Option D: Medicinal Chemistry

Front 1

Drug

Back 1

Any substance that when applied to or introduced into an organism, brings about a change in biological function through its chemical action. The change can be for the better (treatment of diseases) or for the worse (toxicity).

Front 2

Types of drugs

Back 2

1. Relatively crude preparations, obtained by extracting plant or animal materials.

2. Pure compounds isolated from natural sources.

3. Semi-synthetic compounds, produced by chemical modification of pure natural compounds.

4. Synthetic compounds.

Front 3

Medicine

Back 3

Something that treats, prevents or alleviates the symptoms of disease - they have a therapeutic action.

-Usually compound preparations => contain a number of ingredients=> the active drug plus non-active substances that improve the preparation in some way such as taste, consistency or administration of the drug.

Front 4

How do drugs produce an effect?

Back 4

By interacting with a particular target molecule. Usually a protein - enzyme or receptor, but may be a DNA or a lipid in a cell membrane. It can either stop it from functioning or stimulate it. In ether the effect is either therapeutic or harmful.

Front 5

Drug development process

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1. Identification of lead compounds. Done through biological testing of compounds obtained by: isolation from natural source, chemical synthesis, searching through existing banks of compounds already synthesized. Act as a starting point of chemical modification (called lead optimisation)

2. The compound is chosen=> test for toxicity in animals. When drugs fail at this stage - alternative drug structures need to be identified and then developed.

3. Clinical trials

Front 6

Clinical trials

Back 6

-if safe in animals-> it is given to humans.

-Aim: to find out if it is effective in humans and whether it is safe to use.

1. Phase 1: Carried out on a small number of volunteers-> to find the dose range of the drug dose range that gives therapeutic effect and identify side effects.

2. Phase 2: volunteers who have the disease. Establishes whether the drug is effective.

3. Phase 3: much larger group of volunteers-> Confirms the effectiveness and compares its activity with existing drug treatments or placebos. After this stage is marketing authorization.

Front 7

LD50, TD50, ED50 and Therapeutic index

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-LD50-the dose requires to kill 50% of teh animals tested (lethal dose). mg/kg

-TD50- the dose required to produce a toxic effect in 50% of the test population (toxic dose).

-ED50- the dose required to produce therapeutic effect in 50% of the test population (effective dose)

-Therapeutic index (TI): LD50/ED50 or TD50/ED50. High -> large difference between the dose for therap. effect and dose of toxic effect.

Front 8

Therapeutic window

Back 8

The range of dosage between the minimum required to cause a therapeutic effect and the level which produces unacceptable toxic effects.

Front 9

Tolerance

Back 9

-occurs when the body becomes less responsive to the effects of a drug, and so larger and larger doses are needed to produce the same effect.

- Reasons: repeated use of the drug stimulates increased metabolism of that drug; the body may adapt so that it offsets the effects of the drug.

Front 10

Psychological dependence and physical dependence

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Psychological: the need to feel good (cravings)

Physical: body cannot function without a drug

Front 11

The administration of drugs

Back 11

1.Oral (e.g. tablets, capsules, syrups). Convenient for the patient, however the onset of drug is slow because it has to be absorbed first. Some drugs cannot be given orally because they dissolve in the gut (insulin)

2. Rectal (incorporated into suppositories). Can have either local effect or can enter the bloodstream and affect other parts of the body.

3. Pulmonary (thorough lungs). Gases or volatile liquids. Lungs-large surface area -> rapid absorption.

4. Topical (to the skin). Creams e.g. Local effect. Trans-dermal patches May also be used and allow penetration of the drug to access blood circulation.

5. By injection: Intravenous (directly into the bloodstream; Intramuscular (into skeletal muscle); Subcutaneous (under the skin) - sustained effect.

Front 12

Bioavailability

Back 12

The proportion of an administered drug dose that reaches the general blood circulation - and then is available to travel around the body to where it is needed. However, not all the drug that enters the circulation will be distributed (reach the target site).

- If through intravenous - bioavailability is 100%

-Depends on solubility of a drug in water. Drugs that are fat-soluble will pass through cell membranes more quickly.

-The presence of polar groups and functional groups that can undergo ionization affect solubility.

