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 as, because of its orientation, it can bond with DNA in the nucleus of cancer cells.

transplatin• cannot act as an antic-cancer

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

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.

• 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.

• Some enantiomers are harmful to humans.

Optical isomerism

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 alleviates morning sickness in pregnant women

• other enantiomer causes deformities in the limbs of the fetus

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

the other – identify the chiral centre in your data booklet

• 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.• Morphine/codeine/heroin: there are 5 chiral

centres in each of these molecules; only one enantiomer is analgesic.

enantiomerism in heroin• Identify the chiral centres and the type of

hybridisation of the chiral carbons

How many chiral centres in fluoxetine?

Effect of chirality on development of drugs

• Each enantiomer of a chiral drug must be tested for its physiological effects.

• Modern drugs may have only one enantiomeric form instead of a racemic mixture. This is achieved by using chiral auxiliaries – see D9.

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 structure are only 90° this puts the beta-lactam ring structure under strain.

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

instance, 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.

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 non-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.