PHA114 Chirality 24-25 - Abridged Version PDF

WEEK 20 MPharm Programme Chirality (abridged version) Dr Matt Smith Slide 1 MPharm PHA114 Chirality (Abridged) WEEK 20 Constitutional isomerism Constitutional isomerism (also called...

WEEK 20 MPharm Programme Chirality (abridged version) Dr Matt Smith Slide 1 MPharm PHA114 Chirality (Abridged) WEEK 20 Constitutional isomerism Constitutional isomerism (also called structural isomerism) Molecules with same formulae but different connectivity of C skeleton are constitutional isomers Isomers have different physical properties (e.g. m.p., b.p., solubility, density) Isomers have different chemical and pharmaceutical properties The atoms and groups are often arranged differently Different connectivity of atoms can result in diverse functional groups in isomers, even although they have same formulae Constitutional isomers cannot interconvert Slide 2 MPharm PHA114 Chirality (Abridged)  Example: 3 constitutional isomers WEEK 20 of C9H8O4 Aspirin Caffeic acid 4-Hydroxyphenyl- Plant origin/synthetic Plant origin pyruvic acid Analgesic, Key intermediate in Animal origin antipyretic, biosynthesis of Intermediate in tyrosine antiplatelet, NSAID lignin metabolism; if not metabolised efficiently, (non-steroidal anti- Anti-cancer and excess is converted into inflammatory drug) antioxidant activity toxic metabolite CO2H O O O CH3 HO OH OH O O HO HO Slide 3 MPharm PHA114 Chirality (Abridged)  Geometric isomerism - cis and trans WEEK 20 Geometric isomerism – may have covered cis and trans alkenes previously Same formulae, but different spatial arrangement of substituents around alkene Two substituents on opposite ends of π-bond – On same face: cis – On opposite faces: trans No interconversion between cis and trans forms at ambient or body temperatures Slide 4 MPharm PHA114 Chirality (Abridged)  Examples of C4H4O4 WEEK 20 Maleic acid Fumaric acid Cis-form Trans-form Often used as salt for basic Often used as salt for basic medicines in pharmaceutical medicines in pharmaceutical manufacture manufacture Melting point: 139 – 140oC Melting point: 287oC H H H CO2H HO2C CO2H HO2C H Slide 5 MPharm PHA114 Chirality (Abridged) WEEK 20 IUPAC nomenclature for alkenes: Cahn-Ingold-Prelog (CIP) Rules If the priority 1 groups are on the same face of the alkene, use the prefix Z (from the German zusammen, meaning ‘together’) X X C C If the priority 1 groups are on opposite faces, use the prefix E (from the German entgegen, meaning ‘across’) X C C X Slide 6 MPharm PHA114 Chirality (Abridged) WEEK 20 Example H 1 CO2H HO2C H 1 We have already met maleic and fumaric acids Let’s look at fumaric acid: Consider the two ends of the alkene separately On the LHS, there is a C and an H atom attached to the alkene The C atom takes priority 1 as the atomic number is 6; H atomic number is 1 The same exercise with the RHS gives the C priority 1 Overall, the priority 1 groups are on opposite faces, so fumaric acid has E geometry Slide 7 MPharm PHA114 Chirality (Abridged) WEEK 19 Why is Geometry Important? The Z (trans) geometry of tamoxifen gives it the correct shape to bind tightly to the estrogen receptor causing inhibition of the signalling that would result in cell growth In this way, breast cancer cell growth can be inhibited Slide 8 MPharm PHA114 Chirality 1 WEEK 20 Key Messages: Alkene Geometry Z and E allow unambiguous naming of any alkene Consider ends of alkene separately and prioritise the 2 substituents – If priority 1 groups on same face: Z – If priority 1 groups on opposite faces: E Use Z and E for pharmaceuticals (not cis and trans) Alkene geometry essential for binding to targets Correct geometry for binding correlates to greater potency of drugs Slide 9 MPharm PHA114 Chirality (Abridged) WEEK 20 Stereoisomerism Stereoisomerism (also called optical or configurational isomerism, or chirality) Stereoisomers are not interconvertible Stereoisomerism usually arises due to asymmetry around a saturated carbon atom Stereoisomerism is a very important aspect of the pharmaceutical industry and of medicinal use Adverse effects have been seen in patients due to