O PTION D M EDICINES & D RUGS - HL D RUG A CTION – G EOMETRIC ISOMERISM Shows itself in both organic and inorganic compounds. Example: diamminedichloroplatinum(II) exists in both cis-and trans- forms due to its square planar shape Cisplatin is used to treat testicular and ovarian cancers in addition to other forms of cancer. Transplatin is an ineffective cancer treatment.

D RUG A CTION – G EOMETRIC ISOMERISM Cisplatin diffuses through the cancer cell membrane Once inside the cell it exchanges a chloride ion for a molecule of water to form [Pt(NH 3 ) 2 Cl(H 2 O)] +. This complex ion enters the cell nucleus, where it binds to the guanine of the DNA at two locations by exchanging another chloride ion to form [Pt(NH 3 ) 2 (DNA)] 2+. This alters the cancer cell’s DNA so that when the cell tries to replicate it cannot be copied correctly and the cell dies.

D RUG A CTION - C HIRALITY Asymmetric or chiral carbon atoms form two different optically active forms of a drug. Because of the stereochemistry, they can behave in very different ways in the body. In many cases one form gives the desired effect whereas the 2 nd form has negative side effects as in thalidomide. Many new drugs today are synthesized based on pharmacological activity of both forms. Chiral carbon

D RUG A CTION - P OLARITY Substances that are more polar tend to have a greater effect in the body. The nonpolar substances can move through the lipid bi-layer of the cell membrane more easily. For example, heroin is much more potent & produces a much greater high / euphoria than morphine. Morphine has two polar –OH groups, making it polar. In heroin, the hydroxyl groups are replaced by less polar ethanoate groups which allows it to rapidly penetrate the lipid- based blood-brain barrier. Ester group

D RUG A CTION – R ING S TRAIN Beta-lactam ring – a four part ring that contains 2 carbon atoms that are sp 3 hybridized (4 total bonds), a carbon atom that is sp 2 hybridized (3 total bonds) and a nitrogen atom that is sp 3 hybridized (3 bonds & one lone pair of electrons).

D RUG A CTION – R ING S TRAIN Normal bond angles would be 109.5° and 120 °, but because the ring has only four sections, the angles are much tighter which causes the amide group in it, to be highly reactive since the bond will easily break due to strained angles.

D RUG A CTION – R ING S TRAIN In penicillin, the beta-lactum ring is similar to a combination of the two amino acids, cysteine and valine. When the ring breaks open, the penicillin mimics the amino acids and covalently bonds to the enzyme that synthesizes the cell walls of the bacterium, therefore blocking its action and preventing the production of bacterial cell walls.

D RUG D ESIGN I – C OMBINATORIAL C HEMISTRY AND P ARALLEL S YNTHESIS In the past many drugs were synthesized, purified and screened by traditional methods that tended to be slow and tedious. With today’s technology, detection by mass spectrometers can lead to combinatorial libraries. Small amounts of substance can be combined into a large number of related compounds which can be prepared quickly using computer controlled syringes that carry out repetitive chemical techniques with very little error. Much of the research today is solid phase organic chemistry.

Essentially, the process involves taking a small number of starting compounds and reacting these with a larger number of reagents. For example, with 20 starting compounds and 50 reagents, 1000 products can be generated. These products can be reacted with a further collection of 50 reagents. The result would be second generation products, all based on the 20 starting compounds which would be known as 'skeletons'.

There are two major approaches in combinatorial chemistry. The ‘mix (pool) and split method' involves attaching the starting compounds to polymer beads. The second method is called 'parallel synthesis'. All the different chemical structure combinations are prepared separately, in parallel, using thousands of reaction vessels and a robot programmed to add the appropriate reagents to each one. In the mix and split method the starting material is covalently bonded to very small beads of polystyrene- based resin. Using just 3 amino acids, after joining to the beads, they are mixed/reacted and split to look at the 9 possible dipeptides that are formed. These are then mixed and split to study the 27 possible tripeptides that could be formed.

If all 20 commonly occurring amino acids are used, each cycle would produce 400 dipeptides, 8,000 tripepties, and 160,000 tetrapeptides, etc. The resin beads can be filtered and washed off of the final products. The screening for drug activity can then take place in vitro or in vivo by measuring the ability of a compound to affect enzymes and bind to receptor cells. Once a drug is identified as potentially useful, it can be made on a larger scale. In the future virtual libraries may be created based on the shape of both the active site on the enzyme or receptor and the shape of the active groups in the potential drug.

Parallel synthesis is carried in reaction vessels on a much larger scale using robotics to mix reactants. Sets of individual compounds are prepared simultaneously by reacting with a number of different reagents without interchange of intermediates during the assemble process. This gives a more focused library that doesn’t have to undergo laborious identification techniques.

