (2008). Kim D, Wang L, Beconi M, Eiermann GJ, Al. E. 2R-4Oxo-4-[3-trifluoromethyl-5,6-dihydro[1,2,4]triazolo[4,3-a] pyrazin-7,8H-yl]-1–2,4,5-trifluorophenyl butan-2-amine: a potent, orally active dipeptidyl peptidase IV inhibitor for the treatment of Type 2 diabetes. J. Med. Chem. 48(1), 141–151 (2005).

•

Highlight the important influence of perfluoro-groups in the optimization of biological active compounds.

31

Mccormck PL. Celecoxib a review of its use for symptomatic relief in the treatment of osteoarthritis, rheumatoid arthritis and ankylosing spondylitis. Drugs 71(18), 2457–2489 (2011).

32

Lindberg P, Carlsson E. Esomeprazole in the framework of proton-pump inhibitor development. In: Analogue-based Drug Discovery. Wiley-VCH Verlag GmbH & Co. KGaA, 81–113 (2006).

33

Satoh H. Discovery of lansoprazole and its unique pharmacological properties independent from anti-secretory activity. Curr. Pharm. Design 19(1), 67–75 (2013).

34

Kubo K, Oda K, Kaneko T, Satoh H, Nohara A. Synthesis of 2,4-fluoroalkoxy-2-pyridylmethyl]sulfinyl]-1H-benzimidazoles as antiulcer agents. Chem. Bull. Pharm. 38(10), 2853–2858 (1990).

35

Senn-Bilfinger J, Sturm E. The development of a new protonpump inhibitor: the case history of pantoprazole. In: Analoguebased Drug Discovery. Wiley-VCH Verlag GmbH & Co. KGaA. 115–136 (2006).

36

Yuasa K, Kanoh Y, Okumura K, Omori K. Genomic organization of the human phosphodiesterase PDE11A gene. Evolutionary relatedness with other PDEs containing GAF domains. Eur. J. Biochem. 268(1), 168–178 (2001).

37

38

Soderling SH, Beavo JA. Regulation of cAMP and cGMP signaling: new phosphodiesterases and new functions. Curr. Opin. Cell. Biol. 12(2), 174–179 (2000). Guay D, Hamel P, Blouin M et al. Discovery of L-791943 A potent, selective, non emetic and orally active phosphodiesterase-4 inhibitor. Bioorg. Med. Chem. Lett. 12(11), 1457–1461 (2002).

39

Hansch C, Leo A. Substituent Constants For Correlation Analysis In Chemistry And Biology. Wiley, New York, NY 339 (1979).

40

Tse C, Shoemaker AR, Adickes J et al. ABT-263 A potent and orally bioavailable Bcl-2 family inhibitor. Cancer Res. 68(9), 3421–3428 (2008).

41

Petros AM, Dinges J, Augeri DJ et al. Discovery of a potent inhibitor of the antiapoptotic protein Bcl-xL from NMR and parallel synthesis. J. Med. Chem. 49(2), 656–663 (2006).

future science group

42

Wendt MD, Shen W, Kunzer A. Discovery and structure?activity relationship of antagonists of B Cell lymphoma. J. Med. Chem. 49(3), 1165–1181 (2006).

43

Bruncko M, Oost TK, Belli B A et al. Studies leading to potent, dual inhibitors of Bcl-2 and Bcl-xL. J. Med. Chem. 50(4), 641–662 (2007).

44

Park CM, Bruncko M, Adickes J et al. Discovery of an orally bioavailable small molecule inhibitor of prosurvival B-Cell Lymphoma 2 proteins. J. Med. Chem. 51(21), 6902–6915 (2008).

45

Kuo EA, Hambleton PT, Kay DP et al. Synthesis, structure– activity relationships, and pharmacokinetic properties of dihydroorotate dehydrogenase inhibitors: 2-cyano-3cyclopropyl-3-hydroxy-N-[3’-methyl-4’-(trifluoromethyl) phenyl]propenamide and related compounds. J. Med. Chem. 39(23), 4608–4621 (1996).

