Option Unit D - Medicinal Chemistry

Drug vs Medicine

Drug: A chemical that affects the body in a good or bad way
Medicine: a substance that improves health, known as a therapeutic effect

Effect of Pharmaceutical Products on the target molecule

Can stop the target molecule from functioning or stimulate it.

Stages of Drug Development

Discovery Research, development research, regulatory review, post marketing monotoring

Stage 1: Discovery Research

1. Identification of lead compounds (usually from plants)

2. Optimization (analogues tested through combinatory chemistry or high-throughput screening)

   analogues: chemically related compounds

3. Initial Testing of the potential medicine (determines human dosage)

Stage 2: Development research

3 clinical trials on humans. Each phase increases the # of patients

Stage 3+4: regulatory review and post-marketing monitoring

application for marketing of the product, collection of any adverse drug reactions

Drug Doses

LD50, TD50, ED50

LD50

Lethal Dose
Dose of drug required to kill 50% of the laboratory animals tests (mass/kg)

TD50

Toxic Dose
Dose required to produce a toxic effect on 50% of the tested human population

ED50

Effective Dose
Minimum dose required to produce a therapeutic effect in 50% of the population

Therapeutic Index

TI = LD50/ED50 or TI = TD50/ED50
The greater the TI, the safer the drug

Therapeutic Window

Range of dosage between the minimum required to cause a therapeutic effect and the level that produces toxic effects

Drug Administration

Depends on:
chemical nature of drug, condition of patient, bioavailability

Methods of administrating drugs

oral, inhalation, skin patches, suppositories (rectal), ear/eye drops, paranetal (injection)

Intramuscular (deepest), intravenous, subcutaneous (needles)

Bioavailability

The fraction of the administered dosage that is absorbed into the bloodstream and reaches the target sit

Intravenous injection = 100% bioavailability

Depends on: solubility, polarity, presence of functional groups

Analgesics

Drugs that relieve pain

Mild: aspirin, ibuprofen

Strong: morphine, heroin, codeine

how are pain receptors stimulated

Stimulated by prostaglandins, which are released from cells damaged by thermal, mechanical or chemical energy

Prostaglandins

Mediate the inflammatory response, causing dilation of blood vessels near the site of the injury and may result in fever

Produce thromboxanes, which stimulate the clustering of platelets and blood clots

Mild Analgesics (non-narcotics)

Act by preventing stimulation of the nerve endings at the site of pain

Inhibit the release of prostaglandins at the site of injury by inhibiting an enzyme (cox)

Key enzyme in the synthesis of prostaglandins

COX (cyclooxygenase)

Mild Analgesics: Salicylic Acid

relatively strong acid, unpleasant to take orally and damages the membrane lining of the mouth, esophagus and stomach

sodium salicylate also used, but same side effect

Ester of Salicylic Acid (Acetyl Salicylic Acid → Aspirin)

Pro: reduces fever and pain, reduces risk of colon cancer, prevents the formation of thromboxanes (clusters of platelets), anticoagulant (reduces risk of stroke/heart attack)

Con: causes irritation/bleeding in stomach/duodenum, Reye’s syndrome (kids under 12 → liver/brain damage), allergies, acidosis (decreased pH of blood)

Synergism

when 2+ drugs, given at the same time, have an effect on the body that is greater than the sum of their individual effects
ex: alcohol + aspirin: increased risk of bleeding in the stomach

Purification of Aspirin

Crude sample of aspirin contains impurities and must be purified using recrystallization with hot ethanol

How Aspirin is purified

• solubility of a compound in a solvent increases with temperature

• as the solution cools, crystal forms

• molecules in a crystal have a greater affinity for molecules of the same kind

Determination of purity (aspirin)

By chromatography or by measuring the melting point

• pure substances has a well defined melting point

• impurities lower the melting point (138-140 ºC) and increases the range

IR spectrum: 2 peaks in the C=O region, very broad O-H stretch

Solubility of Aspirin

Insoluble, meaning limited bioavailability

The carbox. acid group can be made into an ionic salt by reacting it with NaOH

Penicillin

Bicyclic structure, contains a beta-lactam ring

Penicillin G (Benzylpenicillin)

First one to be isolated and purified, but its is easily broken down in the stomach and must be injected

Modern/Semi-synthetic penicillin (ampicillin)

Side chain has been modified to alter its properties

Pro: reduces occurrence of penicillin resistant bacteria, resistant to breakdowns from stomach acid

Action on bacteria cell walls (penicillin)

Deactivates the transpeptidase enzyme, prevents formation of cross links in the cell wall.

