D8.1 Describe the importance of geometricalisomerism in drug actionWhat is geometrical isomerism? (cis-trans isomerism) A form of isomerism where atoms are bonded in the same orderbut are arranged differently in spaceInorganic - usually occurs in octahedral or square planarstructuresOrganic Isomerism that occurs when there is restricted rotationaround a bond so that the position of atoms cannot change. -Double C=C bonds (but also in inorganic double bonds)
D.8.1Two important types: Cis and TransCis - same side, Trans - same side
D.8.1Whether a molecule is a cis isomer or trans isomer cancreate different pharmacological effectsConsider the isomers of diamminedichloroplatinum(ii):Cisplatin is highly effective in treating testicular and ovariancancers while transplatin is not very effective
D.8.1 -Both molecules contain no overall charge so they can diffuse through the cell membrane -Once inside, Cl- exchanged for H2O to make [Pt(NH3)2Cl(H2O)]+ so it can enter the nucleus -Inside the nucleus, only the cisisomer has the correctorientation to bind the the cancercells DNA. This alters the cells DNA, sowhen it tries to replicate, it cantbe copied correctly and dies
D.8.2 Discuss the importance of chirality in drug action. Optical isomers are the mirror image of one another, so that their structures cannot be superimposed (in other words, if it is asymmetric) These are called chiral molecules, and their different structures are called enantiomers The term ‘chiral’ is derived from the Greek word for ‘handedness’ – ie. right-handedness or left-handedness. Your hands are chiral: your right hand is a mirror image of your left hand, but if you place one hand on top of the other, both palms down, you see that they are not superimposable.
D.8.2 Chiral carbon atoms in molecules form two optically active isomers. Because of the different stereochemistry, the two enantiomers act in different ways in the body. Different isomers can also interact differently with disease organisms.
D.8.2 In synthetic drugs, both enantionmers are created, making a racemic mixture (50% of both isomers) Currently there is no effective way to separate the two enantiomers from each other within a synthetic drug because the two are identical in nearly every way
D.8.2 Therefore, many drugs produce harmful side effects EX: Thalidomide has two enantiomers 1. Alleviates morning sickness 2. Causes deformities in the limbs of fetuses Scientists now study the effects of both enantiomers when new drugs are synthesized
D.8.2 However, not all racemic mixtures have harmful effects on the body and sometimes one enantiomer will provide the desired pharmacological properties while the other will have no effect on the body EX: Amino acid, DOPA’s L-isomer is an intermediate in dopamine biosynthesis and is given to patients to help manage Parkinson’s Disease -The D-isomer has no biological effect on the body
D.8.3 Explain the importance ofthe beta-lactam ring action ofpenicillin Beta lactim rings are four membered lactim rings (basically a cyclic amide) The amide group is attached to the beta carbon relative to the carbonyl It is part of the core structure of many antibiotics, and generally work by inhibiting bacterial cell wall biosynthesis.
D.8.3 cont. They are more reactive to hydrolysis conditions than linear amides.
D.8.3 Explain the importance ofthe beta-lactam ring action ofpenicillin All penicillin contains a 4-membered beta-lactam ring containing two carbon atoms that are sp³ hybridized, a nitrogen atom that is sp³ hybridized, and a carbon atom that is sp² hybridized. Restrictions of the ring cause normal bond angles (109.5 and 120) to not occur
D.8.3 Cont. Amide group in the ring is highly reactive is a result of the ring being readily able to break due to the strained angles. When the ring opens, the penicillin becomes covalently bonded to the enzyme that synthesizes bacterial cell walls, thus blocking its action
D.8.4 Explain the increasedpotency of diamorphine (heroin)compared to morphine Heroin is more potent and produces greater feelings of euphoria Caused by the difference in the polarity of the two substances.
D.8.4 cont. Morphine contain 2 polar –OH groups When it is converted to heroin, these are replaced by ethanoate groups (less polar) Heroin, subsequently, is more soluble in lipids (non-polar) Thus, it’s able to penetrate the lipid-based blood-brain barrier and reach the brain in higher concentrations than morphine.