46

Gard GL. Recent milestone in SF5-chemistry. Chem. Today 27, 10–13 (2009).

47

Altomonte S, Zanda M. Synthetic chemistry and biological activity of pentafluorosulphanyl (SF5) organic molecules. J. Fluor. Chem. 143, 57–93 (2012).

48

Verma R, Kirchmeier R, Shreeve J. Advances in Inorganic Chemistry. Elsevier 125–169 (1994).

49

Lentz D, Seppelt K. The SF5, SeF5 and TeF5 groups in organic chemistry. In: Chemistry of Hypervalent Compounds. Wiley VCH, New York, NY 323(1999), (1999).

50

Sæthre LJ, Berrah N, Bozek JD. Chemical insights from high resolution X ray photoelectron spectroscopy and ab initio theory: propyne, trifluoropropyne, and ethylsulfur pentafluoride. J. Am. Chem. Soc. 123, 10729–10737 (2001).

51

Jackson DA, Mabury SA. Breaking down the substituent of the future: environmental properties of pentafluorosulfanyl compounds. Presented at: 236th ACS National Meeting. Philadelphia, PA, USA, August, (2008).

52

Masereel L, Pochet L, Laeckmann D. An overview of inhibitors of Na +/H + exchanger. Eur. J. Med. Chem. 38(6), 547–554 (2003).

53

Scholz W, Albus U, Lang H, Al. E. Hoe 694, a new Na +/H + exchange inhibitor and its effects in cardiac ischaemia. Br. J. Pharmacol. 109(2), 562–568 (1993).

54

Kleemann H W: US2003216476, (2003).

55

Kleemann H W: US2005043401, (2005).

56

Fairlamb AH, Blackburn P, Ulrich P, Chait BT, Cerami A. Trypanothione a novel bis glutathionyl spermidine cofactor for glutathione reductase in trypanosomatids. Science 227(4693), 1485–1487 (1985).

57

Parveen S, Khan MOF, Austin SE et al. Antitrypanosomal, antileishmanial, and antimalarial activities of quaternary arylalkylammonium 2-amino-4-chlorophenyl phenyl sulfides, a new class of trypanothione reductase inhibitor, and of N-acyl derivatives of 2-amino-4-chlorophenyl phenyl sulfide. J. Med. Chem. 48(25), 8087–8097 (2005).

58

Stump B, Eberle C, Schweizer WB. Pentafluorosulfanyl as a novel building block for enzyme inhibitors: Trypanothione Reductase inhibition and antiprotozoal activities of diarylamines. ChemBioChem 10(1), 79–83 (2009).

www.future-science.com

Review

545

Review  Bassetto, Ferla & Pertusati •

69

Drexler J, Groth U. Trifluoromethylated Nucleosides: A building block approach to cytotoxic adenosine analogues. Eur. J. Org. Chem. 28, 6314–6320 (2014)

70

Martin JC, Mcgee DP, Jeffrey GA. Synthesis and anti-herpes virus activity of acyclic 2’-deoxyguanosine analogs related to 9-[1,3-dihydroxy-2-propoxy methyl]guanine. J. Med. Chem. 29(8), 1384–1389 (1986).

59

Tokoyama A, Nakai Y, Yoneda S, Kurita Y, Niitani H. Activity of gemcitabine in the treatment of patients with non small cell lung cancer: a multicenter Phase II study. Anti Cancer Drugs 8(6), 574–581 (1997).

71

•

Highlights the importance of the introduction of fluorine in nucleosides which led to their approval as anti-cancer and as anti-viral.

Harnden MR, Jarvest RL, Bacon TH, Boyd MR. Synthesis and antiviral activity of 9-[4-hydroxy-3-(hydroxymethyl)but1-yl]purines J. Med. Chem. 30(9), 1636–1642 (1987).

72

60

Prakash GKS, Zibinsky M, Upton TG, Al. E. Synthesis and biological evaluation of fluorinated deoxynucleotide analogs based on bis-(difluoromethylene)triphosphoric acid. Proc Natl Acad. Sci. USA 107(36), 15693–15698 (2010).