stereoisomerism and caused major changes to registration and licensing of new medicines Slide 10 MPharm PHA114 Chirality (Abridged) WEEK 20 Terminology Many terms are used interchangeably and are considered analogous – Stereoisomerism = chirality – Chiral carbon (atom) = stereocentre = stereogenic carbon (atom) – Chirality = stereochemistry = configuration – Racemic mixture = racemate = 1 : 1 mixture of enantiomers – Optically inactive suggests something is achiral = not chiral (or a racemic mixture) – Enantiomers = non-superimposable mirror images – Diastereoisomers = non-superimposable non-mirror images (Chirality 3, slide 3) Slide 11 MPharm PHA114 Chirality (Abridged) WEEK 20 What is a Chiral Carbon? Usually, a chiral carbon atom is sp3 hybridised and has four different atoms or groups attached to it One test for a chiral carbon in a compound is whether or not its mirror image is superimposable – If superimposable, it is achiral (not chiral) – If non-superimposable, it is chiral The non-superimposable mirror image forms are called enantiomers Slide 12 MPharm PHA114 Chirality (Abridged) WEEK 20 Practice: Identify the Chiral Carbons HO OH COOH NH2 HO O H2N O O NH2 HO OH HO HO O OH OH HO N Latanoprost O H NH2 treat glaucoma H Amikacin H2N antibiotic (streptomycin class) CO2H N H CH2CH2CH3 H N Perindopril O CO2CH2CH3 ACE inhibitor (anti- H CH3 hypertensive) S CH3 O H HO Me NMe 2 HO H H N N H OH HO H H NH2 O NH Nelfinavir OH HIV protease OH O OH O O inhibitor Tetracycline antibiotic Slide 13 MPharm PHA114 Chirality (Abridged) WEEK 20 Practice: Identify the Chiral Carbons HO OH * * COOH O * NH2 HO * H2N * * * * * O NH2 * * O * OH HO HO HO * O * * * * * OH OH HO * N Latanoprost O * * H NH2 treat glaucoma H Amikacin H2N antibiotic (streptomycin class) * CO2H * * N CH2CH2CH3 H H N * Perindopril * O CO2CH2CH3 ACE inhibitor (anti- H CH3 hypertensive) S CH3 O * * * H HO Me NMe 2 HO N * H H N H * OH HO H H * * * * * NH2 O NH Nelfinavir OH HIV protease OH O OH O O inhibitor Tetracycline antibiotic Slide 14 MPharm PHA114 Chirality (Abridged) WEEK 20 Nomenclature IUPAC adopted the Cahn-Ingold-Prelog (CIP) rules to provide unambiguous naming system Prioritise atoms / groups around chiral carbon – If clockwise order: R (from Latin Rectus) – If anticlockwise order: S (from Latin Sinister) Slide 15 MPharm PHA114 Chirality (Abridged) WEEK 20 Steps to Classify Chirality 1. Ensure chiral C drawn in 3D with wedge bonds 2. Prioritise atoms directly attached to chiral C using atomic number (not atomic mass) – If atoms attached to chiral C are same, look at next atoms attached until find difference 3. Make sure priority 4 atom at back on dashed wedge bond. C 4. Add priority numbers to remaining atoms – If order 1→ 2→ 3 (not 4) clockwise, classify as R – If order 1→ 2→ 3 anticlockwise, classify as S Slide 16 MPharm PHA114 Chirality (Abridged) WEEK 20 Worked Example: Acebutolol The active enantiomer of acebutolol is shown below Identify the chiral carbon and ensure it is drawn in 3D Prioritise the atoms attached directly to it by atomic number O has highest priority (Z = 8), then C (Z = 6), then H O has priority 1 and H priority 4; to differentiate the two C atoms, we need to look at the atoms attached directly to them The CH2 on the LHS is attached to O, while the CH2 on the RHS is attached to N – O has a higher atomic number than N (Z = 7), so CH2O takes priority 2 and CH2N priority 3 Make sure the priority 4 atom 4 1 is at the back, then look at the H OH H direction of 1→ 2→ 3 O O N Me It is anticlockwise, so the active 2 3 Me Me enantiomer of acebutolol Me N S has S stereochemistry H O Acebutolol Slide 17 MPharm PHA114 Chirality (Abridged) WEEK 20 What do we do if Priority 4 Atom not at back? If priority 4 atom is at front instead….. We are viewing the molecule from the opposite side Anything that looks clockwise is really anticlockwise, and vice versa Assign chirality as usual, then reverse answer Consider cetirizine’s active enantiomer – Assign as usual – Anticlockwise direction of 1→ 2→ 3 – Looks like S chirality, but H at front, so reverse….. It has R chirality O CO2H HO 2C O 4 N N Cl