• Beta-lactam ring opens, covalent bonds form between the enzymes active site and penicillin leading to deactivation.

Bacteria will absorb water and burst

Bacterial Resistance

Resistant bacteria produces penicillinase, an enzyme which breaks open the Beta-lactam ring in the penicillin molecule

• resistance arises from mutations in the bacterial DNA

The more bacteria are exposed to antibacterials, the more opportunities for the bacteria to mutate

Strong Analgesics (opiates)

temporarily binds to the opioid receptors in the brain, which then blocks the transmission of the pain signals and alters the perception of pain without depressing the nervous system

Narcotics

act on the brain and can cause drowsiness and changes in behaviour and mood

Opium

• extract from poppy seeds

• contains naturally occurring nitrogen containing compounds (alkaloids)

Narcotics derived from opiates

codeine < morphine < heroine

Codeine: 0.5% of raw opium

Morphine: 10% of raw opium

Heroine: synthesized from morphine

Blood-Brain barrier

a series of lipophilic cell membranes that coat the blood vessels in the brain and prevent polar molecules from entering the CNS

• the psychological activity of opiates depends on their ability to cross the barrier

Opiates and the blood-brain barrier

heroine: 2 ester groups, less polar, H-bonds

Morphine: 2 hydroxyl groups

Codeine readily crosses the barrier but is metabolized slowly (does not bind to the opioid receptor because of the steric effect of the ester group)

pH of the stomach

pH of 1-2, generated by hydrochloric acid from the gastric glands. produced by parietal cells in the lining of the stomach

acid environment needed to:

• kill bacteria

• provide the optimum pH environment for digestive enzymes to act

Excess acid production in the stomach

can be caused by excess alcohol consumption, smoking stress, and anti-inflammatory drugs

leads to the following issues:

• acid indigestion

• heartburn (acid reflux)

• ulcer

Antacids

neutralize the excess hydrochloric acid

• common bases: Mg/Al hydroxide, Ca/Na carbonate, Na bicarbonate

• not Na/K hydroxide since they are strong alkalis and corrode body tissue

Alginates

Some antacides contain alginates. They float to the top of the stomach and form a “raft”. Acts as a barrier and prevents reflux into the oesophagus.

Anti-foaming agents

Antacids with carbonates. ex: dimethicone

Reduce bloating

Treatment of peptic ulcers

treated by regulating the acid levels

2 main approaches: stopping the production of acid, preventing the release of the acid into the stomach

Ranitidine (Zantac)

inhibits the production of the acid, short term relief

binds to the receptor protein (histamine H2-receptor) in the membrane of the parietal cells.

stops histamine from binding to turn on the the production of acid

Omeprazole (losec, prilosec) and esomeprazole (nexium)

proton pump inhibitors - prevent the release of acid, long term

non polar (lipid soluble), so they can cross the cell membrane of parietal cells

become protonated inside the cell due to the acidic environment

• binds irreversible to the proton pump

• effective until the cell produces new proton pumps

Active Metabolites

active form of drugs after they have been processed in the body

ex:

• codeine converts to morphine in the body, which binds more strongly

• omeprazole/esomeprazole: converted to different forms that bind to proton pumps

• aspirin: converted into the active form (salicylic acid)

Why is treatment and prevention for antiviral medications difficult

• viruses multiply quickly, they spread throughout the body before symptoms appear

• can multiply their DNA/RNA (provides drug resistance)

• hard to target only the virus without affecting the host

Antiviral drugs work in a number of ways

• alter the genetic material within cells

• inhibit the activity of enzymes within the host cell

• prevent binding of the virus to the host cell surface by binding to the cell receptor or capsid protein

