Medicinal Chemistry

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Medicinal Chemistry

Medicinal applications of perfluoroalkylated chain-containing compounds

Compounds with polyfluorinated molecular fragments possess unique properties associated with the presence of a large number of fluorine atoms that affect lipophilicity and conformational rigidity of the parent molecule along with other effects. The aim of this review is to provide an overview of synthesized compounds possessing perfluoroalkylated or polyfluorinated chains that have been tested for bioactivity or as potential drug candidates for the treatment of various diseases. As far as the length of the perfluoroalkylated chain is concerned the focus is centered on the compound bearing perfluoroethyl or tetrafluoroethyl as well as longer chains. The perfluoroalkylated compounds discussed are classified according to their biological activity.

The introduction of fluorine to organic molecules can profoundly change their properties. The high electronegativity of the fluorine atom in combination with its rather small size (it is isosteric with the hydroxyl group) makes it a highly interesting candidate for modification of organic compounds and especially of various biologically active molecules. Drug candidates with one or more fluorine atoms have become commonplace. The special nature of fluorine imparts a variety of properties to certain medicines, including enhanced binding interactions, metabolic stability, changes in physical properties and selective reactivities. Advances in fluorine chemistry have presented the synthetic chemists with a wide variety of reagents for the selective introduction of fluorine or fluoroalkyl groups into specific locations in their target molecules. The incorporation of fluorine is a simple process of modification, which often results in better medicinal candidates compared with lead compounds. Research has shown that, in general, fluorinated compounds require a far lower effective dosage than their ­a nalogous nonfluorinated pharmaceuticals. Fluorinated organic compounds represent a rapidly expanding proportion of molecules

10.4155/FMC.14.53 © 2014 Future Science Ltd

Eva Prchalová1, Ondřej Štěpánek1, Stanislav Smrček‡,1 & Martin Kotora*,‡,1 1 Department of Organic Chemistry, Faculty of Science, Charles University in Prague, Hlavova 8, 128 43 Praha 2, Czech Republic *Author for correspondence: Tel.: +420 221 951 058 Fax: +420 221 951 326 [email protected] ‡ Authors contributed equally

that are used as pharmaceuticals, diagnostics, agrochemicals and materials. Such compounds comprise of the most successful pharmaceuticals on the market today, including the antidepressants Prozac® (Eli Lilly) and Paxil®, and the widely prescribed antibiotic Ciprofloxacin® (Bayer) [1] . There have been a number of various reviews on this topic in the last two decades [2–15] . The use of fluorine in medicinal chemistry has been reviewed elsewhere [16] , as has the influence of fluorine on the physical properties of fluorinated compounds [17–21] . Interestingly, most of the fluorinated compounds possess one, two or three fluorine atoms. The latter also includes a large family of substances bearing a trifluoromethyl group. However, perfluoroalkylated compounds bearing perfluoroalkylated chains starting with the perfluoroethyl group have not been at the center of interest. To the best of our knowledge, there has been only one review published on the current and future perspectives of perfluorinated compounds [22] . This review aims to fill this gap by providing an overview of compounds containing the perfluoroethyl group and longer perfluorinated chains that have been tested as candidates for drug development.

Future Med. Chem. (2014) 6(10), 1201–1229

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ISSN 1756-8919

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Review  Prchalová, Štěpánek, Smrček & Kotora

Key terms Medicinal chemistry: A discipline at the intersection of synthetic organic chemistry, pharmacology and various other biological specialties, which is involved with design, chemical synthesis and development for market of pharmaceutical agents or bioactive molecules. Perfluoroalkylated compound: A compound possessing a highly fluorinated alkyl moiety with general formula CF3 (CF2) n (CH2) m-,CHF2(CF2) n (CH2) m-, or -(CH2) m (CF2) n (CH2) m- where n ≥ 2 and m ≥ 0.

Inhibitors Carbonic anhydrase inhibitors

Carbonic anhydrase (CA) inhibitors have been used as pressure lowering systematic drugs in the treatment of open-angle glaucoma as well as other diseases. The initial impetus for endeavors in this area were the results showing that sulfonamides (compound 1) showed good inhibition of CA II [23] . In this respect the number of sulfonamides bearing perfluoroalkylsulfonyl chains (n-C4F9SO2 and n-C8F17SO2) and perfluoroalkylcarbonyl chains (n-C8F17CO) were studied for affinity towards isozymes of I, II, and IV of human CA (hCA). In general, the perfluoroalkylated derivatives exhibited very good inhibition activity. The most successful derivatives bearing perfluoroalkylated chains were compounds 2, 3, and 4. Inhibition data (K i) for hCA I were in the range of 19–59 nM, for hCA II were in the range of 3–10.5 nM, and for hCA IV were in the range of 5–14 nM [24] . In a similar manner, a series of sulfonylated iminoacyl hydroxamates (compound 5) bearing n-C4F9SO2 chain were tested. They showed interesting but not the best inhibition of the abovementioned isozymes of CA. The inhibition values were in the range of 14 to >200 nM depending on the substitution pattern. In a similar manner, perfluoroalkylated sulfonylsulfacetamines bearing n-C4F9SO2 and n-C8F17SO2 chains (compounds 6a and 6b) were tested. They Table 1. Carbonic anhydrase activity of the selected perfluoroalkylated compounds. Compound

IC50 (nM)

 

hCA I

hCA II

hCA IV

6a

35000 ± 200

5 ± 0.2

12 ± 0.7

6b

27000 ± 300

3 ± 0.1

10 ± 0.5

7

1400

66

850

8

10 6 

9000

 

11b

 

122

 

hCA: Human carbonic anhydrase.

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exhibited particularly good inhibitory properties for hCA types II and IV with IC50 values in the range of 3–12 nM, whereas for hCA type I they were mostly inactive (Table 1) [25] . Lower inhibition properties were observed for sulfonamide possessing an n-C8F17CO chain (compound 7) [26] . Interestingly, even simple n-nonafluorobutansulfoamide (compond 8) showed excellent inhibition properties for hCA I [27] . On the other hand sulfamates bearing the perfluorohexyl (compound 9a) and perfluorooctyl (compound 9b) chains had a very low activity [28] . A series of symmetric bisperfluoroalkanesulfonylimides (compound 10) were prepared and their bovine CA inhibition activity was tested. They exhibited 65–97% inhibition at 1.35 × 10-4 M concentration [29] . Later series of perfluoroalkanesulfonamides (compound 8 and 11), their sodium salts (compound 12) and perfluoroalkylethylsulfonamides (compound 13) were tested for bovine CA activity. They all exhibited activity expressed as IC50 in the range of 1.3–2.1 μM. Compound 11b was also tested on hCA II [30] . Pefluoroalkylated derivatives of thiadiazole, namely compound 14, showed very high activity against CA of Plasmodium falciparum. It was one of the most potent inhibitors, with a K i of 0.192 μM [31] . Experimental comparison of ligand properties of alkyl- and perfluoroalkyl- containing benzenesulfonamides in the interaction with CA II was evaluated as well. It concluded that the main difference is in their hydrophobic surface area rather than physical properties [32] (Supplementary Figure 1) . Protease inhibitors

Matrix metalloproteinases (MMPs) are interesting targets for drug design in the search for novel types of agents useful in the management of anti-inflammatory processes, cancer and arthritis. Similarly, Clostridum histolycum collagenase (ChC) is zinc-protein that is responsible for dismantling of collagen. A series of amino acids hydroxamates bearing perfluoroalkylsulfonyl chains (n-C4F9SO2 and n-C8F17SO2) on the nitrogen atom was tested as inhibitors of four MMPs (MMP1, MMP2, MMP8, and MMP9), and ChC. The tested compounds were based on β-alanine (compound 15 [33]), alanine (compound 16 [34] and 17 [35]), valine (compound 18 [36]) and glycine (compound 19 [37] and 20 [38]). As far as the inhibition of ChC is concerned, all compounds with an n-C4F9SO2 chain had a K i in the range of 10–15 nM, whereas those with a longer perfluoroalkylated chain had a Ki in the range of 7–9 nM. Their parental carboxylic acids exerted lower activity. Regarding inhibition activity of MMPs, compounds 15 and 20 were tested and showed K i values of single digit nanomolar activity for MMP2, MMP8 and MMP9.

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Medicinal applications of perfluoroalkylated chain-containing compounds 

Thrombin has become important target for drug design in search of selective inhibitors with application of diagnostic and therapeutic agents for thrombic diseases. Potential inhibitors were synthesized such as perfluoroalkylated (n-C4F9 and n-C8F17) sulfonylguanidines (compound 21) and sulfonyl-O-methylisoureas (compound 22) [39] . These compounds were tested for inhibition of human thrombin and human trypsin; however, they were among the most ineffective inhibitors in the whole series of prepared compounds. NF-κB is an inducible transcription factor that regulates proinflammatory proteins and cytokines. It is therefore a target for regulating inflammatory processes. A peptidic perfluoroethylketone (compound 23) was tested as a potential inhibitor, but it displayed low activity against IκB protease (IC50 >30 μM) [40] (Supplementary Figure 2) . Lipase inhibitors

Alkylated aromatic compounds bearing perfluoroalkylated moieties (compound 24 and 25) were tested as inhibitors of the group via calcium-independent phospholipase A 2. Although the highest activity was observed for a compound bearing the trifluoromethyl group, the one possessing the perfluoropropyl group (compound 25b) also showed very good inhibition activity, with an ΧI(50) value of 0.001 while inhibiting the other intracellular GIVA cPLA 2 and GV sPLA 2 at least 90-times less potently [41] . It is worth noting that perfluorocarboxylic acids used as additives have been shown to fine-tune lipase activity. For example, during hydrolysis of 4-nitrofenol esters using Thermobacterium thermohydrosulfuricum, an activity enhancement of 260% was observed in the presence of perfluorodecanoic acid [42] . On the other hand, the use of perfluorinated alcohols did not have any beneficial effect (Supplementary Figure 3) .

