Apr
29
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.
.
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.
.
By: kalyan kumar dhar
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.
.
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.
.
By: kalyan kumar dhar
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