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REACTIVITY, STRUCTURE AND FUNCTIONS OF FLUORINATED MATERIALS
by dott. Kalyan Kumar Dhar

Acknowledgements At the outset I would like to thank Prof. Giuseppe Resnati for giving me the opportunity to carry out this project. The encouragement and advice of our respectable professor during the entire process is appreciated. I would like to specially thank to our professor for his help, suggestions, feedbacks and support without which this report would not have been possible. I am grateful as a student of this course as well as this project for making my project report a memorable one. It was a pleasure to study with this project and also this course. Finally, I would like to thank my loving mother for her constant support and encouragement. Outline of the project : 1).The reasons why fluorine is introduced in drugs . 2) Physical and chemical properties of fluorine. 3) Fluorine containing Drugs in medicinal chemistry and the advantages/disadvantages it gives in drugs and blood substitute. 4) Some therapeutic applications of fluorinated small molecules 5) Anticancer agents. 6) Artificial blood. 7)Safety aspects & finally conclusion will be end our report. 8)conclusion. Introduction :The reason why fluorine is introduced in drugs Fluorinated chemicals are of growing importance, with applications in medicine. Fluorine substitution has profound effects on the properties of organic compounds. The very high electro negativity of fluorine can modify electron distribution in the molecule, affecting its absorption, distribution and metabolism. Fluorinecontaining drugs are used in medicine as anaesthetics, antibiotics, anti-cancer and anti-inflammatory agents, psycho pharmaceuticals, and in many other applications. with this project our great attention is focused on the fluorinated materials and their application of Medicinal chemistry .The small and highly electronegative fluorine atom can play a remarkable role in medicinal chemistry. Selective installation of fluorine into a therapeutic or diagnostic small molecule candidate can enhance a number of pharmacokinetic and physicochemical properties such as improved metabolic stability and enhanced membrane permeation. Increased binding affinity of fluorinated drug candidates to target protein has also been documented in a number of cases. A further emerging application of the fluorine atom is the use of Fluroine-18 as a radiolabel tracer atom in the exquisitely sensitive technique of Positron Emission Tomography (PET) imaging. This short review aims to bring together these various aspects of the use of fluorine in medicinal chemistry applications, citing selected examples from across a variety of therapeutic and diagnostic settings. The increasingly routine incorporation of fluorine atom(s) into drug candidates suggests a bright future for fluorine in drug discovery and development. A major challenge moving forward will be how and where to install fluorine in a rational sense to best optimise molecular properties. Compounds of fluorine, including sodium fluoride (NaF), stannous fluoride (SnF2) and sodium MFP, are used in toothpaste to prevent dental cavities. These compounds are also added to municipal water supplies, a process called water fluoridation, though a number of health concerns has sometimes led to controversy. Many important agents for general anaesthesia such as sevoflurane, desflurane, and isoflurane are hydro fluorocarbon derivatives. The fluorinated anti-inflammatory dexamethasone and triamcinolone are among the most potent of the synthetic corticosteroids class of drugs. Fludrocortisone ("Florinef") is one of the most common mineral corticoids, a class of drugs which mimics the actions of aldosterone. Fluconazole is a triazole antifungal drug used in the treatment and prevention of superficial and systemic fungal infections. Fluoroquinolones are a family of broad-spectrum antibiotics. SSRI antidepressants, except in a few instances, are fluorinated molecules. These include citalopram, escitalopram oxalate,fluoxetine,fluvoxamine maleate, and paroxetine. A notable exception is sertraline. Because of the difficulty of biological systems in dealing with metabolism of fluorinated molecules, fluorinated antibiotics and antidepressants are among the major fluorinated organics found in treated city sewage and wastewater. 18F, a radioactive isotope that emits positrons, is often used in positron emission tomography, because its half-life of 110 minutes is long by the standards of positron-emitters. Many new agricultural and pharmaceutical active ingredients contain F atoms at strategic positions. A reason for this is the fact that the replacement of hydrogen by fluorine (isosteric substitution) or of hydroxyl groups by fluorine (is polar substitution) very often leads to an improvement in the activity. The selective introduction of fluorine into organic molecules has therefore become a very important task in modern chemistry. Although the introduction of diethylaminosulfur trifluoride and other reagents in this class of compounds has achieved a breakthrough in the field of nucleophilic fluorination, there is a further need for safe, mild and efficient electrophilic fluorinating agents. Most of such electrophilic reagents, such as perchloryl fluoride, trifluoromethyl hypo fluoride, CsSO4 F, etc, are toxic and very aggressive chemicals with which explosions are not infrequently observed. Furthermore, the storage stability of such materials is very limited. "F.sym." reagents based on N-F-containing compounds have been investigated very intensively, since some of these materials have proven to be readily isolable, storage-stable and efficient fluorinating agents. The first experiments in this direction were carried out using perfluoro-N-fluoropiperidine (A) (J. Chem. Soc. Perkin Trans. I 1988, 2805). However, owing to the complicated synthesis (yield max. 13%) and the side reaction during fluorination, this compound is not of interest for practical purposes. Other known N-F fluorinating agents are N-fluoropyridin-2-(1H)one (B) (J. Org. Chem. 1983, 43, 761), N-fluorosulfonamides (C) (U.S. Pat. Nos. 4,479,901, 4,828,764, DE 36 23 184 A); camphor N-fluorosultam (D) (Tetrahedron Lett. 1988, 29, 6087) N-alkyl radical, an HF elimination can very easily occur as a side reaction. In the case of N-alkyl radicals which possess no hydrogen atoms in the a position., e.g. a t-butyl group, the yield in the preparation of the NF compound is very small. Although the charged systems (H), (F) are very efficient fluorinating agents, a decisive disadvantage of these systems is their limited solubility in the usual organic solvents. F-Teda (H) additionally has the disadvantage that a Hofmann elimination often takes place in the case of this quaternary ammonium salt. This is a particular problem in the fluorination of strong carbanions. There is therefore a great need for an electrophilic fluorinating agent which does not have the disadvantages described, can be easily prepared from readily available starting materials and possesses a high storage stability. The strength of weak interactions: aromatic fluorine in drug design. Selective aromatic fluorine substitution can increase the affinity of a molecule for a macromolecular recognition site through non-covalent interactions. These effects are evaluated most accurately by direct comparison of binding affinities of selectively fluorinated compounds with their corresponding hydrocarbons. In cases where structural data confirm similar binding geometries for the fluorocarbon and hydrocarbon analogues, reliable estimates for the impact of fluorination upon arene-pi...X and C-F...X interaction energies are possible. Existing studies show that fluorination's impact on any individual molecular interaction is quite modest. Upon binding to a protein receptor, cumulative fluorinated aromatic quadrupolar and C-F...X dipolar interaction energies rarely differ from those the corresponding hydrocarbons by more than 1.3 kcal/mol, and most individual interactions appear to be in the 0.1-0.4 kcal/mol range. Similarly, non-ideal selective fluorination is rarely associated with a dramatic decrease in affinity, because the impact of weak repulsive interactions in the bound state is counterbalanced by increased lipophilicity. There details description and adverse effect are described in the appropriate section in our project report. Physical and Chemical properties of fluorine that make useful of fluorine in medicinal chemistry Fluorine is the chemical element with the symbol F and atomic number 9. Atomic fluorine is univalent and is the most chemically reactive and electronegative of all the elements. In its elementally isolated (pure) form, fluorine is a poisonous, pale, yellowish brown gas, with chemical formula F2. Like other halogens, molecular fluorine is highly dangerous; it causes severe chemical burns on contact with skin. Fluorine's large electro negativity and small atomic radius gives it interesting bonding characteristics, particularly in conjunction with carbon, with which it forms stable compounds with a wide range of industrial applications& in medicinal chemistry which also a industrial application. Pure fluorine is a corrosive pale yellow or brown gas that is a powerful oxidizing agent. It is the most reactive and most electronegative of all the elements (4.0), and readily forms compounds with most other elements. It has an oxidation number -1, except when bonded to another fluorine in F2 which gives it an oxidation number of 0. Fluorine even combines with argon, krypton, xenon, and radon. Even in dark, cool conditions, fluorine reacts explosively with hydrogen. The reaction with hydrogen occurs even at extremely low temperatures, using liquid hydrogen and solid fluorine. It is so reactive that metals, and even water, as well as other substances, burn with a bright flame in a jet of fluorine gas. It is far too reactive to be found in elemental form. In moist air it reacts with water to form also-dangerous hydrofluoric acid. Fluorides are compounds that combine fluorine with some positively charged counterpart. They often consist of crystalline ionic salts. Fluorine compounds with metals are among the most stable of salts. Hydrogen fluoride is a weak acid when dissolved in water. Consequently, fluorides of alkali metals produce basic solutions. In general the physical and chemical properties of fluorine that must be keep in mind during the design as well as manufacture of fluorinated medicinal compound also other compound are hereby listed below : Physical Properties of Fluorine • Atomic Mass Average: 18.9984 • Boiling Point: 85.1K -188.05°C -306.49°F • Coefficient of lineal thermal expansion/K-1: N/A • Conductivity Electrical: Thermal: 0.000279 W/cmK • Density: 1.696g/L @ 273K & 1atm • Description: Greenish-yellow gas of the Halogen family • Enthalpy of Atomization: 79.08 kJ/mole @ 25°C • Enthalpy of Fusion: 0.26 kJ/mole • Enthalpy of Vaporization: 3.31 kJ/mole • Flammability Class: Non-flammable gas (extreme oxidizer) • Freezing Point: see melting point • Heat of Vaporization: 3.2698kJ/mol • Melting Point: 53.63K -219.52°C -363.14°F • Molar Volume: 17.1 cm3/mole • Optical Refractive Index: 1.000195 • Physical State (at 20°C & 1atm): Gas • Relative Gas Density (Air=1) = 1.31 Specific Heat: 0.82J/gK Chemical Properties of Fluorine • Electrochemical Equivalent: 0.70883g/amp-hr • Electron Work Function: • Electro negativity: 3.98 (Pauling); 4.1 (Allrod Rochow) • Heat of Fusion: 0.2552kJ/mol • Incompatibilities: Water, nitric acid, oxidizers, organic compounds • Ionization Potential o First: 17.422 o Second: 34.97 o Third: 62.707 Valence Electron Potential (-eV): -10.1 Atomic Structure of Fluorine • Atomic Radius: 0.57Å • Atomic Volume: 17.1cm3/mol • Covalent Radius: 0.72Å • Cross Section (Thermal Neutron Capture) a/barns: 0.0096 • Crystal Structure: Cubic • Electron Configuration: 1s2 2s2p5 • Electrons per Energy Level: 2,7 • Ionic Radius: 1.33Å • Filling Orbital: 2p5 • Number of Electrons (with no charge): 9 • Number of Neutrons (most common/stable nuclide): 10 • Number of Protons: 9 • Oxidation States: -1 • Valence Electrons: 2s2p5 Electron Dot Model Compound of fluorine : Fluorine forms a variety of very different compounds, owing to its small atomic size and covalent behaviour, and on the other hand, its oxidizing ability and extreme electro negativity. For example, hydrofluoric acid is extremely dangerous, while in synthetic drugs incorporating an aromatic ring (e.g. flumazenil), fluorine is used to prevent toxication or to delay metabolism. The fluoride ion is basic, therefore hydrofluoric acid is a weak acid in water solution. However, water is not an inert solvent in this case: when less basic solvents such as anhydrous acetic acid are used, hydrofluoric acid is the strongest of the hydrohalogenic acids. Also, owing to the basicity of the fluoride ion, soluble fluorides give basic water solutions. The fluoride ion is a Lewis base, and has a high affinity to certain elements such as calcium and