-Bioavail. affected by the formulation of the drug.

Front 13

drug-receptor interactions

Back 13

-It can bind to a cell membrane protein receptor, mimicking the efect of the normal molecule that binds and cause a series of reactions in a cell (processes on/off) - receptor agonist

-It can bind to a cell-membrane protein receptor so that the normal molecule can't - it prevents a particular response from a cell- receptor antagonist.

Front 14

Analgesics

Back 14

Drugs that reduce pain. Mild or strong.

Front 15

Mild analgesics

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E.g. Aspirin and ibuprofen prevent the production of prostaglandins (cause different physiological effects in the body) by inhibiting an enzyme cyclooxygenase (COX) - key enzyme in the synthesis of prostaglandins.

Mild analgesics act at the source of pain by inhibiting the production of chemical messengers that causes the sensation of pain, swelling and etc.

Front 16

Aspirin (acetylsalicylic acid)

Back 16

-an ester of salicylic acid

-non-steroidal anti-inflammatory drug (also ibuprofen)

-Used for headaches and fevers, but cal also act as an anticoagulant ->anti-blood-clotting effect-> help prevent recurrent heart attacks or strokes.

-Prophylactic - taken to prevent a disease happening in the first place.

- Prostaglandins also have a purpose of maintaining mucous layer in the stomach-> side effect of aspirin is gastric irritation.

-Some people are sensitive to it (hypersensitivity) e.g. those who have asthma.

-Not recommended for children under 16 -> associated with Reye's syndrome.

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Synergism

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Can happen when two or more drugs, given at the same time, have an effect on the body that is greater than the sum of their individual effects. IOW, certain drugs can increase the effect of others if taken at the same time.

Front 18

The synergistic effect of ethanol

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-increase effects of other drugs-> careful when alcoholic drinks are taken by people on certain types of medication. May be harmful, even fatal.

-When taken with aspirin -> risk of hemorrhage (bleeding) in the stomach.

Front 19

Synthesis of aspirin

Back 19

-Aspirin can be made from 2-hydroxybenzoic acid (salicylic acid) by warming with excess ethanoic anhydride.

-Reaction: addition-elimination (The CH3CO group is added to aspirin and ethanoic acid is eliminated).

-In presence of small amount of sulfuric acid.

-Not very soluble in H2O-> the addition od water causes a precipitate of aspirin to form + breaking down any unreacted ethanoic anhydride to ethanoic acid.-> the precipitate is then filtered off and washed with cold water and left to dry(in a desiccator or warm oven) to give crude product.-> mass of product is recorded-> yield worked out.

Front 20

Purification of aspirin

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- Main impurities- salicylic acid -> process of recrystallisation (a solid is dissolved in a solvent in which it is soluble at raised temperatures but much less soluble at lower temperatures).

-Aspirin can be recrystallised from ethyl ethanoate or ethanol. water is generally not used because aspirin tends to decompose i hot water.

Front 21

Characterization of aspirin

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1. Determination of purity: chromatography or by measuring melting point. The presence of impurities lowers the melting point. Pure aspirin- 138-140 C. If lower (approx 1125-132)- quite impure.

2. The infrared spectrum of aspirin: to determine which bonds/functional groups are present +whether or not a particular compound has been made -> Two peaks in the carbonyl region (C=O) bc 2 C=O groups are present - ester and carboxyl. Comparing to salicylic acid IR -> in sal. acid C=O stretch from ester (approx 1700cm-) is missing.

3. Solubility in other drugs: to increase the aqueous solubility of acid/base drug create an ionic salt of the drug. Aspirin - acidic -> has a carboxyl group that can react with strong alkali to from salt -> converts acid group to anion (COO-) -> most common drug salt -sodium -> the sodium salt of aspirin is more water soluble so absorbed more rapidly and increases bioavailability.

Front 22

The formation of fluoxetine hydrochloride (Prozac)

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-many drugs contain an amine(amino) group e.g. opioid drugs, amphetamines and some antidepressants. So does Prozac.

-Because amine group is basic-> converted into salts by reacting the amine group with a strong acid ( e.g. HCl) -> produces cation -> most common salt is chloride salt.