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The former exhibited average activity (63.6% inbition at 3 mg/kg) and the latter was not effective at all [44] (Supplementary Figure 5) . Inhibitors of cholesterol ester hydrolase

Inhibition of pancreatic ester hydrolase that catalyzes dietary cholesterol ester hydrolysis represents a strategy for reducing cholesterol levels in the blood. Among various compounds tested for inhibition activity was a set of perfluoroalkylated ketones (compound 29). The apparent IC50 values of the abovementioned compounds in the inhibition test were in the 10–15 μM range [45] (Supplementary Figure 6) . Inhibition of G6PDH

A series of 3-perfluoroalkylated androst-5-en-17-ones was synthesized and tested as potential inhibitors of G6PDH. The activity of all three derivatives (compounds 30a–30c; 45, 56 and 53% inhibition at 10-5 M, respectively) was comparable to dehydroepiandrosterone [46] (Supplementary Figure 7) . BACE-1

A compound bearing a pentafluoropropyl amine moiety (compound 31) was tested among many other compounds as a candidate for the inhibition of BACE1. The IC50 (μM) value for BACE-1 was 0.032 [47] (Supplementary Figure 8) . γ-secretase inhibitor

Dibenzazepinones functionalized with the 2,2,3,3,3-pentafluoroethyl group in the side chains (compound 32 and 33) were prepared as potential γ-secretase inhibitors during the effort to synthesize derivatives of LY411575. The obtained derivatives had improved microsomal stability and single-digit nanomolar inhibitory activity in vitro [48] (Supplementary Figure 8) .

V-ATPase activity

Photoaffinity labels bearing perfluoroalkylated chains were attached to potent V-ATPase inhibitors such as concamycin A (compound 26) and bafilomycin (compound 27). The former derivatives retained a high and specific binding affinity. However, the latter seemed to be more sensitive to the disturbing presence of the perfluoroalkyl chains and had low binding activities [43] (Supplementary Figure 4) .

Inhibitors of cathepsin K

Substances acting as inhibitors of cathepsin K may be effective as an antiresorptive agents for treatment of osteoporosis. Amines (compound 34) possessing the perfluoroethyl group exhibited very similar activity as the trifluoromethyl derivatives, with an IC50 value of 2.4 nM [49] (Supplementary Figure 9) . Esterase inhibitors

Proton pump inhibitors

A series of benzimidazoles was tested for antisecretory activity against pentagastrin-induced gastric acid secretion in rats. Among other compounds tested, there were two analogs also bearing the tetrafluoroethyl and perfluoroethyl fragments (compound 28).

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A set of aryliminophosphonates (compound 35) was tested as inhibitors of acetylcholine and butyrylcholin esterases [50] . Polyfluoroalkoxy phosphonates and phosphinates (compound 36 and 37) were tested in a similar manner for esterase activity against acetylcholine, butyrylcholine esterases and an esterase isolated from a

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Review  Prchalová, Štěpánek, Smrček & Kotora strain of Gram-positive soil bacteria Bacillus subtilis. It is worth mentioning that all polyfluorinated compounds had higher activity than nonfluorinated analogs [51] . Phosphonophosphates (compound 38) were also tested in a similar way [52] (Supplementary Figure 10) . Inhibitors of AP-1 & NF-κB-mediated gene expression

In activated T-cells, transcription factors such as AP-1 regulate proinflammatory IL-2 and matrix metalloenzymes, while NF-κB is essential for transcriptional regulation of the proinflammatory cytokines. Very few compounds are known to inhibit both processes thus in a project to look for further candidates, a set of substituted pyridines was studied. Among the tested compounds there were also two derivatives bearing the perfluoroethyl side chain (compound 39a and 39b). Both compounds had a good activity values with an IC50 of 0.2 and 0.35 μM, respectively [53] (Supplementary Figure 11) .

Hepatitis C virus inhibitor

One of the most intensively studied targets for antiviral therapy against hepatitis C virus is the serine protease of the NS3 protein. Peptides with a pentafluoroethylketone moiety (compound 43 and 44) were tested as protease inhibitor candidates [57] . Although they exhibited interesting activity with K i values in the range of 0.081–2.9 μM, they were two orders of magnitude less effective than other examined derivatives [58] (Supplementary Figure 15) . Phosphatase inhibitor

A tetronic acid derivative possessing the perfluoro­ octyl side chain (compound 45) was tested as a potential inhibitor of protein tyrosine phosphatases and dual specifity protein phosphatases such as VHR and cdc25B. Unfortunately, in all cases it did not exhibit any activity that would justify further structural tuning [59] (Supplementary Figure 16) . Histidinol dehydrogenase inhibitor

Inhibitors of prostaglandine & leukotriene biosynthesis

A set of acyldopamines was tested as inhibitors of arachidonate 5-lypoxygenase of RBL-1 cells (the first enzyme of leukotriene biosynthesis). Among them was also N-perfluoropelargonoyldopamine (compound 40) with an IC50 value of 66 nM. This value was higher than for N-pelargonoyldopamine (IC50 value of 45 nM) [54] (Supplementary Figure 12) . Angiogenesis inhibitors

A thalidoimide derivative (compound 41) with a grafted fluorinated amphiphilic carrier was tested as a potential antiangiogenic and multiple sclerosis agent [55] . The derivative (compound 41) was tested in in vivo experiments on the experimental autoimmune encephalomyelitis model and it showed decreased clinical signs (Supplementary Figure 13) . Dihydrofolate reductase inhibitors

Perfluoroalkylated diaminoquinazolines (compound 42) bearing the perfluoroethyl and perfluoropropyl groups were tested as potential inhibitors against Pneumocystis carinii and rat liver dihydrofolate reductases. However, the experiments revealed that the presence of perfluorinated groups had unfavorable effects on binding to both enzymes in comparison with nonfluorinated analogs. IC50 values of 54 and 0.41 μM for compound 42a and corresponding nonfluorinated analog, and 71 and 6.1 for compound 42b and corresponding nonfluorinated analog were obtained, respectively [56] (Supplementary Figure 14) .

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An electrophilic ketone derived from histidine bearing the perfluoroethyl group (compound 46) was tested as a histidinol dehydrogenase inhibitor. It exhibited very low activity with an IC50 value of 20 μM [60] (Supplementary Figure 17) . Elastase inhibitors

Three representatives of four H-benzoxazinones bearing the perfluoroethyl and perfluoropropyl groups (compound 47) were tested as potential human leuko­cyte elastase inhibitors. They did not exhibit any special or interesting activities [61] . Several Val-Pro-Val-pentafluoroethylketones with various amino-terminal protecting groups (compound 48) were tested as human neutrophile elastase inhibitors. Their K i values varied in the range of 25–170 nM, but their ED50 values after oral administration were similar [62] . Further development in this direction led to synthesis of a series of modified peptides with the perfluoroethyl and perfluoropropyl groups with activities in the range of K i = 20–340 nM [63] . An oligopeptide bearing an heptafluorobutyl ester group (compound 49) was tested as an inhibitor of porcine pancreatic elastase. It exhibited a good inhibitory activity with K i = 82.1 μM. This compound was selective towards porcine pancreatic elastase as demonstrated by the lack of activity to serine-dependent proteases [64] (Supplementary Figure 18) . Efflux pump inhibitors

Active efflux of antimicrobial agents is increasingly being recognized as a major course of antimicrobial resistance. In this respect a compound bearing the

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Medicinal applications of perfluoroalkylated chain-containing compounds 

perfluoroethyl group (compound 50) was tested as a potential efflux inhibitor in Pseudomonas aeruginosa. Disappointingly, its activity was lower in comparison with alkylated compounds [65] . The toxicological effects of perfluoroalkyl acids on P-glycoprotein cellular efflux transporters were investigated using marine mussel Mytilus californianus as a model system. The inhibitory potency was maximal for longer chain acids such as perfluorononanoate and perfluorodecanoate (compound 51a and 51b) with respective average IC50 values of 4.8 and 7.1 μM, respectively [66] (Supplementary Figure 19) .

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derivative (compound 57) inhibited CK2 with a good activity (K i = 0.07 μM) [73] (Supplementary Figure 23) . Cyclin-dependent kinase inhibitors

The cell cycle can be interrupted by inhibition of cyclindependent kinases (CDK) and this modulatory effect might be utilized in the treatment of proliferative diseases. A substituted quinazoline (compound 58) possessing the perfluoroethyl group was tested as a potential inhibitor. However, it did not exhibit any significant activity as the inhibitor towards CDK4 and CDK2 having IC50 values of >20 and 11.9 μM, respectively [74] (Supplementary Figure 24) .

Hsp90 inhibitors

ITZ-1 bearing the perfluoroethyl moiety (compound 52) is a chondroprotective agent that inhibits IL-1β-induced MMP-13 production and suppresses nitric oxide-induced chondrocyte death. It targets Hsp90 and selectively inhibits it [67] (Supplementary Figure 20).

Protein kinase C inhibitors

ChoK is an enzyme that plays a vital role in cell signaling pathways and in the regulation of cell growth, being also involved in malignant transformations. A series of bispyridinium compounds (compound 53) bearing various perfluoroethyl and perfluoropropyl chains and a perfluoroalkylidene linker were tested as possible enzyme inhibitors. Their IC50 values were in the range of 0.30–17.30 (μM) [68] (Supplementary Figure 21) .

Protein kinases C (PKC) are known to participate in the processing of APP. Abnormal processing leads to the production of neurotoxic fragments that are believed to take part in the etiology of Alzheimer’s disease. PKC activation enhances α-secretase activity, which results in a decrease of the amyloidogenic products of β-secretase. Two compounds possessing highly unsaturated and saturated fluorinated chains (compound 59 and 60) were tested as modulators of sAPPα (APP secretase-α). Interestingly the former compound had a good binding constant (K i = 11 nM) and absence of activity, whereas the latter retained the activity with the comparable K i = 9 nM [75] (Supplementary Figure 25) .