• prevent the virus from leaving host cell (oseltamivir & zanamivir)

• inhibits the uncoating/injection of the virus into the cell

Neuraminidase

enzyme that breaks down the membrane of host cells, allowing the virus access to target cells “budding”

Influenza

antiviral drugs are neuraminidase inhibitors

nuclear waste

byproduct of the use of radioisotopes in medicine

low level nuclear waste

• low activity, contains isotopes with short half lives

• includes items that have been contaminated with radioactive material or have been exposed to radioactivity

Disposal strategies of low level nuclear waste

may be stored on site until it has decayed enough to dispose ordinarily, may be incinerated, can be buried underground

High level nuclear waste

• high activity, contains isotopes with longer half lives

• includes spent fuel rods and other material from nuclear reactions

• remains hazardous to humans and other living things for thousands of years

disposal of high level nuclear waste

can be converted to glass (vitrification), kept in storage pools underwater then moved to dry storage casks inside concrete bunkers, long term storage is problematic

release of antibiotics into the environment

can enter the water supply by several routes:

• incorrect disposal of unwanted medicines

• agriculture

problematic:

• causes damage to aquatic organisms

• results in increased resistance of bacteria to antibiotics

Green Chemistry

seeks to minimize the production of hazardous substances and their release in the environmet

Best synthetic routes to a drug

• use readily available and safe materials

• have the minimum number of steps

• convert as much of the starting materials as possible into the required product at each step

• use as little solvents and energy possible

Atom economy

measures how efficient a particular reaction is

molar mass of desired product / total molar mass of all reactants

Synthesis of oseltamivir

uses a naturally occurring material - shikimic acid - as a starting material

• extracted from star anise, glucose by fermentation using GMO’d bacteria

Waste Solvents

used as a medium for reactions or in the extraction/purification of compounds

• many are non-polar, organic, but toxic

chirality in drugs

enantiomers can behave differently in the body as a result of their different shaped

ex: enantiomer of thalidomide caused birth defects

Obtaining a single enantiomer in drug synthesis DELETE

1. synthesis of a racemic mixture followed by separation using chiral chromatography

2. stereoselective (asymmetric synthesis) - a synthesis reaction is used selectively to produce one of the enantiomers

Chiral auxilary

one enantiomer of an optically active substance that is temporarily incorporates into a non-chiral molecule to produce a single enantiomer of a product in an organic synthesis reaction

identify/purity found with a polarimeter

Taxol (paclitaxel)

used to treat several forms of cancer

usually given intravenously, acts by preventing cell division

• binds to microtubules in the cytoplasm, preventing them from breaking down during cell division

Semi-synthesis of taxol (chiral auxiliary)

• originally obtained from pacific yew tree bark

• takes bark from more than one tree to provide enough to treat one patient

• semi-synthetic process was developed

  • uses the needles

nuclear reactions

involves changes of the nuclei of atoms

• results in particles and sometimes also electromagnetic radiation being emitted from the nucleus (alpha and beta)

After a drug has been synthesized, 2 steps occur:

1. extraction of the drug from the reaction mixture

2. purification of the drug

extraction of the drug from the reaction mixture

• solvent extraction using a separatory funnel (drugs will seperate into the non-polar organic bilayer)

• high density is at the bottom, low density is at the top

• several rounds done to increase yield

after drug extraction:

• a drying agent is added to remove residual water

• drying agent is then filtered off and the organic solvent is removed using a rotary evaporator

purification of the drug

recrystallization, distillation, or chromatography

purification via chromatography

fractional distillation

• separates liquids that have similar boiling points

• the liquid with the lower boiling point is collected by condensing the vapour

Raoult’s Law

the partial vapour pressure of any volatile component of an ideal solution is equal to the vapour pressure of the pure liquid manipulated by the mole fraction that liquid in the solution

Vapour pressure

Pressure exerted by a vapor when the rate of condensation = the rate of evaporation

for a pure liquid, the vp depends on:

• the nature of the liquid

• the temperature

for a mixture, the vp depends on how much of each liquid is present

BP of a liquid (raoult’s law)

the more volatile (how fast something evaporates), the higher the vapour pressure, the lower the boiling point

How is the lead compound/new chemical entity found

Drug Discovery: isolated from natural products with known therapeutic effects or synthesized in the laboratory and screened against cell cultures, bacteria or animals. Slow, expensive, and inefficient. Often Fails.