silicon. For example, deprotection of silicon protecting groups is achieved with a fluoride. The fluoride ion is poisonous. Fluorine as a freely reacting oxidant gives the strongest oxidants known. Chlorine trifluoride, for example, can burn water and sand, both compounds of a weaker oxidant, oxygen. The carbon-fluoride bond is covalent and very stable. Organofluorines may be safely used in applications such as drugs, without the risk of release of toxic fluoride. In synthetic drugs, toxication can be prevented. For example, an aromatic ring is useful but presents a safety problem: enzymes in the body metabolize some of them into poisonous epoxides. When the Para position is substituted with fluorine, the aromatic ring is protected and epoxide is no longer produced. The substitution of hydrogen for fluorine in organic compounds offers a very large number of compounds. An estimated fifth of pharmaceutical compounds and 30% of agrochemical compounds contain fluorine.] The -CF3 and -OCF3 moieties provide further variation, and more recently the -SF5 group. FLUORINE-CONTAINING DRUGS: Artificial fluorine substitution of biologically active molecules exercise an influence on their properties and activities. The replacement of a hydrogen atom and/or a hydroxyl group by a fluorine atom are common strategies in drug development (Alkorta etal. 2000). Fluorine substitution in a drug molecule can influence not only pharmacokinetic properties, such as absorption, tissue distribution, secretion, and the route and rate of biotransformation but also its pharmacodynamics and toxicology (Wakselman 1999). At present more than two hundred fluorinated pharmaceuticals are available and others are appearing. The benefit of fluorinated drugs for human medicine is very well known; much less is known about the danger of these compounds for human health. The mechanism of fluorine participation in their different undesirable effects has not been fully explained. Defluorination of fluorinated drugs can readily occur during biotransformation, or may also occur spontaneously, if a molecule is sufficiently electrophilic to undergo direct reaction with a nucleophilic group present in proteins and amino acids, such as the amino group in lysine, the sulphydryl group in cysteine or the hydroxyl group in serine (Park et al. 2001). Such defluorination was observed for example in the case of an antimalarial drug 5-fluoroamodiaquine (Harrison et al. 1992) or hormone 2-fluoroethynilestradiol (Morgan et al. 1992). In rare instances, even the trifluoromethyl group may undergo defluorination (Thompson et al. 2000). Fluorine-containing volatile anesthetics The first inhalation anesthetic, methoxyfluran, was widely used in clinical anesthesia until its association with nephrotoxicity was reported (Crandell et al. 1966). In some cases fatal renal failure was described (Panner et al.1970). A high urine output syndrome leading to dehydration was related to the extensive metabolism of methoxyflurane joined with high serum concentrations of inorganic fluoride, since methoxyflurane is metabolized to oxalic acid and free fluoride. The increased intrarenal fluoride concentration has been suggested as the most important factor in methoxyflurane nephrotoxicity (Kusume 1999). Further volatile fluorine-containing anesthetics such as halothane, isoflurane, sevoflurane, enflurane, and desflurane were synthesized later. A concern about the potential nephrotoxicity and/or hepatotoxicity of new anesthetics have led to numerous clinical studies during the last two decades. The toxicity of these anesthetics might be caused by their biotransformation to toxic metabolites. Flurane anesthetics are metabolized to hexa-fluoro-isopropanol and inorganic fluoride by the human liver (Kharasch 1996). In vitro investigations have identified a role for human cytochrome P450 (CYP 2E1 and 2A6) in oxidation and CYPs 2A6 and 3A4 in reduction. Kharash and Thummel (1993) demonstrated that CYP2E1 is the principal, if not sole human liver microsomal enzyme catalyzing the defluorination of the fluorinated ether anesthetics in vivo. The rank order of anesthetic metabolism, assessed by fluoride production at saturating substrate concentrations, was methoxyflurane > sevoflurane > enflurane > isoflurane > desflurane > 0. Until recently, inorganic fluoride has been thought to be the main etiological agent responsible for fluorinated anesthetic nephrotoxicity, with a toxic concentration threshold of 50 μmol/L in serum (Gentz and Malan 2001), exceeded the reported basal values (about 3 μmol/L) 5.20 times. However, numerous studies including hundreds of patients have not shown evidence of their nephrotoxicity based on the biochemical parameters for kidney functions examined after the termination of anesthetic administration (Gentz and Malan 2001, Conzen et al. 2002). It seems that the human body has an efficient homeostatic mechanism to respond to a short time peak in the serum fluoride level. However, the wide scale of variations in the serum fluoride level and case reports of the individual adverse effects indicate caution in using flurane anesthetics particularly when prolonged anesthesia and surgery are planned. It has been reported that AlFx can affect the activity of many ion channels and enzymes in the kidney (Strunecká and Patočka 1999). When AlF3 or NaF at various concentrations were given to rats in drinking water for 45 weeks (Varner et al. 1998), pathological changes were found in the kidneys of all groups. The kidneys from rats drinking the NaF water exhibited glomerular hypercellularity, renal mesangial proliferation, and the deposition of proteins in the renal tubules. Histological evidence of glomerular distortions was present in both the AlF3 and NaF groups. Formation of nephrotoxic halogenated alkenes during alkaline degradation in carbon dioxide absorbers, such as 1-chloro-1,2-difluorovinyl difluoromethyl ether or fluoromethyl-2,2-difluoro-1- (trifluoromethyl)vinyl ether (compound A) were suggested as an alternative mechanism for renal toxicity (Orhan et al. 2001). The mechanism of compound A renal toxicity is controversial, with the debate focused on the role of the renal cysteine conjugate β-lyase pathway in the biotransformation of compound A. Fluorine-containing antiviral and antibacterial compounds Some new fluorine containing substituted 3-thioxo-1, 2, 4-triazin-5-ones have been synthesized and many of them have retained a significant antiviral activity (Abdel-Rahman 1991). Also some fluorinated purine nucleotides and nucleosides show significant antiviral (anti-HIV) activity (Marquez et al. 1990). Fluorine has been introduced into both the base and the sugar residue. Fluorine-containing antimetabolites are of interest in the development of anti-HIV drugs, such as alovudine, the direct fluorine analogue of zidovudine (3- azidothymidine, AZT). Alovudine is phosphorylated in cells to the 5- triphosphate, which is the active inhibitor of HIV-associated reverse transcriptase (Matthes et al. 1988). Recently, emtricitabine [ (-)-beta-L- 2’,3’- dideoxy-5-fluoro-3’-thiacytidine] has been approved by the Food and Drug Administration for the treatment of human immunodeficiency virus (HIV) (Anonymous 2003). 