Deacetylase inhibitors

Glycosidase inhibitors

A series of compounds with fluorous tags bearing n-C8F17 tails were synthesized and used in a small-molecule microarray to discover new substances to be used as histone deacetylase inhibitors [69] . A 2,5-diacylated thiophene (compound 54) was one of several compounds tested as potential histone deacetylase inhibitors. The introduction of the perfluoroethyl group had detrimental effect on activity in comparison with the trifluoromethyl derivatives [70] . A similar effect was observed in a series of cyclic tetrapeptides bearing the perfluoroalkyl moiety. The perfluoroethyl derivative (compound 55) was slightly less active than the trifluoromethyl one [71] (Supplementary Figure 22) .

A series of compounds with saccharide scaffolds (compound 61–65) were evaluated as potential glycosidase inhibitors [76] . They exhibited activity expressed as K i values in the range of 0.36–450 and were considered as promising for further evaluation and structural elaboration (Supplementary Figure 26) .

ChoK inhibitors

Casein kinase inhibitors

A series of polybrominated and polyiodinated benzimidazoles bearing additional perfluoroalkylated chains (compound 56 and 57) were tested as potential candidates for casein kinases (CK1, CK2 and CK-G). The polybrominated derivative (compound 56) did not significantly inhibit CK1 and CK-G, but exhibited reasonable inhibition of CK2 (inhibition constants were in the range 0.40–1.48) [72] . The polyiodinated

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Galactoside specific lectin inhibitors

The trivalent cluster bearing a highly fluorinated side chain (compound 66) was tested on two types of galactose-binding lectins. It did not have a better activity relative to lactose [77] (Supplementary Figure 27) . Antagonists please see Supplementary Figure 28 for more information on the antagonists discussed below. Peptidoleukotriene antagonist

The peptidyl leukotrienes are known to exert profound pharmacological effects on respiratory smooth muscle contractibility and microvascular permeability. As part of the search for antagonists of leukotrienes, an indolol derivative with a perfluoroamide moiety

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Review  Prchalová, Štěpánek, Smrček & Kotora (compound 67) was also tested. In comparison with non-fluorinated derivatives it exhibited lower efficacy in inhibition (40%, 10 μM) [78] .

as antagonists for NaV1.7 and NaV1.8 sodium channels. They exhibited only modest in vivo efficacy [84] . Endothelin antagonist

CXC antagonists

The CXC-chemokines promote the accumulation and activation of neutrophiles and have been implicated in a wide range of acute and chronic inflammatory disorders. 3,4-diaminocyclobutenedione with the perfluoroethyl side-chain (compound 68) exhibited good activity as a CXCR2–CXCR1 dual antagonist with K i values of 4 and 10 nM [79] . Vitronectin receptor antagonists

Vitronectin receptor αVβ3 is a member of the integrin superfamily of cellular adhesion receptors. Its antagonism is implicated in a variety of disease states. A biphenyl possessing a pentafluoropropyl side chain (compound 69) was tested as a potential antagonist; however, its activity, expressed by a K i value of 80 nM, was worse than nonfluorinated analogs [80] . Human pregnane receptor antagonists

The human pregnane receptor is a key regulator of the expression of genes central to xenobiotic metabolism and excretion. Among various compounds tested was also compound 70, which bound reasonably well to the receptor with a pIC50 value of 7.7 and served well as an effective antagonist [81] . Androgen receptor antagonist

Androgens mediate protein metabolism and affect basal metabolism through the upregulation of the androgen receptor (AR). Endogenous androgens stimulate hyperplasia of the prostate and exacerbate androgen-dependent prostate cancer. A perfluoroethyl substituted 5,6-dichlorobenzimidazole derivative (compound 71) was considered as a potential AR antagonist. However, unlike trifluoromethylated derivatives it was found to be exceedingly toxic and was not thus suitable for further testing [82] .

Endothelin (ET) is a family of peptides that mediate vasodilation or vasoconstriction depending on their tissue localization. Endothelin receptor blockade has been proposed as a target for therapeutic intervention in numerous diseases. Pyrazoles bearing the perfluoroethyl or perfluoropropyl group (compound 74) exhibited improved binding to ET receptors. IC50 values for ETA were 0.11 and 0.14 μM, and for ET B were 3.3 and 1.0 μM [85] . Also compound 83 (see the ‘Angiotensin receptor antagonists’ section later) was tested but it exhibited a very low activity. Chemokine receptor antagonists

Chemokine receptors, CCR5 and CXC4, are imperative for HIV-1 infection and growth. In particular, CCR5 is an attractive target because blocking it can inhibit HIV-1 replication and the destruction of the immune system. Among variously substituted spirodiketopiperazines tested in this respect, a derivative possessing a pentafluoropropyl group (compound 75) was also screened, but it showed sevenfold reduced activity in comparison with the most active lead [86] . CCR2 is the primary receptor present at sites of inflammation and its inhibition reduces inflammation. Benzamide (compound 76) bearing the perfluoroethyl group was tested as a potential inhibitor of CCR2. Its activity was lower than that of the trifluoromethyl derivative [87] . Vaniloid receptor antagonists

TRPV1 is expressed in sensory neurons located in the dorsal root ganglia. Its activation leads to a burning sensation and a prolonged stimulation can desensitize sensory nerves. A substituted thiazole bearing the perfluoroethyl group (compound 77) was slightly less active (IC50 = 0.29 μM) in comparison with the trifluoromethyl analog [88] . Calcium channel antagonists

Retinoid X receptor antagonists

Trienoic acid possessing the perfluoroethyl substituent (compound 72) was tested as a retinoid X receptor modulator. It exhibited retinoid X receptor homodimer antagonist activity (IC50 10.7 ± 6.4) [83] . Sodium channel antagonists

Sodium channel antagonists are known to play an important role in the pathogenesis of neuropathic pain. They can be used to relieve pain. Several biphenyl compounds (compound 73) possessing a pentafluoropropyloxy moiety have been tested in this respect

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Calcium antagonists are a well established class of agents that are finding application in the treatment of cardiovascular diseases. A dihydropyridine derivative possessing a pentafluoropropyloxy group (compound 78) was one of the tested compounds in in vitro calcium antagonist activity. It did not exhibited any significant activity (pIC50 = 6.4) in comparison with other tested derivatives [89] . Analgesics Arylated 1,2,4-triazoles were tested for analgetic activity. Among the screened compounds there also was

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Medicinal applications of perfluoroalkylated chain-containing compounds 

a substance bearing the perfluoroethyl group (compound 79). However, it exhibited low activity [90] . Biological properties of peptides (compound 80) bearing pentafluoropropyl groups were examined by receptor binding properties of μ-, δ- and κ-receptors, and analgesic activity in the tail pinch test. Interestingly, μ-receptor affinity was exhibited, but the tail pinch test was negative [91] (Supplementary Figure 29) . Angiotensin receptor antagonists Synthesis of various angiotensin II receptor antagonists has attracted considerable attention. Among them was DuP 532 (compund 81), which is an analog that does not require metabolic activation. It has been found to be longer acting and about three-times more potent than DuP 753 when given orally [92–94] . A tripeptide (compound 82) bearing a perfluoro-2-propoxypropionyl ester moiety was found to be a potent angiotensin antagonist with an IC50 = 1.5 μM [95] . A peptidomimetic with the perfluoroethyl group (compound 83) was examined and found to be angiotensin-converting enzyme inhibitor. Its activity (IC50 = 1010 nM) was lower than that of the trifluoromethyl derivative [96] (Supplementary Figure 30) . Antiatherosclerotic agents Alkylaminobenzoic acids – cetaben analogs – were investigated as potential antiatherosclerotic agents. Among a variety of tested compounds, there were substances bearing perfluorinated side chains on the nitrogen atom (compound 84) or with a perfluoroamide moiety (compound 85). The former exhibited excellent hypolipidemic activity [97] . Compound 84 was also tested as an ACAT inhibitor with an inhibition value of 7 and 42% (the mean percent inhibition of enzyme at a drug concentration of 5.2 pg/ml), respectively (Supplementary Figure 31) . K+ channel openers Opening of K+ channels, caused by K+ channel openers, results in hyperpolarization of cell membranes and leads to smooth muscle relaxant activity. The K+channel openers have therapeutic potential for the treatment of hypertension. Early examples clearly showed that benzensulfonylamides (compound 86) and benzothiadiazines (compound 87) bearing perfluoroalkylated chains of various lengths exhibited significant antihypertensive effects [98] . Another compound tested for vasorelaxant activity and hypotensive effect was perfluoroethylated 2 H-benzoxazine (compound 88). Its value of relaxation of rat aorta EC50 was 3.3 μM with a K ratio of 0.1 (vasorelaxation ratio), which was the borderline value for being considered as a K+ channel opener (the value should be 100 μM, respectively. It was discovered that pentafluoropropoxy derivatives of salicylic acid (compound 105; UR-1505) inhibited T-cell activation and showed an intestinal anti-inflammatory effect [107,108] . 2,3-diarylthiophene compound (compound 106) possessing the perfluoroethyl side chain exhibited very potent inhibitory activity toward rat adjuvant arthritis (88% inhibition at 10 mg/kg). Better results were obtained for the trifluoromethyl derivative [109] . Pyra­ zolotriazine, with the perfluoroethyl side chain (compound 107), was tested in carrageenan-induced edema and exhibited significant activity (18% inhibition at 4 mg/kg dose) [110] (Supplementary Figure 34) .

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Table 2. Vasorelaxant properties of compounds 90–99.

Helicobacter pylori

Piperidinomethylthiophene derivatives (compound 112a and 112b) bearing the perfluoroethyl and perfluoropropyl groups were synthesized and exerted moderate activity with minimum inhibitory concentration (MIC) values of 6.25 and 25 μg/ml [116] (Supplementary Figure 37) .