Front 23

Penicillin

Back 23

-Antibacterial drugs that are toxic to bacteria but are relatively safe for the patients. Act on sites in the bacterial cells that are either different from those in our cells or do not exist in our cells at all.

-Produced by some fungi of the Penicillium strain (e.g. Penicillium chrysogenum)

-important natural penicillin: benzylpenicillin. Produced by fermentation of a mixture of corn-steep liquor, sugars, minerals and phenylethanoic acid using a penicillin fungus, in a controlled environment.

-Contanis beta-lactam ring (a cyclic amide) -essential for its function

Front 24

Penicillin effect on bacterial cell walls

Back 24

-cell wall contains a polymer made up of sugar chains cross-linked with peptides.

-Penicillin inhibits an enzyme (transpeptidase) involved in the cross-linking of this polymer, weakening cell wall and causing the bacterial cell to burst due to high osmotic pressure cause by water from the surroundings entering the bacterial cell.

Front 25

Bacterial resistance of penicillin

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-Bacterial resistance: the widespread use of penicillins has resulted in the development of bacteria that have become resistant to their antibacterial effects (because of mutations in DNA of bacteria)

-Enzyme penicillinase (a beta-lactarnase) is produced in some bacteria that opens the beta ring, making penicillin inactive.

-Modifying the side-chain in penicillins makes them more resistant to the penicillinase enzyme.

-bacterial resistance is due to extensive use of antibacterials -> increased exposure of bacteria to the drug

Front 26

Strong analgesics/Opiates

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-opiate/opioid are strong analgesics for moderate to severe pain, such as in terminally ill patients.

-Opiates-natural narcotic(sleep-inducing) analgesics derived from opium poppy. Contains approx 25 different nitrogen-containing compounds - most important morphine (10%). +codeine that is a bit milder

Front 27

How do strong analgesics work? Their effects?

Back 27

-Strong analgesics work by temporarily binding to opioid receptors in the brain, which block the transmission of pain signals in the brain.

-Opiates cause a number of effects on the body through binding to opioid receptors. (e.g. sedation, analgesia). They are used medically for pain relief and the treatment of coughs and diarrhea.

-Both the medicinal effects of opiates and their addictive properties are caused by binding to the same opioid receptors in the brain.

Front 28

Difference between codeine, morphine and diamorphine and the function of diamorphine

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-all have a tertiary amine group and a benzene ring.

the difference between codeine and morphine is a methoxyl(-OCH3) group (ethr func gr) on the benzene ring in codeine instead of hydroxyl(-OH) group (attached to the benzene ring->gives rise to phenol) in morphine.

-when codeine enters the body-> acted on by enzymes-> remove methyl group-> converted to morphine.

-Diamorphine (heroin) is a semi-synthetic morphine derivative. It contains two ester (CH3COO) groups, whereas morphine contains 2 OH.

-Diamorphine is a more potent analgesic that morphine because it is better to cross the blood-brain carrier. (more lipid soluble).

- Once it has entered the brain, it is hydrolysed by enzymes to monoester and to morphine-> these bind to opioid receptors producing an alagesic effect.

Front 29

Synthesis of diamorphine

Back 29

-synthesised from morphine by heating with ethanoic anhydride -> converts two hydroxyl group in morphine to ester groups.

-addition-elimination reaction (esterification)

Front 30

Synthesis of codeine

Back 30

-from morphine

-Original process: morphine reacted with iodomethane in the presence of base -> the presence of a strong base converts OH of the phenol to O-.

-The reaction is nucleophilic substitution.

-Nowadays a salt of C6H5N(CH3) (e.g. C6H5N(CH3)+(C2H5O-) is used.

Front 31

Advantages and disadvantages of opiate analgesics

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-Can cause nausea, vomiting, constipation, respiratory depression, drowsiness and euphoria; in the long term- dependence and tolerance, chronic constipation and decrease in sex drive.

- Dependence from opiates is usually physical (not psychological)

-Abuse of opiates -> euphoric feeling, injected intravenously. Treatment may involve decreasing in dosage or administration of a substitute methadone. -> patients are at risk of HIV/AIDS and hepatitis by sharing needles.