5-fluorouracil is a major antimetabolite used in the treatment of solid cancers. This compound is converted into a pharmacologically active metabolite 5-fluoro-deoxyuridine monophosphate, which inhibits the enzyme thymidylate synthetase, which then results in diminished formation of one of DNA wall stone. thymidine (Thomas and Zalcberg 1998, Feng et al. 2004). Because 5-fluorouracil and its metabolites are concentrated in cancer cells, the enzymatic blockade inhibits tumor growth. 5-fluorouracil is also metabolised into the highly toxic fluoroacetate, by scission of the pyrimidine ring (Arellano et al. 1998). The toxicity of fluoroacetate is evoked by its entry into the tricarboxylic acid cycle in mammalian cells and its conversion into fluorocitric acid (Patočka and Cabal 1999). In addition, a catabolite of 5-fluorouracil after fluorinated pyrimidine degradation induces cytotoxicity in tumors (Kubota 2003). Anthracycline derivatives with fluorine atom in different position of the molecules have also found use in modern oncology. The most known and very much used fluorine containing antibacterial compounds are fluoroquinolone antibiotics. A fluorine substituent strongly enhances the antibacterial potential of the drug. Fluoroquinolones features a broad antimicrobial spectrum. In general, fluoroquinolones were considered to be remarkably safe. Nevertheless, several side-effect were reported, including hepatic reactions, neurotoxicity, photo toxicity, cardio toxicity, tendinopathy, and chondrotoxicity (Stahlmann 2002). In premarketing trials with 7000 patients, trovafloxacin was associated with no cases of liver failure and about 2.5 million patients received Trovan®, up to 300,000 prescriptions per month. In July 1998, the FDA advised revision of the package insert to reflect hepatic toxicity. A public health advisor reported 140 patients with serious hepatic events. Fourteen patients developed acute hepatic failure: 5 received liver transplants (1 died), 5 patients died without transplantation, and 4 others recovered. Hepatotoxicity occurs after an unpredictable trovafloxacin exposure time, ranging from 2 to 60 days. There appears to be increased risk with greater than 14 days of use, and some cases occurred after re-exposure. Six out of the first 40 reported patients had peripheral eosinophilia, suggesting a hypersensitivity reaction (Rubinstein 2001). The use of trovafloxacin has been significantly restricted due to substantial mortality and morbidity associated with liver toxicity (Bertino and Fish 2000). The most common adverse events in clinical use of fluoroquinolones are nausea, diarrhea, headache, and dizziness. All fluoroquinolones have the potential to cause photosensitivity (Chignell 1998).Photosensitization can result when light interacts with chemical agents in the skin and eyes. This process can produce undesirable clinical consequences, such as photo toxicity (i.e. exaggerated sunburn), photo allergy or photo carcinogenicity. People receiving fluoroquinolones are warned on the product inserts not to expose themselves to direct sunlight. The first symptom is a developing rash on the exposed areas. In order to suppress the toxic effect of fluorine in chinolones, new compounds without the usual 6-fluorine substituent have been recently described as potent antibacterial agents. A series of non fluorinated analogues of the antibacterial quinolone levofloxacin were synthesized and tested (Gray et al. 2003). Moxifloxacin shares the quinolone-class warnings and precautions regarding use in pediatric populations, pregnant women, nursing women, and patients with central nervous system disorders. The class warnings regarding convulsions, increased intra-cranial pressure, psychosis, central nervous system stimulation, hypersensitivity reactions, pseudo membranous colitis, and tendon ruptures are also similar. Since the introduction of fluoroquinolones on the market in 1987 more than 200 cases of rhabdomyolysis, tendinitis, tendon rupture etc. have been reported in the literature (Ramanujam 2001). In October 1994 the Japan Pharmaceutical Affairs Burelu (JPAB) was the first to amend the product information for fluoroquinolones to state that muscle destruction. a condition known as rhabdomyolysis may occur (JPAB 1994). For example ciprofloxacin, which has been in use since 1987 for a variety of other indications and was the most-widely used fluoroquinolone in humans and animals worldwide, was withdrawn because of strong adverse effects. Fatal liver failure associated with ciprofloxacin was reported by Fuchs et al. (1994). The most common side-effects of ciprofloxacin are gastrointestinal in nature such as nausea, diarrhea, vomiting, and abdominal pain. In 2000 the FDA approved its use in treatment for inhalational anthrax. As soon as the first cases of anthrax resulting from suspicious mail became known, ciprofloxacin was bought on a mass scale. Ciprofloxacin administration results in elevated serum fluoride levels. In a series of tests evaluating the safety of ciprofloxacin in children, serum fluoride levels increased after 12 hours in 79% of the children; on day 7 the 24-hour urinary fluoride excretion was higher in 88.9% of children observed (Pradhan et al. 1995). Ciprofloxacin has been implicated in several cases of acute renal failure (Zimpfer et al. 2004). Fluorine-containing anti-inflammatory compounds Anti-inflammatory drugs are medications which, as well as having pain-relieving (analgesic) effects, have the effect of reducing inflammation when used over a period of time. Also in this group of drugs there are quite a number of fluorinated derivatives. The drugs vary in strength and side effects. There are many other potential side effects, but these vary according to the drug chosen and the individual taking it. Fluorine-containing anti-inflammatory drugs can be metabolized by defluorination, which