Compound

pEC50 

IA (%)

90

8.20 ± 0.02

77.6 ± 4.2

91

8.41 ± 0.1

65.6 ± 1.7

92

7.92 ± 0.14

82.8 ± 3.6

93

8.82 ± 0.06

68.6 ± 7.8

94

8.25 ± 0.08

72.0 ± 5.4

Staphylococcus aureus

95

8.53 ± 0.04

69.2 ± 3.9

96

8.77 ± 0.16

68.2 ± 4.1

97

8.40 ± 0.22

64.4 ± 2.4

98a

8.14 ± 0.06

63.7 ± 4.2

98b

7.91 ± 0.11

67.2 ± 1.7

98c

6.65 ± 0.03

80.9 ± 2.9

99a

8.43 ± 0.03

71.0 ± 2.1

99b

8.10 ± 0.06

74.4 ± 2.7 

Transition metal complexes of macrocyclic ligands (compound 113) with Fe, Cr, Mn, Fe, Co, Ni, Cu and Zn were tested for antimicrobial activity against Staphylococcus aureus and Escherichia coli. In general, they exhibited higher antimicrobial activity in comparison with gentamicin, which was used as the standard drug [117] . Also a polymeric compound (compound 143) exhibited activity against S. aureus (see the ‘Anti-HIV compounds’ section later) (Supplementary Figure 37) .

99c

7.17 ± 0.04 

79.8 ± 1.7

IA: Intrinsic activity.

Antidiabetic agents A series of perfluoroalkyl-N-[4-(1 H-tetrazol-5-ylmethyl)phenyl]alkane amides (compound 108) was tested for antidiabetic activity in insulin-resistant animals with the objective of discovering novel antihyperglycemic agents [111,112] . It was found that longer perfluoroalkylated chains, namely C7F15, confer the desired activity in a wide variety of tested structures. Unfortunately, these compounds exhibited undesirable liver toxicity. In a similar manner substituted azoles bearing pentafluoroethyl and heptafluoropropylsubstituents (compound 109) were tested as glucose-lowering agents on db/db mice. Unlike the trifluoromethyl derivative, compound 109a and 109b were not active at all [113] (Supplementary Figure 35) . Antiallergic agents A series of compounds were tested for their ability to inhibit anti-IgE-induced histamine release from the bronchoalveoar mast cells. Among them were the perfluoroethyl and perfluoropropyl derivatives, compounds 110a and 110b [114] . Pentadecylcatechol, an allergenic constituent of poison ivy, is responsible for allergic contact dermatitis. Interestingly, its perfluorinated analogs possessing the perfluorobutyl (compound 111a) and perfluorohexyl (compound 111b) moieties exhibit ­antiallergic properties [115] (Supplementary Figure 36) . Antibacterial compounds Perfluoroalkylated compounds tested for or possessing antibacterial properties encompass a large spectrum of substances.

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Mycobacterium tuberculosis, Mycobacterium kansasii & Mycobacterium avium

A series of 4,6-dichlorobenzimidazoles (compound 114), 5,6-dichlorobenzimidazoles (compound 115), 4,6-dibromobenzimidazoles (compound 116) and tetrabromobenzimidazoles (compound 117) possessing polyfluorinated chains at position 2 were synthesized and tested as antimicrobials for several Mycobacterium strains such as M. tuberculosis (My 331/88), M. kansasii (My 235/80 and 6509/96) and M. avium (My 330/88). Among the tested polyfluorinated substances, compound 116c showed the highest activity against all tested Myco­bacterium strains expressed as a MIC value of 4 μmol/l  [118] (Supplementary Figure 37) . Dental bacteria

Perfluorosulfonamidoalkyl ester of phosphorous acid (compound 118) was tested as a surface coating agent for saliva coated hydroxyapatite beads as a model to study adherence of Streptococcus mutans or Actinomyces viscosus strains. The testing revealed that with compound 118, a significantly reduced adherence of the aforementioned bacteria was observed. Evaluation was carried out in vivo in rats and beagle dogs with positive results [119] . A test with perfluoroiodonium salt (compound 119) against a representative group of unique strains of dental and oral pathogens was carried out in a similar manner. However, its activity was rather poor with values in the range of 8–64 (or higher) μg/ml [120] (Supplementary Figure 37) . Antimicrobial materials

A series of monomers (compound 120–122) possessing different linkers and perfluoroalkylated chains

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Medicinal applications of perfluoroalkylated chain-containing compounds 

were tested for antimicrobial properties on P. aeruginosa, Candida albicans, Aspergillus niger and S. aureus. Important antimicrobial activity expressed in MIC values was found for compound 120 against C. albicans and A. niger (in the range of 8–84 μmol/l). For S. aureus it was in the range of 63–135 μmol/l. Lengthening of the perfluoroalkylated chain led to a decrease of MIC values. The effect of chemical linker G in compound 120–122 was tested on S. aureus and it did not have a significant effect on activity, which was in the range of 60–180 μmol/l [121] . A series of variously substituted quinazolines bearing perfluoroalkylated triazole fragments (compound 123–125) were tested for antibacterial activity on various bacterial strains such as Bacillus subtilis, S. aureus, Staphylococcus epidermis, E. coli, P. aeruginosa and fungal cultures such as C. albicans, A. niger among others. Compound 123c (MIC 18.75–75 μg/ml) and 124b (MIC 9.375–75 μg/ml) exhibited significant antibacterial activity against bacterial strains, whereas compounds 123a, 125a and 125e were active against fungal cultures [122] (Supplementary Figure 38) . Quaternary ammonium salts (surfactants)

Quaternary ammonium salts are often effective antimicrobial agents used in a number of domains. The efficacy of these agents is conditioned by the amphiphilic nature of the molecule and consequently by its surfactant properties. Among various compounds synthesized and tested as potential antimicrobial agents, is the quaternary ammonium gemini surfactants such as compounds 126a–126f and 127 [123] , the quaternary ammonium thiols (compounds 128a–128c) and disulfides (compounds 129a–129c) [124] . The results of antimicrobial activity of the selected compounds are displayed in Table 3. Further elaboration of the linkers led to development of derivatives with improved activity [125] . Also, diallylammonium salts (compound 130a) [126] and 130b–d [127]) and the quaternary ammonium coupling agent (compound 131 [128]) were tested for antimicrobial activity. Compounds 130a–d were tested against S. aureus with MIC values of ∼2.5  μg/ml, and for E. coli MIC values were >100 μg/ml and for Candida albicans they were in the range of 50–100 μg/ml. Compound 131 was tested for treatment of a fabric specimen and further testing showed a 93.7% reduction in the number of colonies of S. aureus. Surfactants containing a β-lactam and the perfluorohexyl and perfluorooctyl moieties (compound 132) were tested as potential antibacterial ­compounds [129] (Supplementary Figure 39) . l-carnitine esters (compound 133) with highly fluorinated chains were tested for antimicrobial and antifungal properties. However, the presence of the fluo-

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Review

rine resulted in reduced activities in comparison with the nonfluorinated derivatives [130] . l-lysine gemini surfactant (compound 134) with the perfluoroheptyl group was more efficient against gram-positive bacterial strains (S. aureus; MIC: 7.81 μmol/l) and yeast (C. albicans; MIC: 7.81 μmol/) than nonfluorinated analogs [131] . Antifungal compounds A series of triazolones and tetrazolones bearing tetrafluoroethoxy, tetrafluoropropoxy and pentafluoropropoxy side chains (compounds 135–137) were tested as antifungal compounds. They were evaluated for in vitro and in vivo antifungal activity against C. albicans. In the in vivo assays, compounds 135–137 had a strong protective effect expressed in ED50 values in the range of 0.16–2.8 mg/kg [132] . Perfluoroacyl nystatin analogues (compounds 138) bearing the perfluoroethyl and perfluoropropyl fragments were tested as potential antimycotic agents against candiditis. Antimycotic activity of the prepared compounds was in the range of 0.78–25.0 μg/ml and the acute toxicity in the range of 160–170 mg/kg as determined by intraperitoneal injections to white mice [133] . Benzo-1,2,3-thiadiazole-7-carboxylate ester (compound 139) possessing the perfluoroethyl moiety exhibited significant activity on cucumber against Erisyphe cichoracearum and Colletotrichum lagenarium with inhibition rates above 98% at 7 days after inoculations [134] (Supplementary Figure 40) . Antiviral compounds A number of perfluoroalkylated compounds with different structural framework have been tested for antiviral activity (Supplementary Figure 41) . Anti-HIV compounds

Among compounds tested for anti-HIV activity is carboxamide (compound 140) possessing the perfluoro­propyl group. However, its anti-HIV-1 and anti-HIV-2 activity was rather poor with an EC50 value of 8 μg/ml. In addition, its antiviral activity was tested against human cytomegalovirus and varicellazoster virus with IC50 values >0.5 μg/ml. However, it displayed a high cytotoxicity expressed as CC50 and minimal cytotoxic concentration with values of 15 and 2, respectively [135] . Compound 141 – an efaviKey term Perfluoroacyl: A compound possessing a highlyfluorinated fatty acid moiety with general formula CF3 (CF2) nCO- or CHF2(CF2) nCO-where n ≥ 1.

