Option DD.8 drug action

Some aspects of molecular structure that affect the action of

a drug • stereo isomerism

o geometric (cis/trans)o optical isomerism (enantiomers)

• strain in ring structure• molecular polarity (solubility and uptake)

Example: Geometric isomerism in diaminedichloro platinum (II) complex ion used in a drug

cisplatin• can act as an anti-cancer

drug because of its orientation, it can bond with DNA in the nucleus of cancer cells and cause the cell to die.

transplatin• cannot act as an antic-cancer

drug as nitrogen atoms are too far apart to react with DNA – no pharmaceutical effect – actually toxic to body

Inorganic transition complex

with a square planar shape, 900 bond angles and dative covalent bonds

Optical isomerism• Synthesis of chiral drug molecules in laboratories produces

racemic mixtures i.e. equimolar solution of both enantiomers.• These are known as “in vitro” drugs.• Such drugs were often prescribed as racemic mixtures or

racemates.• Each enantiomer also has different biological activity as they

behave differently with other chiral molecules in the body.• Pharmaceutical companies must analyze effects of each

isomer, and determine if it should be marketed as a racemate or if they need to then produce the single enantiomer.

• Some enantiomers are harmful to humans.

Optical isomerism(2/3 of drugs on the market are chiral!)

Carbon atoms in ring structures (in which there is no delocalization to have 4 different atoms) can also be chiral if the part of the ring on one side of the carbon atom is different from the part of the ring on the other side of the carbon atom.

Each side of a ring is classified as a different group if, when moving around the ring from the chiral centre or carbon, the order of atoms is different each way. It is said the chiral atom has two different views around the ring.

thalidomide

Identify the chiral carbon in the structure below

• One enantiomer (R) alleviates morning sickness in pregnant women and induced sleep and calmness

• Other enantiomer (S) is a teratogenic - causes deformities in the fetus

• Later discovered that administering just the R enantiomer was no good either. It is able to turn into S inside the body.

thalidomide

Identify the chiral carbon in the structure below This carbon has the N-ring, two

different sides of the benzene structure, and a H (not shown)

How many chiral centres in fluoxetine?

More examples of chiral drugs• Ibuprofen: one enantiomer is more effective than the

other – identify the chiral centre in your data booklet (in vitro)

• DOPA: this is a drug which is used in the treatment of Parkinson disease; one isomer is effective whilst the other isomer has no physiological effect

• Fluoxetine (Prozac) – used to treat depression (in vitro)• Morphine/codeine/heroin: there are 5 chiral centres in

each of these molecules; only one enantiomer is analgesic. (in vivo – only one enantiomer b/c harvested naturally)

beta-lactam ring in penicillin

a four-membered square ring structure which contains an amide group

(-CONH-) and consists of one nitrogen atom and three carbon atoms (and two hydrogen atoms).

beta-lactam ring

• For each carbon and the nitrogen atom, identify the type of hybridization and preferred bond angles around each atom.

• Referring to bond angles say why the ring is a strained structure

What causes the strain?

• As a result of the sp3 hybridisation of two of the three carbon atoms and the single nitrogen atom and the sp2 hybridisation of the third carbon atom, the preferred bond angles are 109 and 120.

• However, the bond angles in the beta-lactam ring are reduced to only 90° and this puts the beta-lactam ring structure under strain weakening the bonds.

beta-lactam ring• Strains makes ring reactive.• Ring easily breaks open in the amide group,(in

the presence of an enzyme such as transpeptidase) to form covalent bonds with the transpeptidase.

• This deactivates the transpeptidase that synthesizes the bacterial cell walls, thus inhibiting the growth of bacterial cell walls.

• As a result water enters the bacteria cell causing it to burst due to increased osmotic pressure.

(between the N and the sp2 C)

beta-lactam ring

Sad

Happy

Drug Structure and Solubility

• Drugs need to efficiently reach target receptors in the body.

• Body is water soluble environment so water soluble drugs are good and can reach blood stream.

• If CNS is the target, drug needs to reach brain.– Brain is surrounded by a “blood-brain” barrier

which protects it from restricting what can enter from the blood. It is hydrophobic, and non-polar so polar molecules cannot easily cross.

Why is Heroin more potent than morphine?

morphine• Two hydroxyl groups

heroin• Both hydroxyl groups

replaced by ester groups

Heroin more potent than morphine

• Diamorphine is less polar than morphine as it does not have the polar hydroxyl groups anymore but two less polar ester groups.

• Diamorphine (heroin) cannot form any hydrogen bonds and is therefore less soluble in polar substances such as water but more soluble in non-polar fatty tissue, which makes up the central nervous system.

• Heroin can therefore cross the blood-brain barrier faster/more easily than morphine.