Front 32

Irritation of stomach lining

Back 32

Causes indigestion (irritation by excess acid), heartburn-acid reflux, Peptic ulcer (erosion of part of the gut lining).

Front 33

Antacids

Back 33

Treat the irritation of the stomach lining

- weakly basic compounds that neutralise acids

-most commonly used: Mg(OH)2, Al(OH)3, CaCO3, NaHCO3.

Front 34

Treatment of peptic ulcers

Back 34

-Ranitidine or Zantac - a drug that inhibits the production of acid by binding to a receptor protein in the membrane of the parietal calls, which stops the normal chemical messenger (histamine) from binding to turn on the chain of events for producing acid. - H2 receptor antagonist.

-Omeprazole (losec) and esomeprazole (nexium) - are proton pump inhibitors and work by preventing the release of acid from parietal cells into the stomach. Protonation inside the parietal cells starts a series of reactions that changes the structure of drug molecule to one that can bind irreversibly to proton pump-> stop it from functioning.

Front 35

Active metabolites

Back 35

-Are the active forms of drugs after they have been processed in the body. (Aim: to avoid side effects, to allow the drug to pass through cell membranes,to allow it to dissolve in water more easily, to target particular area)

Front 36

Buffer solution

Back 36

-Is a solution that resists changes in pH when small amounts of acid or alkali are added.

-consists of an acid and a base

-ca only be made from weak acid and its conjugate base or a weak base and its conjugate acid.

Front 37

How to calculate the pH of a buffer solution

Back 37

- pH=pKa + log10([base]/[acid])

Front 38

Viruses

Back 38

-parasites that invade host cells and use the materials and processes within those cells to produce new viruses (cannot replicate outside host cells).

-Different structures, but all have a core consisting of genetic information (DNA or RNA) surrounded by a protein coat - capsid, which consists of capsomeres and protects genetic information. Capsid+ genetic information =nucleocapsid.

- not living cells

-bind to the cell-> release genetic material in the cytoplasm

Front 39

Treatment and prevention of viral diseases

Back 39

-Difficulties: once the virus is inside it multiplies very quickly, they can mutate their DNA or RNA that could make them resistant to drugs, use the host cells own processes and materials so its difficult to target only the virus.

-Vaccines (stimulate body's natural defences to produce antibodies) and antiviral drugs (some alter the genetic material, some inhibit the activity of enzymes, some stop the viruses by preventing them from binding to the host cell surface and some prevent the virus from leaving the host cell).

Front 40

Influenza antiviral drugs

Back 40

-such as Oseltamivir and zanamivir - are neuraminidase inhibitors. Bind to an active site of the neuraminidase enzyme, which prevents it from catalysing the hydrolysis of the sialic acid residue from the glycoproteins in the cell membranem so that viruses remain anchored to the cell and cannot infect other cells.

Front 41

Comparing structures of oseltamivir and zanamivir

Back 41

Both: primary amine (NH2), secondary amide/carboxamide, Alkene (C=C), ether.

Only zanamivir: OH (hydroxyl), secondary amine (N-H).

Front 42

Ionising radiation

Back 42

Radioactive isotopes undergo decay by emission of alpha, beta particles or gamme rays. Cause the formation of ions by ejection of electrons when they interact with matter.

-can damage cells, main effect comes from damage to DNA.

-Radioactive waste is a byproduct

Front 43

Radioactive waste

Back 43

- Low level has a low activity (not many radioactive nuclei decay each secind to produce ionising radiation) and usually contains isotopes with short half-lives (ionising radiation is given off for a shorter period of time). Includes items that have been contaminated with radioactive material or have been exposed to radioactivity. Must be stored on site until decay-> disposal.Often buried underground.

-High level waste has a high activity and usually contains isotopes with longer half -lives. Includes spent fuel rods and other materials from nuclear reactors. Can be converted to glass (vitrification) for storage. Kept in storage pools under water.Then in dry casks in bunkers.

-Disposal: 'dilute and disperse', 'delay and decay', 'confine and contain'.The lastter is always for high level waste.