favours formation of the stable and toxic fluoride ion (Boiteau et al. 1979). An example of the toxic action of the fluorinated anti-inflammatory drug, niflumic acid, has been described in France. An86 year-old man who for many years took 500 mg of niflumic acid a day, suffered heavy osteofluorosis and had severe renal insufficiency (Welsch et al. 1990). Similar health problems were suffered by a 61 year-old man who consumed 2.5 l a day of Vichy St-Yorre (a mineral water containing 8 mg of fluorine ions per litre) for 11 years. These two observations serve as a reminder of the indispensable precautions to be observed when prescribing fluorine salts in the treatment of osteoporosis and prescribing fluorine-containing drugs generally. Fluorine-containing psycho-pharmaceuticals The introduction of fluorine into psycho pharmaceuticals escalates penetration of the drug across membranes to the site of action. obviously the central nervous system. Centrally acting drugs must pass through the blood-brain barrier in sufficient concentration to elicit their pharmacological effect. For example some neuroleptics that act by blocking dopamine receptors in the CNS, such as butyrophenones, diaylbutylamines or tricycles contain either fluorophenyl or trifluoromethyl group, which contribute to the pharmacological activity of these drugs by enhancing CNS penetration. The most widely used butyrophenone is haloperidol. In the search for more potent neuroleptics, it was found that a compound which contains fluorophenyl groups was longer acting than haloperidol (Park and Kitteringham 1994). Also fluorine-containing phenothiazines. fluphenazine, trifluoropromazine, and trifluperazine, are more active than the mother compound chlorpromazine (Resnati 1990). The most often used fluorine-containing psycho pharmaceuticals are antidepressants and antipsychotic. Particularly, fluoxetine (Prozac) and citalopram are very favoured. Prozac is widely used for the treatment of depression, obsessive-compulsive disorder, and bulimia nervosa. Fluoxetine and citalopram can cause nausea, headache, anxiety, insomnia, drowsiness, and loss of appetite (Edwards and Anderson 1999). Fluoxetine has been implicated in serious skin rashes and vasculitis (Sannicandro et al. 2002). Increased blood pressure can occur and should be monitored. Seizures have been reported. Life threatening interactions can occur in combination with MAO inhibitors. MAO inhibitors and fluoxetine should not be taken together and a waiting period of 14 days between taking these two classes of medications is strongly advised (Sternbach 1988). Selective F substitution of H opened up new horizons in biochemistry: Properties � Increased metabolic stability � Increased lipophilicity � Increased bio-availability � Modified biological activity Applications � Antibacterial � Ant fungicides � Antibiotics � Protease inhibitors � Anticancer � Antidepressant � Fungicides � Herbicides � Insecticides C-F isosteric with C-H cause Early studies suggested that, due to the ease with which organic F was introduced in the metabolic pathway undisturbed, C-F was isosteric with C-H. Recent studies, however, suggest that C-F (van der Waals radius = 1.47 Å) is more nearly isosteric with C-O (van der Waals radius = 1.52 Å) rather than with the C-H bond (van der Waals radius = 1.2 Å); but F is still the smallest substituent and can be used as replacement for the C-H bond. Fluorine substitution is often used as a strategy to: 1. develop enzyme inhibitors 2. render a compound resistant to chemical degradation 3. enhanced binding (lower Ki)to specific active sites. Fluoroacetate: a potent TCA cycle inhibitor 1)Fluoroacetate is one of the most deadly simple molecules known. It occurs naturally in the leaves of a variety of poisonous tropical plants and it is used as rat poison. 2)Fluorocitrate inhibits the TCA transport in the mitochondria and the enzyme cisaconitase. 3) It became immediately obvious that fluorine alters biological activity. Biological role of fluorocarbon Although there are thousands of known naturally-occurring organic compounds containing chlorine and bromine, there are only a handful of natural fluorocarbons. They have been found in microorganisms and plants, but not animals. The most common natural fluorocarbon is fluoroacetic acid, a potent toxin found in a few species of plants. Others included ω-fluoro fatty acids, fluoroacetone, and 2-fluorocitrate which are all believed to be biosynthesized from fluoroacetic acid. Since the C-F bond is generally metabolically stable and fluorine is considered a bioisostere of the hydrogen atom, many pharmaceuticals contain C-F bonds. An example of this is fluorinated uracil. When elemental fluorine is reacted with uracil, 5-fluorouracil is produced. The resulting compound is an anticancer drug (antimetabolite) used to masquerade as uracil during the nucleic acid replication process. This can lead to the incorporation of 5-fluorouracil into DNA and RNA as well as inhibition of the enzymes that are responsible for the synthesis of the normal components of DNA. These factors can be toxic to cancer cells that need to rapidly produce normal nucleic acids in order to continue growing. Well known pharmaceutical drugs incorporating fluorine include fluoxetine (Prozac), paroxetine (Paxil), ciprofloxacin (Cipro), mefloquine, fluconazole, and many more. Antidepressants – Serotonin (5-HT) reuptake inhibition 1. In research that led to the development of fluoxetine, a series of N-methyl phenoxyphenylpropylamines was studied. The parent compound effectively blocked 5- HT uptake with an inhibition constant (Ki) of 102 nM but also blocked norepinephrine uptake with a Ki of twice this concentration. 2. The para-trifluoromethyl substituted analogue (fluoxetine) increased potency and selectivity, having a six-fold increase in potency for inhibition of 5-HT uptake, but a 100-fold decrease in potency for inhibition of norepinephrine uptake Treatment of Diabetes Glucagon-Like-Peptide-1 (GLP-1) stimulates insulin release and inhibits glucagons production. Glucagons stimulates an increased sugar concentration in the blood. GLP-1 is inactivated by the serine protease Dipeptidyl peptidase IV (DDP-IV). THEREFORE finding a DDP-IV inhibitor prolongs the beneficial effects of GLP-1. MK431 was developed. Deletion of the –CF3 group reduced bioavailability of MK431 in rats and led to a 4-fold decrease in enzyme affinity (Ki). Anti-obesity agents 1. Melanin Stimulating Hormone (MSH) is involved in feeding behaviour: 2 Mice lacking MSH gene have a lean phenotype (“feel full”). Therefore antagonists of MSH have been developed as anti obesity agents. 