H 1 4 N H Cl N 2 1 2 3 Cetirizine 3 Cetirizine R Check by rotating in space Slide 18 MPharm PHA114 Chirality (Abridged) WEEK 20 What do we do if Priority 4 Atom not at back? If priority 4 atom in plane, cannot assign chirality confidently (usually wrong!) Must rotate molecule to get priority 4 atom either at back (preferable) or at front To rotate: – Keep one bond to chiral C (Ar-C in this example) stationary in the plane – Rotate rest of molecule around that one bond, like turning steering wheel CF3 H3C NH O Rotation H CF3 around 1 O H4 2 CH3 Ar-C bond N 2 3 H Fluoxetine (S)-Fluoexetine Slide 19 MPharm PHA114 Chirality (Abridged) WEEK 20 Rotation of PPL by Enantiomers Enantiomers rotate PPL in opposite directions by equal amounts Use + for clockwise (dextrorotatory) and – for anticlockwise (levorotatory) O O antibacterial F COOH F COOH N N N N CH3 N O H N O H3C H3C CH3 (S)-Ofloxacin α[D] -96o (R)-Ofloxacin α[D] +96o The specific rotation (+) or (-) does not tell you if the compound has R or S configuration Slide 20 MPharm PHA114 Chirality (Abridged) WEEK 20 Interactions with other Enantiomers The 3 point model of binding is often used to explain differences in enantiomer interactions with another chiral species, as receptors and enzymes are also chiral because formed from amino acids (chiral). Numerous examples of enantiomers having different activities: – Note that not all pairs of enantiomers have different activities – Important to distinguish undesirable activity in enantiomer from no adverse activity In this example shown….. – Active (R)-enantiomer binds correctly to receptor to trigger response – (S)-enantiomer cannot bind correctly, does not trigger response Slide 21 MPharm PHA114 Chirality (Abridged) WEEK 20 Vigabatrin (Sabril®) Used in treatment of epilepsy and other seizures Seizures thought to be caused by low -aminobtyric acid (GABA) levels in brain (S)-enantiomer active as anti-convulsant Inhibits inactivation of GABA by GABA transaminase Increases levels of GABA and reduces incidence of seizures Marketed as the racemate: (R)-enantiomer has no adverse effects + + NH3 NH3 1 2 - 3 - O2C CO2 GABA transaminase inhibitor anti-convulsant Slide 22 MPharm PHA114 Chirality (Abridged) WEEK 20 Fluoxetine (Prozac®) Marketed as the racemate for treatment of depression Activity as serotonin selective reuptake inhibitor in both enantiomers (R)-enantiomer most rapidly eliminated (S)-fluoxetine considered pharmacological form, as present at highest concentration F F O O 1 2 3 NHCH3 H3CHN Slide 23 MPharm PHA114 Chirality (Abridged) WEEK 20 Warfarin O O 1 3 CH3 2 OH O Administered as the racemate Commonly used to reduce risk of unwanted blood clots Both forms active in inhibiting vitamin K epoxide reductase (VKORC1) (S)-form about 4x more active than (R) in practice (R)-form rapidly metabolised and excreted Overall, (S)-form responsible for anti-coagulant activity Slide 24 MPharm PHA114 Chirality (Abridged) WEEK 20 Why are Amines Rarely Chiral? 2 reasons: 1. If the amine can protonate / deprotonate, then it can invert to opposite stereochemistry H R2 Inversion R2 +H + R1 - H+ N R1 R3 R3 R3 N N R1 N R3 R2 R1 R2 H 2. If amine can resonate lone pair with adjacent group, adopts partial double bond – No chirality with sp2 centre: if N is not tetrahedral, it can not be chiral Br O H H O N Me N S Br H OH O OH H OH Acamprosate Dembrexine Used in the treatment of alcohol dependence Veterinary mucolytic agent Slide 25 MPharm PHA114 Chirality (Abridged) WEEK 20 Key Messages: Many pharmaceuticals have one or more chiral carbon The mirror image forms are non-superimposable The non-superimposable mirror image forms are called enantiomers Chiral centres are assigned using Cahn-Ingold-Prelog rules with R or S stereochemistry Enantiomers have identical chemical and physical properties, except for the interaction with PPL and other chiral species Enantiomers rotate PPL by equal amounts in opposite directions The effect of an inactive enantiomer can be undesirable Rotation of PPL (+) or (-) has no link with if a compound is R or S configuration Slide 26 MPharm PHA114 Chirality (Abridged)