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Patrick: An Introduction to Medicinal Chemistry 3/e Chapter 2: The why and the wherefore – drug targets Answers 1) -D-Glucose and -D-glucose have different optical rotations since they are different structures, where one of the 5 asymmetric centres present. The anomeric carbon) has a different configuration. In solution, -D-glucose ring opens to form an open chain form where an asymmetric sp3 carbon becomes an sp2 hybridised carbonyl carbon. Recyclisation can occur in two ways, either restoring the original -D-glucose or generating -D-glucose. This continues until an equilibrium is reached when the optical rotation reaches +52.5. This corresponds to an equilibrium mixture consisting of 64% -D-glucose and 36% D-glucose. HOCH2 H HO * HO * * O * * OH OH -anomer HOCH2 HO * HO * * * OH O OH H H HOCH2 HO * HO * * O * -anomer * OH OH Methyl -D-glucose has a different structure from either -D-Glucose or -Dglucose and so it has a different optical rotation. The optical rotation remains constant in solution since the methyl group prevents the mechanism by which ring opening takes place. Therefore, an equilibrium between two different anomers is not possible. HOCH2 HO * HO * * O * OH * OMe Methyl--D-glucose 2) The ability of a molecule to cross the fatty cell membrane has little to do with its size, but more with its hydrophobic character. Estrone is more hydrophobic than adrenaline since it has a larger carbon skeleton and only two polar functional groups. Thus, the molecule is hydrophobic in character and can dissolve through the fatty cell membrane. Adrenaline has four polar functional groups and a much smaller carbon skeleton. Thus the polar functional groups dominate in determining the character of the molecule making it very polar and unlikely to pass through the cell membrane. OXFORD © Oxford University Press, 2006. All rights reserved. Higher Education Patrick: An Introduction to Medicinal Chemistry 3/e Chapter 2: The why and the wherefore – drug targets Ketone CH O Alcohol OH Phenol HO 3 NHMe Amine Phenol HO Phenol HO Adrenaline Oestrone (or estrone) There is another factor which makes it difficult for adrenaline to cross the cell membrane. In aqueous solution, the four polar groups will be highly solvated with water molecules. In order to cross the cell membrane, these water molecules have to be 'stripped away' and this involves an energy penalty. The energy of desolvation for estrone would be less since it has only two polar functional groups solvated. 3) Valinomycin has a macrocylic structure where carbonyl oxygens are pointed towards the centre, making this are polar and capable of accommodating a polar ion. The outside of the ring is dominated by alkyl side chains which are hydrophobic in nature. As a result, the molecule can dissolve easily in fatty cell membranes and encapsulate polar ions allowing these ions to be transported across cell membranes. Further details are provided in section 16.6.1. L-Valine Me H NH O L-Lactate H Me O Me Me L-Valine H O Me O L-Valine O O O O NH NH H H Me H Me D-Hyi = D-Hydroxyisovaleric acid Me O O Me D-Hyi O HN H Hydrophobic side chains H Polar centre O O Me O H Me H O O HN D-Valine Me Me NH O O Me D-Valine Me H Me D-Hyi Me L-Lactate Me Me H L-Lactate Me Me D-Valine D-Hyi Valinomycin OXFORD © Oxford University Press, 2006. All rights reserved. Higher Education Patrick: An Introduction to Medicinal Chemistry 3/e Chapter 2: The why and the wherefore – drug targets 4) The alkyl chains are linked to the glycerol skeleton by ether linkages rather than by ester linkages. Ethers are chemically more stable than esters to extreme conditions. ether link Branching Branching O Branching Branching O O P OCH2CH2NH3 O H O glycerol skeleton ether link The long alkyl chains are also branched, unlike those in eukaryotic cell membranes. Branching makes the chains more resistant to oxidation. 