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Review  Prchalová, Štěpánek, Smrček & Kotora

Table 3. Antibacterial activity of the selected perfluoroalkylated quaternary salts against various strains of bacteria cultures. Compound†   

MIC (μmol/l)  Staphylocccus aureus ATCC 9144

Candida albicans ATCC 2091

Aspergilus niger ATCC 6275

Pseudomonas aeruginosa CIP A22

126c

6.7

6.7

4.0

5.8

126d

4.5

6.6

4.6

5.2

126e

3.1

7.6

4.9

5.9

126f

3.0

4.4

3.8

5.5

127

4.3

63

21

7.3

129b

17.4

98.4

62.1

20.6

Only selected compounds with high activities are displayed. ATCC: American Type Culture Collection; CIP: Collection of Institut Pasteur; MIC: Minimum inhibitory concentration.



renz analog – bearing the same penta­fluoropropyl side chain as HIV-1 reverse transcriptase inhibitor was tested in a similar manner. When tested on wild-type virus it showed low activity expressed as an IC50 value of 650.6 nM [136] . Interestingly, acrylic acid polymers containing perfluoro-oxa-alkynene units (compound 142) also displayed anti-HIV-1 activity. It had activity expressed as EC50 of 6.2 μg/ml) with low cytotoxicity (CC50 >100 μg/ml) [137] . Analogically, fluoroalkylated end-capped 2-acrylamido-2-methylpropanesulfonic acid polymers (compound 143) were also tested and exhibited activity in the range of 0.23–2.3 μg/ml and again with low cytotoxicity (CC50 >100 μg/ml) [138] . Another class of compounds tested for anti-HIV activity were oligosaccharides. Sulfated laminara-oligosaccharide glycoside derived from laminara-pentaose bearing a long perfluorinated side-chain (compound 144) was examined for anti-HIV activity. It exhibited a high activity expressed as an EC50 of 0.53 μg/ml with low cytotoxicity (CC50 945 μg/ml) [139] . Galactosphingolipid bearing a perfluorinated chain (compound 145) also exhibited a good antiHIV-1 activity expressed as an IC50 value of 24 μM. Other derivatives were tested as well but with less success [140,141] . Also an adenine derivative with the perfluoropropyl group (compound 146) was tested as potential antiHIV agent, but did not exhibit any activity. On the other hand, it showed antiviral activity against other viruses [142] . Anti-influeza compounds

A series of α-ketoacids (compound 147) and compounds derived thereof bearing the perfluoroethyl, perfluorobutyl, tetrafluoroethyl and octafluorobutyl groups were tested as potential inhibitors of influenza virus reproduction. The best and most promis-

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Future Med. Chem. (2014) 6(10)

ing results, according to the authors’ statement, were obtained with a group of compounds possessing the perfluorobutyl group (compound 148) [143] . Anti-herpes simplex virus compounds

Pyrimidine derivatives (compound 149) were tested for antiherpes activity. Both compounds had substantially reduced activity in comparison with nonfluorinated derivatives. Activity was tested against herpes simplex virus (HSV)-1-77 and HSV-2-82 strains and obtained ID50 values of 270 and 480 μM for compound 149a, and 500 and 500 for compound 149b were obtained, respectively [144] . An activated peptidyl compound possessing the perfluoroethyl group (compound 150) was tested as an inhibitor candidate for human cytomegalovirus protease [145,146] . It was highly active with an IC50 = 0.1 μM. Anti-hepatitis C virus compounds

A tetrapeptide (compound 151) containing the perfluoropropanoyl side chain was evaluated as a potential inhibitor of hepatitis C virus NS3-4A. It failed to show improved binding activity (Ki = 17.5 μM) [147] . Antiprotozoal agents Please see Supplementary Figure 42 for more information on the following antiprotozoal agents. Antiprotozoals

Azauridine (compound 152) was one of a series of compounds tested as a potential antiprotozoal agent against Tetrahymena pyriformis. The concentration of 500 μg/100 ml of compound 152 completely suppressed culture reproduction. The acute toxicity of compound 152 was estimated to be >1000 μg/ml [148] . Compound 159a (see the ‘Anticancer compounds’ section), when tested as an anticancer compound, exhibited interesting antiprotozoal activity against

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Medicinal applications of perfluoroalkylated chain-containing compounds 

Giardia intestinalis, Entamoeba hystolica and Trichomonas vaginalis with IC50 values 0.56, 0.21 and 0.39 μM, respectively.

and a related 1,3-disulfone with a 2-tetrafluoroethoxy group were tested, but their activities were rather low [153] (Supplementary Figure 43) .

Antimalarials

Anticancer compounds The group of compounds with anticancer properties is very wide and encompasses substances with various structural features spanning from small organic compounds across organometallics to transition metal complexes (Supplementary Figures 44–48) . Pentafluoroethylbenzimidazoles (compound 159) were tested for cell inhibition growth activity against three hematopoietic malignant cells lines (IM-9, MOLT-3 and U-937) and cell lines representing breast cancer (MCF-7) and prostate carcinoma (PC-3). According to the data expressed as IC80 (μM) compound 159a had activities with values in the range of 2.7–17.3. For activities of compound 159b see Table 5 [154] . Pyridinium bromides (compound 160) having long polyfluorinated alkyl pendant chains exhibited interesting levels of cytotoxicity for A2780 ovarian cell lines. IC50 values were in the range of 4.9–31.4 μM. There is an obvious trend indicating that compounds with a shorter perfluoroalkyl moiety are more active (see Table 6), but generally, their activities were lower than those without fluorine atoms [155] . Heterocyclic compound 161 exhibited very good activity against breast cancer MCF-7 cell line; however, it was not, despite a better IC50 value, chosen for further evaluation [156] . Among other hetero­ c yclic compounds tested were regioselectively substituted sulfoxylated isoflavones (compounds 162 and 163). The tests were performed on human leukemia HL-60 and human liver cancer BEL-7402 cells. The highest activity, 99% inhibition at 10-8 M concentration, was observed with compound 163. Other compounds were either nonactive or exhibited good inhibition at much higher concentrations (10-5 –10 -4 M) [157] .

The contemporary problem with treatment of malaria leads to further modifications of already used substances. The main drive is associated with increasing resistance to currently used drugs. Modification of chloroquine led to the synthesis of amides (compounds 153 and 154) prepared from the corresponding perfluorobutanoic and perfluoroheptanoic acid. They showed high activity against HB3 (chloroquine sensitive) and Dd2 (chloroquine-resistant strains of Plasmodium falciparum) and low resistance indices were obtained (Table 4). In many cases, the fluorine-containing compounds had better properties than those without [149] . Using the same strategy as above, that is, modification of already used drugs, perfluoroalkyl ethers of artemisin bearing a pentafluoropropyl (compound 155a) and a heptafluorobutyl group (compound 155b) were prepared. The in vitro activity toward Plasmodium falciparum W-2 strain was moderate (Table 4) and in vivo activities against Plasmodium berghei (NT 1273) were excellent [150] . Perfluoroalkylated acetal (compound 156) that showed very interesting results regarding the antimalarial activity against 3D7 (chloroquine sensitive) and Dd2 (chloroquine resistant strains of Plasmodium falciparum) was also prepared in an analogical manner (Table 4) [151] . Antiparasitic compounds Antihelmintic activity of ketoamide (compound 157) bearing pentafluoroethyl group was tested on the parasite Haemonctus confortus, but it did not have better properties in comparison with other nonfluorinated compounds [152] . Similarly, 1,3-bissulfone (compound 158), possessing a 1-n-perfluorobutyl group,

Review

Table 4. Antiplasmodial activity of compounds 153–156 against various strains of Plasmodium falciparum. Compound

IC50 (nM)

 

HB3

Dd2

W2

3D7

RI† 

153a

234

277

 

 

1.2

153b

166

197

 

 

1.2

154a

180

556

 

 

3.1

154b

72

87

 

 

1.2

155a

 

 

27

 

 

155b

 

 

36

 

 

156

 

4.47

 

9.85

 

RI (IC50 CQR)/(IC50 CQS). CQR: Chloroquine-resitant parasites; CQS: chloroquine-sensitive parasites; RI: Resistance index.



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Review  Prchalová, Štěpánek, Smrček & Kotora

Table 5. Activity of the selected perfluoroalkylated compounds against various cancer cell lines. Compound   

 IC50 (μM)   IM-9

MOLT 3

U-937

MCF-7

PC-3

THP-1

Colo205

159b  

5.2

12.7

2.9

1.6

1.3

 

 

161

 

 

 

0.09

 

 

 

164a

 

 

 

 

 

79.12 ± 2.41

79.12 ± 2.41



164c

 

 

124.23 ± 3.67

 

 

 

 

164g

 

 

8.35 ± 0.341

 

 

142.23 ± 5.24

132.42 ± 4.26

164h

 

 

7.56 ± 0.74

 

 

 

 

165a

 

 

22.37 ± 1.73

 

 

107 ± 4.52

 

165b

 

 

9.22 ± 0.76

 

 

 

 

165c

 

 

44.35 ± 2.14

 

 

 

 



166a  

 

 

18 ± 2

 

 

26 ± 2

 

166c‡

 

 

62 ± 5

 

 

52 ± 2

 

These values correpond to IC80 (μM). Measured at 41°C.