D RUG D ESIGN II M ODIFYING THE POLARITY Many drugs are of low polarity therefore they tend to be insoluble in water and other polar environments of the body. To increase their solubility, they can be converted into an ionic salt which is more easily transported around the body. Amine compounds can be converted into their hydrochloride salt. On a very simple scale it is the reaction between ammonia and hydrochloric acid. NH 3 + HCl  NH 4 + Cl -

P ROZAC – FLUOXETINE HYDROCHLORIDE A selective serotonin re-uptake inhibitor which is prescribed for people suffering with depression. A common over-the-counter drug is Allegra, fexofenadine hydrochloride, C 32 H 39 NO 4. HCl, that is an ionic salt. To make the white crystalline form of heroin, diamorphine, soluble so that it can be injected, the amine group is converted to a hydrochloride salt.

D RUGS WITH CARBOXYLIC ACID GROUPS These may be made polar by converting them into their anion and administering them as a sodium or calcium salt. RCOOH + NaOH  RCOO - Na + + H 2 O This is the method used for aspirin, it is a sodium salt. Once it reaches the acid of the stomach, it is converted back to its nonionic form.

U SE OF C HIRAL A UXILLIARIES The production of any chiral compound normally produces a racemic mixture (50:50 mixture) of the two enantiomers. This can be separated by using chromatography with another optically active compound. A newer, better technique is to use chiral auxilliaries which allows synthesis of only one of the two optically active isomers. Attaching another optically active substance creates the stereo chemical conditions so that the one isomer is created. Afterwards the auxilliary is removed and recycled.

T AXOL IS A NATURALLY OCCURING SUBSTANCE USED TO TREAT CANCER, BUT TO MEET DEMANDS, IT MUST BE PRODUCED IN A SEMI - SYNTHETIC PROCESS.

M IND - ALTERING DRUGS – THE INDOLE RING STRUCTURE The hallucinogenic drugs LSD, psilocybin and psilocin (mushrooms) are amines that contain the indole ring structure. Mescaline is another hallucinogenic drug that is an amine, but its 5 member nitrogen ring is not closed.

LSD – L YSERGIC A CID DIETHYLAMIDE Drug that is derived from a wheat fungus, ergot mg will produce a noticeable effect in most people and lasts about 12 hours Short term effects: restlessness, dizziness, desire to laugh and distortions in sound a visual perceptions. In extreme cases unpleasant hallucinations lead to feelings of despair and suicidal thoughts or attempts. At times users think they can fly. Driving is also extremely dangerous.

LSD – L YSERGIC A CID DIETHYLAMIDE Long term effects: severe depression and the return of hallucinations (flashbacks) months or even years following use of LSD. It does not seem to be physically addictive but is may cause psychological dependence. Action: it is thought that it blocks the action of serotonin, one of the compounds responsible for transmitting impulses across synapses in the brain. Indole ring structure

P SILOCYBIN AND PSILOCIN These two compounds are found in the liberty cap muschroom, Psilocybe semilanceata, the ‘magic mushroom’. They are a mild hallucinogen with slight alterations in perceptions and it causes feelings of exhilaration and insight. Tolerance will develop, but it is not thought to be addictive. The main danger is mistaking it for similar-looking toxic/poisonous mushrooms.

M ESCALINE – ONE OF THE OLDEST HALLUCINOGENS Derived from the peyote cactus which is found in Central and South America. Spanish explorers described it & Mexican Indian behavior from it as long ago as It alters visual and auditory perceptions for 2-3 days as well as reducing the appetite In people that are already depressed or anxious, it may cause some unpleasant mental effects. Nausea and trembling are often associated with other components of the plant. Alcohol will enhance its effects. It also seems to cause liver damage. An open indole ring

M ARIJUANA - C ANNABIS A mild hallucinogen made from th tops, stems, leaves, and seeds of the hemp plant, Cannabis sativa. Hashish (hash), is made from the resin of the plant and it is about 5x stronger than marijuana. The active ingredient in marijuana is tetrahydrocannabinol (THC).

M ARIJUANA - C ANNABIS Short term effects – feeling of relaxation and enhanced auditory and visual perception as well as a loss of the sense of time, confusion and emotional distress. Hallucinations are actually rare. It can also have synergistic effects and increase the risk of sedation with depressants such as alcohol. Long term effects – apathy and lethargy as well as a reduction in fertility together with any risk from tobacco use.

S HOULD M ARIJUANA BE LEGALIZED ? P ROS Medicinal use – prevents vomiting (anti-emetic) Pain killer in cancer chemotherapy and AIDS Treatment for glaucoma, epilepsy, Parkinson’s disease and Huntington’s chorea. Lowers Crime Rate – police are able to concentrate on ‘real’ criminal activity Freedom of the individual.

S HOULD M ARIJUANA BE LEGALIZED ?C ONS Cost to society due to increased risk of heart disease and cancer through smoking. Cannabis can lead to use of harder drugs. Risk of driving under the influence.