5) The alkyl group is hydrophobic and is embedded into the cell membrane. As a result, the drug is anchored to the cell membrane and is located on its outer surface such that it is ideally located to interfere with cell wall synthesis. Further details can be found in section 16.5.5.2. HO Alkyl anchor CH2OH O HO N H OH HO HO O O O NHAc C D O O O Cl O E OH Cl O H N H N H H N O N H O CO2 H O H NH3 O H N OH HO A O HO H H H B HO N O OH O OH HO OH OXFORD © Oxford University Press, 2006. All rights reserved. Higher Education Patrick: An Introduction to Medicinal Chemistry 3/e Chapter 2: The why and the wherefore – drug targets Teicoplanin Alkyl chain anchor Cell membrane 6) A hydrophobic chain could be attached to the Ras protein which would serve to anchor it to the inner surface of the cell membrane, in the same way in which teicoplanin is anchored to the outer surface of cell membranes (compare answer 5 above). The actual process by which a hydrophobic chain is attached to the Ras protein is shown below where the chain is attached to a cysteine residue. More details can be found in section 18.6.1. Val Ras H N Cys HS Met O N H H N O O S N H OH Ras O H N O N H S H N O O S N H FTase PPO farnesyl diphosphate Ras H N Further processing O OMe Methyl ester S 7) Cholesterol has one polar group - the alcohol group. This can form a H-bond to the polar head group of phospholipids. The rest of the molecule is hydrophobic and will sink into the cell membrane to form hydrophobic interactions with the alkyl side chains of the phospholipids. OXFORD © Oxford University Press, 2006. All rights reserved. Higher Education OH O Patrick: An Introduction to Medicinal Chemistry 3/e Chapter 2: The why and the wherefore – drug targets Polar Head Group OH CH3 Hydrophobic Tails CH3 CH3 H H H3C CH3 8) cis-double bonds introduce a kink into the chain which will hinder the regular packing of the hydrophobic chains. This increases the fluidity of the cell membrane. NMe3 NMe3 (CH2)2 (CH2)2 O O O O P O P O O O CH2 O CH CH2 O O CH2 O O cis CH CH2 O O O trans 9) The relative order of H-bonding strength is shown below O O C O R RHN C O R R C O R RO C R Increasing strength of carbonyl oxygen as a hydrogen bond acceptor OXFORD © Oxford University Press, 2006. All rights reserved. Higher Education Patrick: An Introduction to Medicinal Chemistry 3/e Chapter 2: The why and the wherefore – drug targets This reflects the fact that the greater the electron density on the carbonyl oxygen, the stronger it will act as a hydrogen bond acceptor. The carboxylate group is the strongest hydrogen bond acceptor since a full negative charge is shared between both oxygens. The carbonyl oxygen of the amide will also act as a good hydrogen bond acceptor since the lone pair of electrons on nitrogen can interact with the carbonyl group to increase electron density on the carbonyl oxygen as shown below. O R N H C O R R N H C R Amide - N acts as poor HBA O acts as a good HBA No such interaction occurs for the ketone or ester carbonyl groups, but the carbonyl groups are still polarised resulting in the oxygen having a slightly negative charge. Consequently it can still act as a hydrogen bond acceptor, but less strongly. 10) The diagram below shows the possible intermolecular bonding interactions for the various functional groups present in each molecule (HBA = hydrogen bond acceptor; HBD = hydrogen bond donor; vdw = van der Waals interactions) HBA HBD O H HBD H HBA O vdw H HBD O HBA Adrenaline H3C H HBA CH3 O dipole-dipole HBD H N HBA Me CH3 CH3 H CH3 HBD H vdw O HBD H vdw O HBA Oestrone Cholesterol Notes * It cannot be assumed that all the interactions shown actually occur. * Adrenaline can also exist in the ionised form below, resulting in the potential interactions shown OXFORD © Oxford University Press, 2006. All rights reserved. Higher Education CH3 Patrick: An Introduction to Medicinal Chemistry 3/e Chapter 2: The why and the wherefore – drug targets HBA HBD O H HBD H HBA O vdw H HBD O HBA Adrenaline HBD H H HBD N Me ionic * The remainder of the carbon skeleton in each molecule has the potential to interact with other hydrophobic molecules through van der Waals interactions. OXFORD © Oxford University Press, 2006. All rights reserved. Higher Education