† ‡

A series of variously substituted pyrido[2,3]pyrimidine derivatives (compound 164 and 165) were screened for anticancer activity against three cancer lines such as U937, THP-1 and Colo205 [158] . However, their activity was lower than those bearing nonfluorinated pendant chains (Table 5). A series of perfluorinated chlorambucil (CLB) derivatives (compound 166) were designed and synthesized as thermoreactive drugs activated by mild hyperthermia (41°C). The prepared compounds were evaluated on A278 and cisplatin-resistant A2780cisR ovarian cell lines (Table 6) . Whereas compounds 166a and 166b exhibited similar cytotoxicity at 37 and 41°C, compound 166c was clearly inactive at 37°C (IC50 >200 μM) and under mild hyperthermia (41°C) it had the same activity as CLB. Similar thermoresponsive effects were observed for compound 166c in the case of U-937 where it was clearly inactive at 37°C (IC50 >200 μM) but under mild hyperthermia (41°C) it had slightly lower activity than CLB. Activities of compounds 166a and 166c were further tested on other tumor tissues such as THP-1 (Table 5), U-937 (Table 5), TK-6, HT-29, HT-1080 and HCEC with IC50 values in the range of 23–125 μM [159] . Pyrimidines 167 and 168 possessing a pentafluoroethyl group in the side chain were tested against a series of human carcinoma cell lines (Molt-4, HCT116, SW620, MCF-7 and H460). While compound 167 exhibited moderate activity (IC50 = 43–76 μM) the demethoxylated congener 168 showed no activity [160] . A curacine analog with the perfluorobutoxy chain (compound 169) was tested for inhibition of MCF-7 growth. Its IC50 value was >10 μM indicating minimal activity [161] . It also exhibited low anti-

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Future Med. Chem. (2014) 6(10)

mitotic activity inhibiting tubuline polymerization (IC50 = 5.4 μM). N-perfluoroacyl derivatives (compound 170; C2F5 and n-C3F7) of daunorubicin, adriamycin and valerate esters thereof, and also anhydroderivatives (compound 171) were tested in vitro against CCRF-CEM cells and in vivo against murine P388 leukemia cells. In all cases fluorinated compounds were less active than the nonfluorinated derivatives. The obtained values are summarized in Table 7 [162] . A large number of transition metal complexes with attached perfluoroalkylated chains have been tested for their anticancer properties. In this respect one large group consists of various η6-arene ruthenium complexes bearing perfluoroalkylated chains on the triazole moiety. These were screened for cytotoxicity in tumorigenic and nontumorigenic cell lines [163] . The prepared complexes (compound 172a, 172b and 173) showed only a modest cytotoxicity against A2780 ovarian cell lines (151, 55 and 125 μM) and cisplatin-resistant A2780cisR cell lines (158, 34 and 142 μM). Ruthenium-phosphine complexes bearing perfluoroalkylated chains on the phosphine moiety (compound 174-177) were screened in a similar manner. In this case the presence of the fluorinated chains had a beneficial effect on cytotoxicity towards the tumor lines in comparison with nonfluorinated derivatives [164] . Luminescent cyclometalated Ir(III)-polypyridine complexes bearing a pendant chain containing the perfluorooctyl group (compound 178) were designed as biological probes. They were also tested in cellular uptake and cytotoxicity to HeLa cells. The measured IC50 values for 178a–d were 6.4 ± 0.5 μM, 7.8 ± 0.6 μM, 25.7 ± 4.9 μM and 5.1 ± 0.8 μM, respectively.

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Medicinal applications of perfluoroalkylated chain-containing compounds 

These were slightly better than the values for cisplatin (17.9 ± 0.4 μM), which was used as the standard [165] . Luminescent Re(I)-polypyridine complexes (compound 179) as trifunctional biological probes were also studied in a similar manner. The cytotoxity was performed on HeLa cells with complexes bearing the perfluorooctyl group and the amino and thiourea groups (compound 179a and 179b). The observed IC50 values were 8.7 and 17.0 μM, respectively [166] . As a part of the anticancer activity study of palladium complexes, a SCN pincer complex bearing the perfluoroalkyl group (compound 180) was tested. Cytotoxicity was performed on three different panels of human leukemia cell lines: HL60 (human promyelocytic leukemia cells), K562 (chronic myelogenous leukemia), and CCRF-CEM (human acute lymphotic leukemia). The obtained IC50 values for complex 180 were 19.9, 9.9 and 4.9 μg/ml-1, respectively [167] . Interestingly, organotin(IV) compounds bearing perfluoroalkylated functionalities were also tested as antitumor compounds. The first group encompasses simple dialkyldihalotin compounds (compound 181) and their bipyridine or phenathridine complexes (not shown). Compound 181b or the respective complexes with bipy and phen were totally inactive in P388 lymphocytic leukemia in CDF1 mice. Only compound 181a exhibited marginal activity [168] . Later were tested two dibutyltin perfluorocarboxylates (compound 182) possessing the perfluoroethyl and perfluoropropyl groups for cytotoxic activity against seven different cancer cell lines. In general their activity was higher than that of cisplatin but lower in comparison to doxorubicine (Table 8) [169] . Arabinofuranosylcytosine is one of the most important antitumor agents used for treatment of leukemias, carcinomas of colon, breast and ovary. Due to low plasma stability and to enhance the pharmacological properties and cytotoxicity it is helpful to link it to a carrier. In this respect cotelomers of tris(hydroxymethyl) aminomethane bearing arabinofuranosylcytosine moieties (compound 183) were tested for antitumor activity on melanoma B16-type cells. The activities, depending on structural features n, nx, R1, R 2, were in the range of IC50 = 0.05–0.56 μM [170,171] . 2´-deoxyuridines appended to a perfluoroalkyltriazole ring (compound 184) were tested against three cancer cell lines PC-3 (prostate), MDA-MB-231 (breast) and ACHN (renal). The most active compound was 184g with cell growth inhibition values of 16.7, 15.9 and 14.2 at 10 μM concentration. Values determined for other compounds were in the range of 77–116 irrespective of the cell line [172] . Kahalalide F is the natural depsipeptide, which mainly shows in vitro activity against prostate and

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Table 6. Cytotoxic properties of the selected perfluoroalkylated compounds on cancer cell lines. Compound  

IC80 (μM) A2780/μM

A2780cisR/μM

160a

7.97

 

160b

11.1

 

160c

14.7

 

160d

4.9

 

160e

9.3

 

160f

11.7

 

160g

31.4

 

166a† 

38 ± 9

67 ± 2

166b

23 ± 7

27 ± 6



166c

37 ± 5

40 ± 4

172a

151

158

172b

55

34



173

125

142

174

16 ± 2

25 ± 2

175a

6 ± 0.5

11 ± 2

175b

>200

>200

176a

1.5 ± 0.3

5 ± 0.5

176b

87 ± 6

108 ± 3

177a

6 ± 1.5

13 ± 1

177b

97 ± 18

>200



Measured at 41°C.

colon cancer. To improve its properties, a number of its derivatives were synthesized, including compound 185, but with domain C modified with a perfluoroalkyl chain. It was tested against 14 different cancer cell lines and exhibited higher activity in comparison with the parent compound (GI50 was in the range of 1 × 10-7–3.16 × 10-6 mol/l) [173] . A muramyl peptide derivative with lipophilic ester moiety containing a perfluorooctyl fragment (compound 186) was tested as a macrophage activator since macrophages can become cytotoxic towards tumor cells by immunomodulator activation. However it did not possess any activity [174] . Perfluoroalkylated sphingosine derivatives (compound 187 and 188) were tested for cytotoxic activity against four cancer cell lines (Table 9) . Whereas compounds 187 and 188b exhibited a good activity on all the cell strains, compound 188a with the acetylated amino moiety was completely inactive [175] . Antiulcer agents A large group of various 2-{[(4-fluoroalkoxy-2-pyridyl) methyl]sulfinyl}-1 H-benzimidazoles was synthesized

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Review  Prchalová, Štěpánek, Smrček & Kotora

Table 7. Activity of compounds 170 and 171 against various strains of cancer cell lines. Compound

in vitro, CCRF-CEM ID50 (μM)

in vivo, optimal dose (mg/kg)/day

P388% ILS† 

170a

1.01

50

+27

170b

>1.35

40

+45

170c

0.41

50

+372

170d

1.49

50

+54

170e

1.18

50

0

170f

>1.14

50

0

171a

0.50

 

 

171b

>13.8

 

 

171c

8.41

 

 

171d

7.30

 

 

171e

0.56

 

 

171f

2.31

 

 

Percentage increase in life span relative to untreated controls. ILS: Increase of life span.



in search of new compounds with antiulcer properties. Out of a number of derivatives only compounds 189a and 189b, with pentafluoropropyl and tetrafluoropropyl chains, had sensible antiulcer activities expressed as ED50 values of 5.1 and 1.2 mg/kg, respectively [176] (Supplementary Figure 49) . Corticotropin-releasing antagonists Corticotropine-releasing factor (CRF), a 41-amino acid neuropeptide produced by hypothalamic nuclei in the brain, plays an important role in the regulation of various processes. Derivatives bearing a 2,2,3,3,3-pentafluoropropyl group were used in testing. Initially, 7-aryl6,7-dihydroimidazoimidazole (compound 190) [177] and imidazo[1,2a] benzimidazoles (compound 191) [178] were screened. They had K i values of 63, 34 and 75 nM, respectively. A series of various N,N-disubstituted aminomethylimidazo[1,2-a]imidazoles were tested as potential CRF antagonists. Among other compounds tested was also compound 192 bearing on the nitrogen atom the 2,2,3,3,3-pentafluoropropyl group. However, its presence had a detrimental effect on its activity (K i = 440 nM), which was approximately 28-times

lower in comparison with the derivative bearing the 3,3,3-trifluoropropyl group [179] . A series of tetra­ hydroimidazopyrimidine derivatives were tested in a similar manner. However, in this case, the presence of 2,2,3,3,3-pentafluoropropyl group in compound 193 had a beneficial effect on the binding ability to hCRF1R with a K i = 14 nM [180] (Supplementary Figure 50) . Steroidal activity Androgen modulators

The AR, a ligand-binding transcription factor in the nuclear hormone receptor superfamily, is a key molecular target in the etiology and progression of prostate cancer. AR antagonists are currently used as hormone therapy for prostate cancer. Potential candidates for AR antagonists can be divided into two groups, those that are based on steroid compounds and their analogs, and those that have different structural features. As representatives of the first group of AR antagonists, 7α-substituted dihydrotestosterones (compound 194) bearing the sulfoxide and pentafluoroethyl moieties in the pendant chain of various length were tested. Only compound 194c showed weak antagonis-

Table 8. Cytotoxic properties† of Sn complexes on cancer cell lines‡. Compound 182a 182b

Cancer cell lines MCF-7

EVSAT-T

WiDr

IGROV

M19 MEL

A 498

H226

64

93

339

121

101

131

120

191

135

340

123

141

177

213

ng/ml MCF-7 (mammary cancer), EVSAT-T (mammary cancer), WiDr (colon carcinoma), IGROV (ovarian cancer), M19 MEL (melanoma), A 498 (renal cancer), H226 (non-small-cell lung cancer).