Front 44

The release of antibiotics in the environment

Back 44

Can enter the water supply by:

-incorrect disposal of unwanted medicines

-agriculture (drugs given to animals will be present in animal waste).

Can damage aquatic animals, result in increased resistance of bacteria to antibiotics.

Front 45

Green chemistry

Back 45

-An approach to chemical research and chemical industrial processes that seeks to minimise the production of hazardous substances and their release into the environment.

-12 principles:

1.Prevention

2. Atom economy

3. Less hazardous chemical syntheses

4. Designing safer chemicals

5. Safer solvent and auxiliaries

6. Design for energy efficiency

7. Use of renewable feedstocks

8. Reduce derivatives

9. Catalysis

10. Design of degradation

11. Real time analysis of pollution prevention

12. Inherently safer chemistry for accident prevention.

Front 46

Best synthetic route to a drug and the equation for atom economy

Back 46

1. Use readily available and safe materials.

2. Have the min number of steps

3. Convert as much of the starting material as possible into the required product at each step

-good atom economy+ yield

4. Use as little solvent as possible

5. Use as little energy as possible

Atom economy= (molar mass of desired product/total molar mass of all reactants) *100%

Front 47

Synthesis of oseltamivir

Back 47

-treatment of influenza-> involves huge amounts of materials and can generate thousands of kg of waste per mol of oseltamivir made.

-Current route: shikimic acid-starting material (renewable and extracted from Chinese anise or obtained from glucose by fermentation using genetically modified bacteria). + 10 more steps.

-The yield from anise is not very high and the production of shikimic acid is linked to the availability of anise. The use of GM bacteria provides a more long-term solution (uses relatively low temp and an aqueous medium -> reasonably green).

Front 48

Waste solvents

Back 48

-used as the medium in which many reactions occur, in the extraction and purification of compounds and so on. Contribute to the amount of energy cost and lost as they are 80%-90% of the mass of substances.

-if a greener solvent cannot be found, then the amount used should be reduced as far as possible.

-If the solvent cannot be reused, then it must be disposed of as safely as possible. (incl. incineration and injection underground).

Incineration produces carbon dioxide, a greenhouse gas, that contributes to climate change and can also produce toxic substances.

Front 49

Chirality and Thalidomide

Back 49

-Chirality is when a molecule contains a c atom bonded to 4 different groups -> two mirror images (enantiomers) exist.

-Thalidomide is a chiral drug that was given to pregnant women to prevent morning sicknesses.-> one of the enantiomers (S) was responsible for producing a tetratogenic effect and cause limb deformities in the fetus.

Front 50

Obtaining single enantiomer of a drug

Back 50

-sysnthesis of a racemic mixture (equimolar mixture of 2 enantiomers)

-followed by separation unsing chiral chromotography or a synthetic reaction may be used that selectively produces one of the enantiomers of the product -stereoselective (asymmetric) synthesis - involves chiral auxiliary (one enantiomer of an optically active substance that is temporarily incorporated into a non-chiral molecule to produce a single enantiomer of a product in an organic synthesis reaction.

Front 51

Taxol

Back 51

-use of chiral auxiliaries in the semi-synthesis (from a natural precursor)

-for the treatment of cancer

-intravenously as a part of chemotherapy

-prevents cell division by binding to microtubules in the cytoplasm, preventing them from breaking down during cell division.

-originally obrained from Pacific yew tree-> killing trees (1 tree per one patient)-> semi-synthethic processes were developed to obtain the drug from another source from the needles of yew trees. Also made by fermentation using plant cell cultures.

Front 52

Polarimeter for distinguishing enantiomers

Back 52

-enantiomers rotate plane-polarised light in opposite directions.

-an enantiomer that rotates plane-polarised light clockwise (dextrarorotatory) is called + enantiomer

-rotates the plave anticlockwise- levototatory- is called - enantiomer.

-X-Ray crystallography can be used to determine the absolute configuration (arrangements of the groups around chiral centre) -> rotation is worked out (alpha).

