? Increased metabolic stability

? Increased lipophilicity

? Increased bio-availability

? Modified biological activity

? Antibacterial

? Ant fungicides

? Antibiotics

? Protease inhibitors

? Anticancer

? Antidepressant

? Fungicides

? Herbicides

? Insecticides

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 Ã…) rather than with the C-H bond (van

der Waals radius = 1.2 Ã…); 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.

 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

             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).

            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.

            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.

            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.

 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.

            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

            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.

            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

             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.

            1. Haemoglobin, one of the main components of blood, is responsible

            for O2 transport in tissues and cells.

            2. ALKYLFLUORIDES AND PERFLUORINATED ETHERS

            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).

             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.

            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.

            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.