Drug Design: Relies on knowledge about drug receptor interactions. If the chemical composition is known a small molecule with a complementary structure can be designed.

How do drugs interact with receptors and enzymes

the structures of drugs are complementary to the structures of active (or allosteric) sites of enzymes or receptors

Drawbacks of natural medicines

low efficiency, variable composition, instability, side effects caused by the presence of many bioactive substances in the same material

Beta-Lactam Ring

four-membraned, responsible for the antibacterial properties of drugs

Bond angles of the C and N are 90º, creates a significant ring strain and make the amide group very reactive

Analgesic Effect

pain reducing

Antipyretic Effect

Fever reducing

Why is codeine most widely used

10 times less potent than morphine, low activity, wide therapeutic window, limited potential for abuse

Diamorphine (AKA Heroin, AKA semi-synthetic morphine)

Both OH groups are substituted with ester groups → reduces polarity, can easily cross blood-brain barrier, easily metabolizes, 5 times more potent than morphine

Side Effects of antacids

Aluminum Hydroxide: reduces the concentration of phosphates in bodily fluids

Carbonates/Hydrogencarbonates: produce CO2, causes bloating and belching

Calcium/Magnesium/Sodium: affects electrolyte balance → diarrhea, kidney stones, hearth failure

Oseltamivir/Zanamivir

prevent the release of virus copies from the cell by inhibiting viral enzymes (neuraminidase). Keeps the viruses trapped within the cell and slows their spreading.

Oseltamivir: in the liver it is hydrolysed to its active metabolite – carboxylate

Docetaxel

More active than taxol, more soluble, remains in cancer cells longer, reduces the effective dose and leads to fewer side effect, more suitable for intravenous administration

radiopharmaceuticals

unstable isotopes + biologically active compounds

drugs that deliver radionuclides to specific tissues or cellular receptors

brachytherapy/internal radiotherapy

radiation sources are inserted into the patients body in the form of metal wires/pellets that deliver radiation directly to the site of disease

External radiotherapy

cancerous cells are destroyed by precisely directed beams of gamma rays, protons, electrons or neutrons

Cancer cells

ionizing radiation induces errors in the DNA sequence, which passes on through division, eventually limiting their ability to grow and multiply

reduced ability to repair their genetic material

Top - mass number (total protons and neutrons)

Botton - atomic number/nuclear charge (number of protons in the nucleus)

Targeted Alpha Therapy

treats leukaemia/dispersed cancers

alpha emitters are delivered by a carrier drug/protein to the cancer cells, which will be destroyed by radiation without damage to surrounding tissue

collision of alpha and beta particles produce secondary gamma radiation, which can be detected and used for mapping the distribution of cancer cells

Alpha Particles

cause most damage to cellular tissue but have low penetrating power and are absorbed within a short range of their emission (0.05-1mm)

lutetium-177

beta/gamma emitter, used for targeted radiotherapy by being incorporated into molecules that can bind to receptors on certain types of cell. Only destroys a particular type of cells within a very limited area, good for neuroendocrine cancers

emits just enough gamma rays for visualizing tumours and monitoring the treatment

Boron neutron capture therapy

uses the ability of boron-10 to absorb neutrons

tumours can be destroyed if they accumulate sufficient boron-10

can be intravenously injected (through organoboron compounds)

Proton Beam Therapy

protons produced by a particle accelerator are released towards the tumour

minimum radiation damage to healthy tissue

Gamma Radiation

multiple low intensity rays or a single ray fired multiple times from different angles

Gamma Knife

treats brain tumors

200 cobalt-60 sources mounted on a heavily shielded helmet, each source emits a narrow ray of radiation

high local effect but sparing normal brain cells from extensive damage

Computed Tomography (CT)

cross-section images generated by a computer from multiple 2D x-ray scans taken at various angles