3. The fluorinated analogy of the parent compounds showed much lower Ki; this translates into a lower dosage of the anti obesity agent. Treatment of cardiovascular diseases 1. An impressive example of drug discovery is found in the development of intestinal cholesterol uptake by developing acyl-CoA cholesterol acyltransferase (ACAT) inhibitors. 2. On ACAT parent compound, oxidation at specific sites increased activity and strategic substitution of fluorine blocked unwanted metabolic oxidation. Fluorinated Antibacterial agents : 1. Research has assessed that fluorination of the phenyl ring of the quinolone moiety improved antibacterial activity as compared to the parent compound by binding with lowered Ki to the P site of the 50S ribosomal subunit impeding transcription and therefore cellular replication and growth. 2. Other improved properties include: a. better acid stability b. prolonged serum half-life c. higher tissue penetration d. better bioavailability. Anti-inflammatory agent 1. 3-R,S thalidomide had been developed as a sedative in the 1950s but its teratogenic effects (cancer causing) led to its withdrawal from the world market in 1962. 2. Recentenly there has been renewed interest in Thalidomide following specific clinical tests that showed its anti-inflammatory properties. 3. In this example fluorine substitution (FLUOROTHALIDOMIDE, 107) showed beneficial effects without teratogenic side effects. Fluorine in this case probably acts as a metabolic cascade modifier. Anticancer agents: blocking ribosomal unit functionality impedes transcription 1. DNA transcription occurs at the Ribosomal units 2. Tumours are an uncontrolled reproduction of certain undesired cellural strains. 3. Impeding transcription causes cellular death. This is the basis of Anti-cancer agents. Note that the 5-Fluorouracyl: the first potent fluorinated chemotherapeutic agent (Heidelberg, 1956). Alternatives to 5-FU as Thimidylate Inhibitors 1. 5-FU results in being fairly toxic with neurotoxic and cardio toxic side-effects due to: a. lack of selectivity b. over production of dUMP to compete with the active site. c. More tolerable fluorinated 5-FU have therefore been developed. Alternatives to wide spectrum anti-tumor agents 1. Methotrexate, a thimidilate antagonist, has historically been developed as a wide spectrum anti-cancer agent. Its fluorinated analogue, ZD-933 now in phase II/III clinical studies, has been found to be a specific antagonist to ovarian cancer cell-lines. 2. In this case fluorine changes the specificity of the compound rather than modify its Action Pancreatic cancer antagonists 1. Polimerase III antagonists are DNA replication antagonists which have been discovered to effectively inhibit cell replication. 2. In the case of Gemzar® (hydrogenated) and Gemcitabine (fluorinated) fluorine substitution increases potency of the drug with respect to its hydrogenated analogue. Microtubule antagonists 1. Microtubule synthesis inhibition has been found to effectively inhibit cell proliferation. 2. In this case, fluorine substitution prolongues metabolic life of the anticancer agent with respect to the hydrogenated parent compound.. Estrogen anticancer agents. 1. Mifepristone, the hydrogenated parent compound, has been found to be a good progesterone receptor antagonist. 2. In this case fluorine substitution generated a new generation of progesterone receptor antagonists with the highest receptor selectivity. Protein kinase inhibitors Most signal transduction pathways are mediated by protein kinases regulating every aspect of cell function. Since cancer is recognised to be caused by mutation and aberrant expression of critical genes, protein kinase inhibitors have become the focus of development of new therapies for cancer. 1. In this example, 61 is 100 times more potent than 57. It therefore shows how, by increasing the concentration of fluorine in the portion of the substrate which is in intimate contact with the kinase’s active site increases the effectiveness of the therapeutic agent. And therefore, F in medicinal chemistry...... 2. Fluorine will continue to play an important role in the developing areas of medicinal chemistry due to its attractive properties for inclusion in structure-activity clinical screens. Artificial blood: an O2 transport substitute 1. Haemoglobin, one of the main components of blood, is responsible for O2 transport in tissues and cells. 2. ALKYLFLUORIDES AND PERFLUORINATED ETHERS HAVE DEMONSTRATED REMAKABLE O2 UPTAKE. Loss of blood due to injury or major surgery can be a serious problem in situations where human blood is scarce or absent such as in emerging countries, during epidemics or in mass-surgeries (war time). Per fluorocarbons as artificial blood 1. Per fluorocarbons from 6 –10 carbons in length are used as “artificial blood” for the treatment of heart attacks and other vascular obstructions as well as adjutants in coronary angioplasty. 2. The per fluorocarbons are kept in an aqueous solution by means of emulsifiers and tetra-alkyl ammonium salts; their concentrations range from 0,5 – 2 g/dl 3. The concentration of the per fluorocarbon in the aqueous solution ranges from 5 – 10 g/dl. Perfluorodecalin: a ...bloody special fluorocarbon! made up of atoms of carbon, fluorine, and/or sulphur. 1. liquids are clear, colourless, odourless, non-conducting, and non-flammable. 2. approximately twice as dense as water, and are capable of dissolving large amounts of gases mainly oxygen and carbon dioxide. 3. chemically stable compounds that are not metabolized in body tissues. 4. Require a high FIO2 to maintain high oxygen concentrations within the fluid. It is only the carrier of oxygen and carbon dioxide. 5. Capable of carrying five times more oxygen than haemoglobin. Perfluoroethers and perfluoropolyethers as artificial blood 1. Due their grater chain mobility and also due to their greater chemical affinity for perfluoroethers and perfluoropolyethers O2 are more efficient in delivering “acceptable” (quantities not disclosed) concentrations of O2 both in laboratory animals and clinical testing on humans. 2. Furthermore, due to their greater solubility in aqueous solutions, perfluoroethers and perfluoropolyethers don’t require emulsifiers thus simplifying the “artificial blood” composition. 