Drug Action Drug Action and Designand Design

IB Chemistry Option D: Drugs and IB Chemistry Option D: Drugs and MedicinesMedicines

Drug ActionDrug 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:1. Chirality2. Geometrical isomerism3. Ring strain4. Polarity

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Chirality Affects Drug Chirality Affects Drug BehaviorBehavior

• 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.

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Thalidomide Thalidomide

• 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).

Chiral Carbon

The high incidence of fetal deformities has led to increased diligence in approving drugs for use. When new drugs are developed nowThe pharmacological activity of each optical isomer must be studied separately. 4

Thalidomide and Leprosy Thalidomide and Leprosy

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

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Geometric Isomers Differ in Geometric Isomers Differ in BehaviorBehavior

• 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.

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Cis and TransplatinCis and Transplatin

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

Cis-platin is an effective anticancer drug, while Trans-platin is not effective at all.

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Cisplatin as an Anti-cancer DrugCisplatin 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.

The cis-platin form is just the right size to bind to the guanine bases on the DNA.

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Ring StrainRing StrainThe 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

The four member ring of the betal lactam contains a carbon that is sp2 hybridized and a nitrogen atom and 2 carbon atoms that are sp3 hybridized. The restrictions of the ring prevent the atoms from assuming the normal bond angles of 120o and 109.5o respectively.

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Ring Strain and Drug Ring Strain and Drug ActivityActivity

•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.

Note the similarities in structureto the beta lactam.

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Polarity and Drug BehaviorPolarity and Drug Behavior• The difference in polarity

between molecules affects their behavior in the body.

• The polarity of a molecule affects:

1. its ability to dissolve in lipids,

2. its ability to pass through the lipid membranes

3. the degree to which it may bind to an active site on an enzyme or protein.

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Polarity: Morphine and HeroinPolarity: 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.

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Drug DesignDrug Design

Part 2

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Combinatorial ChemistryCombinatorial 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.

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Combinatorial ChemistryCombinatorial 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.

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Combinatorial ChemistryCombinatorial 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.

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Combinatorial ChemistryCombinatorial ChemistryA combinatorial scheme for amino acids

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Parallel SynthesisParallel 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.

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Drug Polarity ModificationsDrug 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.

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Sertraline is an amine compound that is converted to a hydrochloride salt to make it more soluble.

Aspirin or acetyl salicyclic acid is converted to the sodium salt.

Chiral AuxillariesChiral 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.

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Synthesis with Chiral Synthesis with Chiral AuxilliariesAuxilliaries

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.

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TaxolTaxol

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• 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.