Front 53

radioactive decay

Back 53

involves changes in the nucleus of an atom resulting in particles and sometimes electromagnetic radiation being emitted from the nucleus: two main particles are alpha (helium nuclei - two protons and two neutrons) and beta particles ( electrons formed when a neutron turns into a proton and an electron). +the emission of gamma rays

alpha decay: 226 88 Ra-> 222 86 Rn + 4 2 alpha

beta decay: 12 5 B -> 12 6 C + 0 -1 e

Front 54

Half life

Back 54

the time it takes for the number of radioactive nuclei present in a sample at any given time to fall to half of its value.

-may also be expressed as the number of nuclei that decay per second -> the half life is then the time taken for the activity to drop to half its original value.

Front 55

Rate of radioactive decay per second

Back 55

-radioactive decay is a first order process => rate of decay is proportional to the number of undecayed nuclei remaining. -> in terms of (A) activity (the number of nuclei which decay per second) -> A=decay constant * N (where N is the number of undecayed nuclei present). in Bq

Front 56

Integration of the rate equation for radioactive decay and relation of decay constant to a half-life

Back 56

-> N=N0e^-decay constant*time (where N0 is the initial number of undecayed nuclei present and N is the number of undecayed nuclei present at the time t.)

-> relation: decay constant= ln2/t1/2

Front 57

Radioactivity in medicine

Back 57

-> Alpha, beta, gamma, proton,neutron and positron emissions are used in nuclear medicine.

-> Radiotherapy - treatment using radiation (radioisotopes used - alpha, gamma, beta - ionising radiation)

-> Proton-beam therapy (using protons from article accelerator) also used for some cancers.

-> Neuron therapy (a beam of protons from a particle accelerator strikes a beryllium target to produce a bean of neutrons) - effective against tumours.

-> Positron emitters - commonly used in the diagnosis of cancer but there has been an interest in using it in a therapy as well.

Front 58

Two types of radiotherapy and its side effects

Back 58

-External source (targeting radiation from a machine that generates a beam of radiation onto a specific area - gamma rays, protonsm electorn and x rays) and Internal (brachytherapy or radioisotope therapy)

-Side effects:

hair loss (temporary)

Nausea

Fatigue

Sterility

Front 59

Radioisotopes used in nuclear medicine

Back 59

-Teachnetium is the most common (radioactive tracer in medical imaging to diagnose illness); emits gamma rays that pass out through the body and captured by gamma camera. It is good because it is very close to being a pure emiter of gamma rays, it has a short half life of 6h, has a reasonably extensive chemistry so radioactive atoms can be incorporated into compounds that are soluble and can be transported round the body.

-Targeted Alpha therapy (alpha particles are relatively large and highly chatged and cause a great deal of damage to cells in a very small area. Not penetrating so cannot be used as an external source of radioactivity).

-Boron-neutron-capture therapy (for neck and head cancers: 10 5B + 1 0n -> 11 5B* -> 7 3Li + 4 2He

Front 60

Magnetic resonance imaging

Back 60

-involves the use of nuclear magnetic resonance (NMR) to produce three dimensional images of the internal organs. Although called nuclear, it does not involve any changes to the nucleus of atoms but involves the change in orientation of a spinning nucleus relative to an external magnetic field. (e.g. MRI body scanner - safe non-invasive techniue)

Front 61

Extraction of drugs

Back 61

1. Adding the reaction mixture to ice-water. (if the product is solid/insoluble, it might precipitate at this stage and can be removed from the reaction mixture by filtration). If it does not precipitate (e.g. ethyl ethanoate).- extracted from the aqueous mixture by solvent extraction - after shaking there will be a mixture of 2 layers, an organic one and an aqueous one.

The samples of organic solution are then combined and a drying agent (ahydrous Magnesium sulfate) added to remove any water. The drying agent is filtered off and the org solvent removed by rotary evaporator (takes the solvent under reduced pressure)

Front 62

Solubility factors

Back 62

-molecules tend to dissolve in solvent with similar intermolecular forces - polar in polar solvents; non-polar in in non-polar, organic solvents are generally insoluble in water.

-the ability to form hydrogen bods often makes substances more soluble in water.

-substances containing ions tend to be more soluble in water because of the formation of ion-dipole interactions.

Front 63

Methods of purification

Back 63

-Recrystallisation, distallation/fractional distallation and chtomatography.