3. A specific experimental example developed by the ASP school coordinated by Prof. Walter Navarrini of this Polytechnical Institute is CF3OCF2CF2OCF3 (b.p. = 20°C). Other fluorine-containing drugs It has been shown that fluorinated analogues of naturally occurring biologically active compounds including amino acids, often exhibit unique physiological activity. Fluorination of natural hormones can lead to molecules with new pharmacokinetic and/or pharmacodynamic properties. For example the introduction of fluorine into corticosteroids has a dramatic effect on their metabolism (Bush and Mahesh 1964). Because the metabolism of steroid hormones is very important for their physiological activities, the exchange of a hydrogen atom under fluorine atom can be very meaningful. Also other endogenous compounds markedly exchange their biological properties, if one or more fluorine atoms are installed into their molecule. For example, the potent platelet aggregating agent thromboxane A2 has a half-life in vivo of only 32 seconds. Incorporation of two fluorine atoms into the oxetane ring of thromboxane A2 reduces the rate of carbonium ion formation and acid hydrolysis, so that 7,7-difluoro-thromboxane A2 has a rate of hydrolysis 108-fold slower than the natural substance (Fried et al. 1984). Likewise prostacyclin, which is an inhibitor of platelet aggregation, has a very short biological half-life. Fluorination improves the stability of the molecule toward acid hydrolysis and the stability in organisms. Thus 10,10-difluoro-13-dehydroprostacyclin exhibits a half-life 150 times, and has equal potency to, the natural compound (Fried et al. 1980). Cerivastatin, a fluorinated drug from the statin class, which had caused deaths and serious adverse health effects was withdrawn from the market in 2001 (Furberg and Pitt 2001). It had been linked to at least 31 deaths. Cerivastatin also induced muscle destruction (rhabdomyolysis) and displayed compounded toxicity when used with other drugs. Other non medicinal application : 1. Rrefrigerants: Some fluorocarbons (e.g. Freon) have been used as refrigerants. These fluorocarbons combine good thermodynamic properties (they have boiling points somewhat below typical target temperature, a high heat of vaporization, a moderate density in liquid form and a high density in the gas phase) with a safe (low toxicity and flammability) and no corrosive nature. Because of their negative effect on the ozone layer, many fluorocarbons have been banned as refrigerant after the Montreal Protocol. 2. Propellants: Compounds that have a boiling point just around room temperature, with a high vapour pressure can be used as propellant gas. Some fluorocarbons have these properties, and, before the Montreal Protocol, many of these low boiling fluorocarbons were used as propellants, but now recognized as endangering the ozone layer in the earth's atmosphere. 3. Solvents: Fluorocarbons are used as industrial solvents due to their specific properties, including: non-flammability, stability, excellent dielectric properties, low surface tension and viscosity, very low toxicity and a favorable environmental profile. Prior to the Montreal Protocol, CFCs, such as Freon and chlorodifluoromethane were used as cleaning solvents. Also HFCs were developed with similar properties. Quite often these HFC's are blended with other fluids to obtain tailored properties for specific application. Main applications are: • Precision Cleaning (Degreasing) • Electronic Assemblies Defluxing • Particulate Removal • Drying after Aqueous Cleaning • as a Carrier Fluid • as a Dielectric Coolant HFCs, particularly 1,1,1,2-tetrafluoroethane, are used for specialist extraction of extremely important natural products; such as Taxol for cancer treatment from yew needles, evening primrose oil food supplement, and vanilla. The use of 1,1,1,2-tetrafluroethane compliments other methods of extraction, in being highly selective and allowing high quality and high yield extractions. 4. Lubrication : Fluorocarbons are uncreative and are often used for demanding applications. Also, solid fluoropolymers have a low coefficient of friction, while fluid fluoropolymers can act as lubricants. Teflon and other similar fluoropolymers are applied as layers to help reduce friction. Small, self-lubricated parts such as stopcocks for laboratory glassware may be entirely made of Teflon. Fluorocarbon based greases are sometimes used in demanding applications. Advantages include low reactivity and very high temperature ranges. Examples include Fomblin by Solvay Solexis and Krytox by DuPont. Also used in certain firearm lubricants such as "Tetra Gun" 5.Water repellant and stain repellant products: In general, highly fluorinated organic compounds are hydrophobic and have water-repellant and stain-repellant properties. The original formulations of products such as Scotchgard contained fluorocarbons including perfluorobutane sulfonate and perfluorooctane sulfonate (PFOS). But many of these uses have been phased out due to environmental concerns, such as those associated with perfluorooctanoic acid, an intermediate in the manufacture of PFOS. Similarly, products containing Gore-Tex and Teflon are made from fluoropolymers. Fluorocarbons are also used in fishing line, in myriad precision plastics applications, and in highly precise lubrication applications. 6. Chemical reagents: Triflic acid (CF3SO3H) and trifluoroacetic acid (CF3CO2H) are important reagents in organic synthesis. They are valuable for their properties as very strong acids that are soluble in organic solvents. The electronegative nature of the fluorine atoms stabilizes the dissociated anions of triflic acid and trifluoroacetic acid, leading to stronger acidity compared to their unfluorinated analogs, methanesulfonic acid and acetic acid, respectively. The fluorine atoms also enhance the thermal and chemical stabilities of the conjugate bases. In fact, the polymeric analogue of triflic acid, nafion is used as a proton-exchange material in cells. The triflate-group (the conjugate base of the triflic acid) is a good leaving group in organic chemistry. Carbon-fluorine bonds have found application in non-coordinating anions. In these anions (e.g. BF4 -, PF6 -, B(C6H3(CF3)2)4 -, and B(C6F5)4 - the charge is 'smeared' out over many electronegative atoms. Disadvantages / Pollution effects / Adverse effect/Environmental effect : When fluorine from the air ends up in water it will settle into the sediment. When it ends up in soils, fluorine will become strongly attached to soil particles. In the environment fluorine cannot be destroyed; it can only change form. Fluorine that is located in soils may accumulate in plants. The