1



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Future Med. Chem. (2014) 6(10)

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Medicinal applications of perfluoroalkylated chain-containing compounds 

Review

Table 9. Cytotoxic properties of compounds 187–188 on various cancer cell lines†. Compound

IC50 (μmol-1) HL60

HeLaS3

CCR-CEM

HepG2

187

6.51 ± 0.28

1.97 ± 0.04

1.19 ± 0.28

10.93 ± 1.37

188a

NA

NA

NA

NA

188b

3.02 ± 0.36

2.04 ± 0.05

2.24 ± 0.36

123

XTT cytotoxic assay based colorimetric assay of cell proliferation (Roche). NA: Not active.



tic activity [181] . A similar compound (195), which has a carboxyl moiety in the same position, was also tested, but it exhibited pure agonistic properties (Table 10) [182] . Also compounds based on nortestosterone (compound 196) and testosterone (compound 197) bearing the sulfoxide and pentafluoroethyl moieties in the pendant chain were prepared. However, once again activity of these compounds was rather low [183] . The latter group consists of substituted quinolones such as compound 198, 199 and 200 possessing pentafluoropropyl substituent on the nitrogen atom. Compound 198 showed reasonable antagonistic properties, whereas compound 199 exhibited good agonistic as well as antagonistic properties [184] . On the contrary, compound 200 was a potent agonist [185] . Another class of compounds were studied, pyrano-quinolones, such as compound 201, also proved to be very strong agonists (Table 11) [186] . The last group of the tested compounds were carbazoles (compound 202a and 202b) with binding affinities expressed as IC50 values of 100 and 13 nM [187] (Supplementary Figure 51) . Progesterone receptor antagonists

The progesterone receptor (PR) is a member of the family of ligand-dependent transcription factors. Progesterone, a natural PR agonist, plays important role in

female reproduction. Selective PR antagonists may be potentially used in female contraception and for treatment of various gynecological and obstetric diseases, including hormone-dependent cancers. Oxazepinones bearing the perfluoroethyl group (compound 203 and 204) were examined on T47D cell alkaline phosphatase assay. However, the presence of the perfluoroethyl moiety led to reduction in potency in comparison with compounds bearing nonfluorinated moieties [188] . Other tested candidates were compounds with a pseudosteroid framework (compound 205), which resembled mifepristone (a commonly used PR antagonist; Table 12). In this instance the presence of the perfluoroethyl group did not have a significant effect on the activity [189] . Compounds with the steroid skeleton (compound 206 [ZK 230211] and 207) possessing the pentafluoroethyl group at position 17 showed high progesterone receptor antagonism [190] (Supplementary Figure 52) . Estrogen receptor antagonists

Antiestrogens compete with endogenous estrogens for binding to estrogen receptors (ERs) and control various metabolic processes. Development of antiestrogens is important since they have been used in therapy for breast cancer. Antiestrogens

Table 10. Binding and agonistic/antagonistic activity of 194–197. Compound

 Binding affinity

RGA

IC50 (nM)

pIC50 

FI5 (nM)  

IC50 (nM) ‡ 

194a

6800

 

16

>10000

194b

960

 

200

>10000

194c

110

 

490

  2900

194d

>10000

 

120

>10000

194e

>10000

 

310

>10000

195

410

 

13

>10000

196

 

5.1

 

 

197

 

4.8

 

 



†Agonistic activity. ‡ Antagonistic activity (a compound with FI5 >10000 is considered as a pure antagonist). RGA: Reporter gene assay.

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Table 11. Androgen receptor cotransfection and competitive binding data for 198–201. Compound

hAR agonist  EC50 (nM)

hAR antagonist 

Eff (%)

IC50 (nM)

Eff (%)

hAR whole cell binding, Ki (nM)  

198

 

 

58 ± 9

76 ± 2

36 ± 14

199

246

89

17 ± 5

63 ± 2

78

200

2.3 ± 0.5

94 ± 6

 

 

31

201

13 ± 3

103 ± 16

 

 

5 ± 2

Eff: Efficiency; hAR: Human androgen receptor.

can be divided into two classes, derivatives and analogs of estradiol and small organic molecules (Supplementary Figures 53–55) . As far as the former class of compounds is concerned, there are synthesized derivatives of estradiol bearing usually long lipophilic chains containing perfluoroalkyl moieties in various positions on the steroid framework. A typical example of such a derivative is ICI 182,780 (compound 208; also known as fulvestrant), which bears the lipophilic chain in position 7α. Its binding ability to ERs was expressed as an IC50 value of 9.4 nM with a relative binding affinity of 89% with respect to estradiol as the standard when tested on rat uterine receptor. This compound had pure antiestrogenic activity [191] . Another two compounds (compound 209 [ZK 703] and 210 [ZK 253]) with slightly different side chains and an additional fluorine atom at position 11 were also tested [192] . Another derivative with the pendant chain at position 11β is compound 211 (RU 58668). It exhibited ligand binding affinities for murine and human uterus ERs (estradiol was used as a standard with 100% binding affinity) of 56 ± 7% and 17 ± 2%, respectively [193] . All compounds were tested for activity against MCF-7 cancer cell lines. Improved antitumor capacity of pure anti­ estrogen (compound 211; RU 58668) was observed when it was administered in colloidal nanosystems [194] . Also, 7-perfluorohexylestradiol (compound 212) was tested on MCF-7 breast cancer lines. Antiestrogenic activity was not observed, this compound exhibited weak estrogenic activity [195] . A series of 7α-polyfluoroalkylated estradiol derivatives (comTable 12. Progesterone-induced alkaline phosphatase activity in the human T47D breast carcinoma cell line of 203–205.

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Compound

IC50 (nM)

203

82.4

204

34.1

205a

36

205b

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Future Med. Chem. (2014) 6(10)

pound 213 and 214) bearing lipophilic chains and containing carboxyl group were synthesized as potentially antiestrogenic derivatives. Variation of the chain length and detailed testing led to development of an estrone derivative (compound 214; m = 8, n = 3, l = 3) with powerful antiestrogenic activity. It was shown that the estradiol derivatives were quickly metabolized to estrone derivatives without losing their activity [196] . A series of 11α-polyfluoroalkylated estradiol derivatives (compound 215–218) were synthesized and the binding ability to ERα was tested. The prepared compounds had decreased estrogenic properties (Table 13) [197] . A group of 17α-substituted perfluoroalkylpropenyl and perfluoroalkylbutenyl estradiol derivatives (compound 219 and 220) were tested in a similar manner. These compounds were separately tested for binding activity to ERα and ERβ. Reasonable binding activity was measured for only a handful of compounds (Table 13). Interestingly, compound 219d had reasonably high affinity for ERα with 22× higher selectivity than for ERβ. Most of these ­compounds were almost pure agonists for ER [198] . The second group of ER modulators encompasses stilbene, benzothiophene, indene and chromane-type compounds. Stilbenes (compound 221) differing in the presence of the amide or amino groups in the pendant chain can be considered as fluorinated analogs of tamoxiphene [199] . Their activity was tested on MFC-7 breast cancer cell lines and it was similar to tamoxiphene (Table 14). Derivatives of benzothiophene (compound 222) [200] , indole (compound 223 and 224) [201] were tested in a similar manner. In all cases they had similar activities, but about an order of magnitude lower than the former compound. All of these compounds could be considered as pure antiestrogens. A large series of thiochromanes were tested for receptor binding affinity to ER (Table 15), these compounds emerged from comparison of chromane (compound 225a) and thiochromane (compound 225b) activities. The latter had better properties and some of the tested compounds exhibited comparable or even better activity than pure antiestrogen ICI 182,780 [202] . A variety of other compounds (226–234) with modified skeletons were synthesized as well. Further skeleton mod-

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Medicinal applications of perfluoroalkylated chain-containing compounds 

ifications resulted in the synthesis of diastereoisomeric compounds 226 and 227 [203] .

Table 13. Receptor binding affinity of 215–220 to ERα and ERβ. Compound

RBA for ERᆠ

RBA for ER↠

Brassinosteroid activity

215

50% mortality) for adult stable flies was in the range of 20–30 Table 14. Ligand binding activity of 221–224 to estrogen receptors. Compound

RBA for ER† 

MCP-7 IC50 (nM)

221a

1.9

 

221b

2.2

0.22

222

0.2

5

223a

1.5

6.7

223b

3.8

4.9

224

2.3

0.6

Estradiol used as the standard with RBA value of 100. ER: Estrogen receptor; RBA: Receptor binding affinity.



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Table 15. Ligand binding activity of 225–234 to estrogen receptors. Compound

RBA for ERᆠ

 

 

30 mg/kg sc

Antiestrogen activity, inhibition (%) 10 mg/kg sc

10 mg/kg po

225a

96

 

94

66

225b

200

 

101

51

226a

7

 

52

40

226b

0.8

 

95

77

227

52

 

99

31

228

1.2

 

33

n.t.

229

42

 

100

41

230

57

 

77

1

231a

0.5

n.t.

 

20

231b

0.6

63

 

93

231c

0.3

61

 

93

231d

1.3

69

 

87

231e

0.8

52

 

86

231f

0.3

38

 

85

231g

0.9

45

 

81

231h

0.4

55

 

86

231i

0.2

53

 

79

231j

0.2

n.t.

 

62

232a

230

90

 

43

232b

59

21

 

n.t.

232c

200

83

 

51

232d

220

56

 

29

233

7

2

 

n.t.

