Drug Action and Design ib chemistry Option D: Drugs and Medicines

Drug Action and Design IB Chemistry Option D: Drugs and Medicines

Drug Action

• The effectiveness of a drug is often related to the chemical structure and polarity of the substance.

• Factors that affect how a drug reacts include:

• Chirality
• Geometrical isomerism
• Ring strain
• Polarity

Chirality Affects Drug Behavior

• The presence of an asymmetric or chiral carbon atom in a molecule results in two different optical isomers or enantiomers.

• Two different enantiomers can behave in very different ways in the body.

• The most famous example of this difference was found in with thalidomide.

Thalidomide has two optical isomers, one of which is a tranquilizer while the other is a powerful teratogen.

• Thalidomide has two optical isomers, one of which is a tranquilizer while the other is a powerful teratogen.

• Originally used to treat morning sickness during pregnancy.

• Now Used to treat some symptoms of Hansen’s disease (Leprosy).

Treatment of Erythema nodosum leprosum (ENL), a painful inflammatory dermatologic reaction of leprosy with thalidomide.

• Treatment of Erythema nodosum leprosum (ENL), a painful inflammatory dermatologic reaction of leprosy with thalidomide.

Geometric Isomers Differ in Behavior

• Geometric isomerism occurs in both organic and inorganic compounds.

• Diaminechloroplatnium (II) is an inorganic complex that as been used to treat certain types of ovarian and testicular cancers.

• Diaminechloroplatnium (II) exists in both cis and trans isomers.

Cis and Transplatin

• The structures of the cis and trans forms are shown below:

Cisplatin as an Anti-cancer Drug

• Cisplatin can diffuse through a cancer cell membrane.

• In the cell it exchanges a chloride ion for a water molecule forming a complex ion.

• This complex ion binds to the cancer cell DNA preventing it from replicating correctly.

Ring Strain

• The action of beta lactams in antibacterial drugs such as the penicillins is an example of the effect of ring strain as a drug mechanism.

• The general structure of penicillin

Ring Strain and Drug Activity

• The amide group in the ring is more reactive due to the strained ring.

• The structure of the beta lactam is similar to the structures of cysteine and valine.

• The beta lactam binds to the enzyme that synthesizes the cell wall in bacteria blocking its action.

• As a result the bacteria rupture and break and cannot reproduce.

Polarity and Drug Behavior

• The difference in polarity between molecules affects their behavior in the body.

• The polarity of a molecule affects:

• its ability to dissolve in lipids,
• its ability to pass through the lipid membranes
• the degree to which it may bind to an active site on an enzyme or protein.

Polarity: Morphine and Heroin

• Heroin is much more potent than morphine (and more addictive).

• The –OH groups on morphine are more polar than the ethanoate ester groups on heroin.

• Heroin is more lipid soluble in lipids.

• It can more readily penetrate the blood-brain barrier and it is absorbed in higher concentrations in the brain.

Drug Design

• Part 2

Combinatorial Chemistry

• Drug companies have developed libraries of compounds which have been screened for drug activity.

• With a given core molecule or pharmacore, and a large number of substituents, researchers use computers to enumerate a large number of structural possibilities.

• This virtual library may consist of thousands, or even millions of 'virtual' compounds.

• Researchers select a subset of the 'virtual library' for actual synthesis, based upon various calculations and criteria.

Combinatorial Chemistry

• An example of a pharmacore and a reactant system.

• By examining multiple possibilities pharmaceutical chemists can evaluate the medical efficacy of various molecules for medicinal value.

Combinatorial Chemistry

• The process was originally developed for polypeptide synthesis with amino acids.

• The starting material or pharmacore is covalently bonded to small polystyrene resin beads.

• The beads are reacted with various groups in successive steps.

• The beads are separated from the reaction mixture and then undergo preliminary screening for drug activity.

• This is usually done by measuring how the substance affects enzymes or how it may bind to receptor cells.

Combinatorial Chemistry

• A combinatorial scheme for amino acids

Parallel Synthesis

• Alternative to combinatorial approach,

• Solid state organic.

• Preparation of a highly reactive intermediate.

• Preparation of individual compounds simultaneously with various reagents in separate microcells without mixing intermediates during synthesis.

Drug Polarity Modifications

• Many compounds that are of pharmacological importance are large complex organic molecules that are not very polar

• They are largely insoluble in water. Their ionic salts, either as sodium salts or hydrochloride salts are used to make them more soluble.

Chiral Auxillaries

• Traditional synthesis of optically active compounds results in a racemic mixture with equal amounts of each enantiomer.

• Only one of the enantiomers has pharmacological value. (i.e. thalidomide).

• Separating enantiomers from racemic mixtures is often difficult and complicated.

• The use of chiral auxilliaries makes it possible to synthesize only one of the two enantiomers.

• A chiral auxilliary is a chiral molecule that is attached to the starting material during a synthesis that creates the appropriate stereo-chemical environment so that only one enantiomer is produced.

Synthesis with Chiral Auxilliaries

• A chiral auxiliary is a molecule that is temporarily incorporated into an organic synthesis. Its asymmetry allows the formation of a chiral intermediate followed by selective formation of one of two stereoisomers depending on the reagent and/or reaction conditions.

Taxol

• The anti-cancer drug TAXOL is found in the Pacific Yew tree, but there is not a sufficient supply to meet demand.

• Since Taxol is a very chiral molecule, one possibility is to make it synthetically.

• The potential synthesis is very complicated and would require using several chiral auxilliaries.