amount of uptake by plants depends upon the type of plant and the type of soil and the amount and type of fluorine found in the soil. With plants that are sensitive for fluorine exposure even low concentrations of fluorine can cause leave damage and a decline in growth. Too much fluoride, whether taken in form the soil by roots, or adsorbed from the atmosphere by the leaves, retards the growth of plants and reduces crop yields. Those more affected are corns and apricots. Animals that eat fluorine-containing plants may accumulate large amounts of fluorine in their bodies. Fluorine primarily accumulates in bones. Consequently, animals that are exposed to high concentrations of fluorine suffer from dental decay and bone degradation. Too much fluorine can also cause the uptake of food from the paunch to decline and it can disturb the development of claws. Finally, it can cause low birth-weights. As mentioned above, chlorofluorocarbons have been criticized for their harm to the ozone layer. It is estimated that a single CFC molecule has the ability to decompose approximately 100,000 ozone molecules. However, because fluorocarbons lack a chlorine atom, they cannot participate in the ozone-destroying reactions that are such a problem with CFCs. Fluorocarbons are considered ozone safe. During our discussion in the part of fluorine and medicinal chemistry and their application in human body some of the disadvantages also discussed. here we just show the outline about the pollution effects of fluorine containing compound. There details description and adverse effect of fluorinated medicinal compound are described previous section in our project report. Safety Elemental fluorine Elemental fluorine (fluorine gas) is a highly toxic, corrosive oxidant, which can cause organic material, combustibles, or other flammable materials to ignite. It must be handled with great care and any contact with skin and eyes should be strictly avoided. Fluorine gas has a characteristic pungent odour that is detectable in concentrations as low as 20 ppb. As it is so reactive, all materials of construction must be carefully selected. All metal surfaces must be passivated before exposure to fluorine. Fluoride ion Fluoride ions are also highly toxic and must also be handled with great care and any contact with skin and eyes should be strictly avoided. Hydrogen fluoride and hydrofluoric acid Contact of exposed skin with hydrofluoric acid solutions poses one of the most extreme and insidious industrial threats—one which is exacerbated by the fact that hydrofluoric acid damages nerves in such a way as to make such burns initially painless. The HF molecule is a weaker acid which is significantly nondissociated in water, and the intact molecule is capable of rapidly migrating through lipid layers of cells which would ordinarily stop an ion or partly ionized acid, and the burns it produces are typically deep. HF may react with calcium, permanently damaging the bone. More seriously, HF reaction with the body's calcium inside cells can cause cardiac arrhythmias, followed by cardiac arrest brought on by sudden chemical changes within the body (hypocalcaemia). These cannot always be prevented with local or intravenous injection of calcium salts. Hydrofluoric acid spills over just 2.5% of the body's surface area (about 75 in2 or 5 dm2), despite copious immediate washing, have been fatal.[7] If the patient survives, hydrofluoric acid burns typically produce open wounds of an especially slow-healing nature. Anhydrous hydrogen fluoride will rapidly form hydrofluoric acid on contact with moisture; its physiological effects are then the same. Organic fluorides Per fluorocarbons are generally inert and non-toxic, but there are many other fluorine compounds that have physiological effects, both good and bad. For example, fluoroacetic acid (one of the very few natural fluorine compounds) is very poisonous, while fluorouracil is an anti-cancer drug. Conclusion: Fluorinated compounds are synthesized in pharmaceutical research on a routine basis and many marketed compounds contain fluorine. The present review summarizes some of the most frequently employed strategies for using fluorine substituents in medicinal chemistry. Quite often, fluorine is introduced to improve the metabolic stability by blocking metabolically labile sites. However, fluorine can also be used to modulate the physicochemical properties, such as lipophilicity or basicity. It may exert a substantial effect on the conformation of a molecule. Increasingly, fluorine is used to enhance the binding affinity to the target protein. Recent 3D-structure determinations of protein complexes with bound fluorinated ligands have led to an improved understanding of the nonbonding protein-ligand interactions that involve fluorine. The trend toward fluorinating pharmaceuticals contributes to well-documented human fluoride overload from the living environment (Bryson 2004). Fluoride in the presence of trace amounts of aluminium (which is present everywhere) can act as the messenger of false information, activating G proteins and evoking numerous pathological changes. Moreover, fluoride in the form of aluminofluoride complex might potentiate the sub clinical patho physiological alterations. Serious health problems can arise after application of fluorinated hormones. No one can responsibly predict what happens in a human body after administration of fluorinated compounds. Large groups of people, including neonates, infants, children, and ill patients serve thus as the subjects of pharmacological and clinical research. Albert Gilman said in his Nobel prize lecture: .The ultimate dream is to design drugs that will prevent aberrant G protein action.. Fluoride plus aluminium produce aberration of G proteins. How many human subjects will applied biomedicine need, to accept this knowledge? The awareness of the health risks of an increasing load of fluoride and aluminium ions would contribute significantly to the decline of risks of many severe disorders in the 21st century. In this work I tried to show how Fluorinated compounds applied to medicinal chemistry .From our previous discussion we already showed that F in Medicinal chemistry .The application of fluorinated compound in medicinal chemistry as well as other application, Chemical, Physical properties and some of basic disadvantages, adverse effect ,& safety also discussed. But in my point of view the application of fluorinated compounds applied to medicinal chemistry is important and plays a vital role in our daily life.