Hospers GA, Calogero A, Van Waarde A. Monitoring of herpes simplex virus thymidine kinase enzyme activity using positron emission tomography. Cancer Res. 60(6), 1488–1491 (2000).

73

61

Shakhmin A, Jones J-P, Bychinskaya I et al. Preparation of fluorinated RNA nucleotide analogs potentially stable to enzymatic hydrolysis in RNA and DNA polymerase assays. J. Fluor. Chem. 167(0), 226–230 (2014).

De Vries EF, Van Waarde A, Harmsen M C, Mulder N H, Vaalburg W, Hospers G A. [11C]. FMAU and [18F]FHPG as PET tracers for herpes simplex virus thymidine kinase enzyme activity and human cytomegalovirus infections. Nucl. Med. Biol. 27(2), 113–119 (2000).

62

Santner T, Rieder U, Kreutz C, Micura R. Pseudoknot Preorganization of the PreQ1 Class I Riboswitch. J. Am. Chem. Soc. 134(29), 11928–11931 (2012).

74

63

Košutić M, Jud L, Da Veiga C, Al. E. Surprising base pairing and structural properties of 2’-trifluoromethylthiomodified ribonucleic acids. J. Am. Chem. Soc. 136(18), 6656–6663 (2014).

Alauddin MM, Conti PS. Synthesis and preliminary evaluation of 9-(4-[18F]-fluoro-3-hydroxymethylbutyl) guanine ([18F]FHBG): A new potential imaging agent for viral infection and gene therapy using PET. Nucl. Med. Biol. 25(3), 175–180 (1998).

75

Prekupec S, Makuc D, Plavec J et al. Novel C-6 fluorinated acyclic side chain pyrimidine derivatives ? synthesis, 1H and 13C NMR conformational studies, and antiviral and cytostatic evaluations. J. Med. Chem. 50(13), 3037–3045 (2007).

76

Crank G, Harding DRK, Szinai SS. Perfluoroalkyl carbonyl compounds. J. Med. Chem. Perfluoroaldehyde and perfluorocarboxylic acid derivatives. 13(6), 1212–1215 (1970).

77

Trivedi B K, Bridges AJ, Patt WC, Priebe SR, Brunst RF. Perfluoroalkyl carbonyl compounds. 1. Perfluoro-N-[4-(1Htetrazol-5-ylmethyl)phenyl]-alkanamides. A new class of oral antidiabetic agents. J. Med. Chem. 32(1), 11–13 (1989).

78

The SF5 substituent: Useful in medicinal chemistry or not? https://www.linkedin.com/groups/SF5-substituent-Usefulin-medicinal-923867. S. 5801795069040148483

64

65

66

546

Significant example of how the SF5 introduction can increase the selectivity, reduce the cytotoxicity and improve the activity in comparison with CF3 or C(CH3) 3 group.

Campbell MA, Wengel J. Locked vs. unlocked nucleic acids (LNA vs. UNA): contrasting structures work towards common therapeutic goals. Chem. Soc. Rev. 40, 5680–5689 (2011). Houston ME, Jr, Vander JDL, Honek JF. Synthesis and biological activity of fluorinated intermediates of the methionine salvage pathway. Bioorg. Med. Chem. Lett. 1(11), 623–628 (1991). Joseph EC, Rees JA, Dayan A. Mesenteric Arteriopathy in the rat induced by phosphodiesterase III inhibitors: an investigation of morphological, ultrastructural, and hemodynamic changes. Toxicol. Pathol. 24, 436–450 (1996).

67

Bavetsias V, Sun C, Bouloc N et al. Hit generation and exploration: Imidazo[4,5-b]pyridine derivatives as inhibitors of Aurora kinases. Bioorg. Med. Chem. Lett. 17(23), 6567–6571 (2007).

68

Iaroshenko VO, Ostrovskyi D, Petrosyan A, Mkrtchyan S, Villinger A, Langer P. Synthesis of fluorinated purine and 1-deazapurine glycosides as potential inhibitors of adenosine deaminase. J. Org. Chem. 76(8), 2899–2903 (2011).

Future Med. Chem. (2015) 7(4)

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