Lecture 6 - Fluorine Substitution in Medicinal Chemistry (SAR2) Flashcards
(10 cards)
What are fluorinated compounds used for? Give 7 examples.
Treatment of disease:
- Antidepressants
- Anti-inflammatory agents
- Antimalarial drugs
- Antipsychotics
- Antiviral drugs
- Steroids
- General anaesthetics
What are the effects of fluorine substitution on physicochemical properties and what is the impact on pharmacokinetic, pharmacodynamic and toxicological properties?
Physicochemical properties:
- Bond strength
- Lipophilicity
- Conformation
- Electrostatics
- Dipole
- pKa
Pharmacokinetic properties:
- Tissue distribution
- Clearance
- Route of metabolism
- Rate of metabolism
Pharmacological consequences:
- Pharmacodynamics
- Toxicology
Why is fluorine substitution so commonly used in medicinal chemistry?
- Average C-F bond dissociation energy = 425 kJ/mol (very strong). So C-F bond relatively inert to metabolic cleavage
- Van der Waals radius of F = 1.35 Angstrom (very small, H has radius of 1.2 A). Important since this means F doesn’t exert steric demand at receptor sites
- F can act as H-bond acceptor (like O). C-F bond differs from C-O by only 0.04 A so can be used as isosteric replacment to produce active drug compounds
- Increases lipophilicity of molecule. Can facilitate hydrophobic interactions with enzymes/receptor sites
- F can alter oxidation potential of aromatic system and prevent oxidation of aminophenols to quinoneimines
Give 2 examples of important fluorine substituted drugs and their functions and uses (example of drug, chemistry behind uses, what does F substituent impart/prevent?)
5-fluorouracil (shows 1 and 2):
- Anticancer agent used to treat breast, liver and skin cancers
- Example of Transition State Inhibitor
- Good example of isosteric replacement of H
Selective serotonin uptake inhibitors (shows 3):
- Increase brain’s level of serotonin, improving mood
- Used in treating OCDs, PMT and depression
- E.g. Prozac (fluoxetine)
- Trifluoromethyl function imparts lipophilicity in this compound (important for brain penetration for centrally acting drugs)
- CF3 group also prevents metabolism in aromatic ring
Describe what happens regarding the metabolisation of paracetmol and the detoxification of the toxic metabolite in normal dose vs. overdose of paracetamol
- Paracetamol undergoes P-450 catalysed oxidation to chemically reactive quinoneimine
- After normal dose, small amount of drug oxidised to paracetamol N-acetyl p-benzoquinoneimine (NAPQI)
- Toxic metabolite detoxified by glutathione (GSH) to GSH metabolite excreted into urine and bile
- In overdose, pools of GSH in liver become depleted so NAPQI reacts with liver cells (specifically key sulfurhydryl containing proteins)
- Formation of covalent drug-protein adducts in liver causes liver damage
What was the effect of fluorine substitution in paracetamol (what was prevented)? How were the effects measured and were there any positive side effects?
- Incorporating fluorine into aromatic nucleus of paracetamol prevents oxidation to toxic quinoneimine
- Several analogues prepared and redox potential measured
- Increase in oxidative stability also meant decrease in toxicity and reduced depletion of hepatic GSH
What is primaquine (and side effects), what are the 2 metabolic stages involved? How is F substitution used to block the first metabolic stage (what kind of substituent) and prevent side effects?
- 8-aminoquinoline antimalarial
- Has many toxic side effects such as haemotoxicity
- 2 metabolic stages involved in toxicity of drug:
- 1st stage: P450 mediated aromatic hydroxylation gives 4-aminophenol relative
- 2nd stage: P450 mediated oxidation to reactive quinoneimine (similar to paracetamol)
- 5-fluoro substituent used to block 1st stage
- Resulting analogue 5-fluoro primaquine considerably less haemotoxic than primaquine
What happens in estradiol (and synthetic estrogens) drug metabolism (how is it catalysed, what does it produce) and how does F subtitution prevent this?
- Undergo P450 mediated 2-hydroxylation
- Produces catechol that can undergo oxidation to toxic ortho-quinone
- Fluorine blocks hydroxylation
- Enhances Phase II glucuronidation of A-ring OH function
What are the 3 main approaches to the synthesis of fluorinated drugs? Why can’t elemental fluorine be used to carry out aromatic fluroinations?
- Use of commercially available fluorinated building blocks
- Use of N-Fluoro reagents (F+ sources)
- Use of nucleophilic sources of fluorine
F2 difficult to handle, strong oxidising agent.
What are the 4 effects of fluorine substitution in terms of pharmacodynamics?
- Increases lipophicility
- Increases half-life (t1/2)
- Isosteric replacement: capacity to replace OH or hydrogen
- Similar van der Waals radius to H - no steric effects at receptors/enzymes