234a

150

67

 

33

234b

29

19

 

32

234c

96

90

 

66

234d

37

0

 

13

234e

130

88

 

37

234f

100

81

 

54

Estradiol used as the standard with RBA value of 100. ER: Estrogen receptor; n.t.: Not tested; po: ; RBA: Receptor binding affinity; sc: Subcutaneous.



ppm and for larval blowfly in the range 15–35 ppm [210] . Compound 244 was also tested as an insecticide for blowfly larvae with the lowest effective concentration of 25 ppm (>90% mortality). Synthetic pumiliotoxin analogs were evaluated for toxicity to the larvae of the important cotton pest Heliothis virescens. A derivative bearing the perfluorobutyl group (compound 245) was also tested. In comparison with natural pumiliotoxin this, as well as other synthetic derivatives, exhibited lower ­toxicity [211] .

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Ca dependent production of reactive oxygen metabolites

Fluorinated analogs of propranolol (compound 246) were found to induce reactive oxygen metabolite production in human neutrophiles in a dose-dependent manner. They also caused a transient increase in actin polymerization. The activity was dependent upon the degree of fluorination. The most active substances were those bearing the perfluoroethyl (compound 246a) and perfluoropropyl (compound 246b) moieties [212] .

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Medicinal applications of perfluoroalkylated chain-containing compounds 

Adenosine receptor ligands

A series of perfluoroalkylated thienopyrimidines (compound 247) was prepared, but only compound 247d was tested as an adenosine receptor ligand. It did not exhibit any significant binding ability [213] . Perfluoropropylated adenine (compound 248) and guanine (compound 249) were also examined as potential adenosine receptor ligands, but they did not exhibit any significant activity  [214] . Antiproliferative activity

A 1α,25-dihydroxyvitamin D3 sulfone analog bearing the perfluorobutyl group (compound 250) was tested for antiproliferative activity using a standard murine keratinocyte assay. However, it displayed considerably lower activity in comparison with trifluoromethyl analogs [215] . D1 dopamine receptor agonists

D1 dopamine receptor agonists play an important role in the treatment of Parkinson’s disease. The dinapsoline derivative bearing the perfluorobutyl group (compound 251) was tested among other compounds to obtain more effective substances. However, it displayed rather low activity represented by a high binding concentration [216] . Guanylate cyclase stimulator

Triazole (compound 252) bearing the perfluoroethyl group was tested as candidate for guanylate cyclase stimulator. It did not exhibit any particular activity [217] . Neurothropic activity

A series of perfluoroalkylated silatranes (compound 253) was tested for neurothropic and immuno­modulating properties [218] . According to published data the silatranes decreased the motoric activity, rectal temperature and head-shaking phenomenon of mice and prolonged narcosis produced by chloral hydrate and other compounds. They also exhibited a stimulating/suppressing effect on various subpopulations of T lymphocytes. Phage-inactivating activity

A series of variously substituted perfluoroacylated ascorbic acids (compounds 254) was tested as potential phage-inactivating agents. In general, the presence of perfluoroacyl functions at C2 (compound 254b), C6 (compound 254f) and C3 (compound 254a and g) of ascorbic acid increased the inactivating activity towards a variety of phages [219] . IFN inducers

IFN-α is used in the treatment of hepatitis C. 8-hydroxyadenin derivatives possessing perfluoroalkyl

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Review

Key terms Biological activity: Describes the beneficial or adverse effects of a drug on living matter. Drug: A chemical substance used in the treatment, cure, prevention or diagnosis of disease or used to otherwise enhance physical or mental well-being.

groups at position 3 (compounds 255) were examined as candidates for IFN activation. However, the introduction of perfluoroalkylated groups did not result in the expected elevation of potency [220] . Platelet-activating factors

Unnatural platelet-activating factor derivatives possessing perfluoroalkylated fragments (compound 256) were synthesized and their biological activity was assessed. Although their activity was gradually restored with increasing number of fluorine atoms, they did not prove to be selective agonists [221] . Psychotropic substances

A series of silylated or nonsilylated perfluorobutyl aziridines (compound 257) were synthesized in search of new psychotropic agents. The prepared compounds had pronounced anticonvulsive effects. In fact, compound 257 exhibited the highest activity in preventing corazoleinduced activity of all tested compounds (including nonfluorinated compounds) [222] . Other applications of perfluoroalkylated compounds Perfluoroalkylated compounds have also been used in a number of other applications. Due to their low polarity, perfluorinated compounds easily dissolve oxygen and thefore have been used for its delivery as a blood substitute [223,224] . Among other applications they have been used for drug delivery, as diagnostic contrast agents and devices, for lung surfactant replacement, organ preservation, ophthalmology and for prevention of cell adhesion [225–229] . Other interesting perfluoroalkylated compounds 17β-(1methyl-3-perfluoroalklyl)propyl-3β-androsterol (compound 258) was synthesized and exhibited interesting thermotropic liquid crystalline properties [230] (Supplementary Figure 61). Conclusion A number of perfluoroalkylated compounds with various structural scaffolds have been prepared and tested in numerous assays to evaluate their activities and potential application. This article clearly indicates that the perfluoroalkylated compounds often have interesting

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Table 16. Hormonal properties of compounds 235–239. Compound

PSI (mm)

AA (mol)

235

7.9

10 -10 

236

5.6

10 -7

237

-5.5

10 -10

238a

11.6

10 -10

238b

9.16

10 -10

238c

14.1

10 -10

239a

11.1

10 -10

239b

9.6

10 -10

239c

3.1

10 -10

AA: Amount applied; PSI: Prolongation of the second internode.

and unique properties. On the other hand, their broader application in medicinal chemistry or in the drug industry is rather in its infancy due to various reasons such as suitable solubility, real or potential toxicity, unknown pathways of the metabolism of the perfluoroalkylated chains in living systems, among others. Especially in the case of compounds bearing longer perfluoroalkylated chains, metabolic cleavage of the perfluoroalkylated chain may produce perfluoroalkylated substances that might be harmful [231] . The aforementioned issues currently constitute hurdles that should be overcome and solved in order to allow perfluoroalkylated compounds to become the center of interest for medicinal chemists and the pharmaceutical industry. In this respect, the origin of activity of perfluoroalkylated compounds is also worth mentioning, or in other words: what are or what could be the benefits of the presence of a perfluoroalkyl chain in the molecule and how it could enhance its activity. This concerns mainly compounds bearing longer perfluoroalkylated chains (>C3F7) and this issue has still not yet been clarified. Nonetheless,

some results obtained from other fields of chemistry indicate that the longer perfluoroalkyl chains lack the conformational flexibility of aliphatic chains, and form rather rigid rod like structures with helical arrangements even in solutions [232] . This arrangement was also observed in the x-ray structure of several perfluoroalkylated compounds [233–235] . This arrangement might thus have the crucial effect on their properties and interaction with the surrounding environment. As a typical example, is the case of a clavaminol H derivative and its polyfluorinated congener (compound 187). Both exhibit similar activity, but the former induces apoptosis of cells, whereas the latter induces necrosis. As another example is the perfluorinated derivative of brassinosteroid (compound 239a), which possess activity similar to the natural derivative, but exhibited a longer metabolic stability. It is assumed that in this instance, an electron-withdrawing effect of the perfluoroalkyl group strongly influences reactivity of the neighboring methylene group and its functionalization resulting in the loss of activity. In this respect it is reasonable to presume that the presence of the perfluoroalkylated group could strongly affect the overall behavior by its electronic as well as structural features. Future perspective Out of the listed compounds with perfluoroalkylated chains tested, the largest representation and also highest probability as far as potential application is concerned, have been those possessing the perfluoroethyl or tetrafluoroethyl group. As a representative example of this class of compounds is fulvestrant (sold under the brand name Faslodex®), an ER antagonist used for treatment of hormone receptor-positive metastatic breast cancer in postmenopausal women. As far as the compounds with longer perfluoroalkylated chains are concerned, their testing in general often did not result in improved activity in comparison with their less fluorinated or nonfluorinated

Executive summary • Perfluoroalkylated compounds are an important class of non-natural compounds that have interesting properties as a result of the presence of highly lipophilic fluorinated chains or molecular fragments. • Perfluoroalkylated compounds have been tested for various kinds of biological activity or as potential drug candidates for treatment of various deseases. They have been tested as various types of antagonists, analgesics, potassium channel openers, anticonvulsants, anti-inflammatory, antidiabetic, antibacterial and antifungal agents, antiviral and anticancer compounds, modulators of steroidal activity and many others. • Among various applications, perfluoroalkylated compounds have been intensively studied namely as drug candidates in the area of steroidal activity. They have been tested as androgen modulators, progesterone receptor antagonists, estrogen receptor antagonists, and for brassinosteroidal activity. Attachment of side chains possessing perfluoroalkyl moieties had profound and usually beneficial effects on the activity of the studied compounds. • Out a number of various perfluoroalkylated compounds tested, only fulvestrant (sold under the brand name Faslodex®) – a compound with a modified estrogen skeleton – has found commercially application. Its is used as an estrogen receptor antagonist for the treatment of hormone receptor-positive metastatic breast cancer in postmenopausal women.

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Medicinal applications of perfluoroalkylated chain-containing compounds 

counterparts. In this respect it is possible expect that further interest in this area will focus on the use perfluoroethyl and related groups. On the other hand, it cannot be ruled out that compounds bearing longer perfluoroalkylated chains may find interesting and unique applications (where the presence of the perfluoroalkylated chains will play an irreplaceable role). Supplementary data To ny

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Financial & competing interests disclosure This work was supported by the Grant Agency of the Czech Republic (grant No. 13-15915S). The authors have no other 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 apart from those disclosed. No writing assistance was utilized in the production of this manuscript. 15

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170 Contino C, Ollier M, Maurizis JC, Lacombe, , Pucci B.

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229 Nakahara H, Krafft MP, Shibata A, Shibata O. Interaction

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233 de Wolf E, Spek AL, Kuipers BWM et al. Fluorous

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