med chem

Question 1

nucleophiles

Answer 1

. electron rich, -ve charge/long pair
. hard nucleophile: small, electronegative, basic, low HOMO
. soft nucleophile: large, polarisable outer shell, not basic, high HOMO

Question 2

electrophile

Answer 2

. electron deficient
. hard: +ve charge localised, not spread out over large area
. soft: +ve charge delocalised, spread over large area

Question 3

requirements for delocalisation

Answer 3

1) planar
2) sp2
3) conjugated
4) Huckel’s rule: 4n+2 e-

Question 4

why are reactive metabolites not good

Answer 4

1) inhibit metabolising enzymes
2) induce ADR
3) damage DNA

Question 5

components of P450

Answer 5

1) heme
- large, accommodate to lipophilic molecules
2) flavoprotein
- accept e- from NADPH and transfer e- to p450
3) phosphilipid matrix
- facilitate electron transfer

Question 6

electron cycle for transferring from NADPH to p450

Answer 6

• draw out

Question 7

P450 catalytic cycle

Answer 7

1) R-H bind, displace H2O
2) change in conformation, Fe III unstable
3) accept 1st e- from Fe III, change to Fe II
4) Fe II bind to O2 -> peroxide radical (-O-O.)
5) accept second e- to form peroxide anion (-O-O-), have to happen fast if not can leave as superoxide
6) H+ bind, form Fe-O-OH
7) displacement of water, activate water (O+), resonance structure of O. and Fe IV forms
8) oxygen rebound, back to normal

Question 8

when does reactive metabolite formp450 catalytic cycle?

Answer 8

1) reduction
- more reducible substrate can be reduced instead
- stepwise transfer of e- forms radical

2) oxidation
- stepwise transfer of e- form radicle
- superoxide released instead

3) O2 rebound

Question 9

names of position on the ring

Answer 9

ortho, meta, para !!!

Question 10

ways o-acyl-glucuronides can change

Answer 10

1) hydrolysis
- basically hydrolyse and release glucuronic acid
- CES 1/2
- beta-glucuronidases
- serum albumin, alkaline pH
- acyl-glucuronide > 500 MW: enterohepatic cycling, excreted in bile & hydrolysed by beta-glucuronide, reabsorbed, increase drug exposure

2) intramolecular arrangement
- move to C1, C2, C3 ,C4
- C3, C4: RM cuz hemiacetal structure, can open up ring to expose reactive acetaldehyde

3) transacylation
- transfer acyl group to protein, protein adduct not very immunogenic
- BUT transfer releases glucuronic acid which is the same as ^

Question 11

formation of RM from amine glucuronide

Answer 11

. acidic conditions (urine)
- hydrolysis to produce nitreunium ion (N-)
- electrophilic, can react with macromolecules

Question 12

methods to evaluate bioactivation potential (X3)

Answer 12

1) experimental design
2) daily dosage
3) Structural alerts

Question 13

methods to evaluate bioactivation potential - experimental design

Answer 13

1) covalent binding with radioactive drug
- provide quantitative results, not structural
- in vitro/vivo

2) metabolite identification
- detect stable conjugates of electrophilic metabolite & GSH

Question 14

methods to evaluate bioactivation potential - daily dosage

Answer 14

• lower chance of AE if daily dose < 20 mg

Question 15

methods to evaluate bioactivation potential - structural alerts

Answer 15

• toxicophores
• structural alert -> RM -> structural alert
• done by visual inspection/software

. SA available
- AE: expected
- no AE: low dose drug, other site metabolised instead of AE, not metabolised to great extent

. no SA
- AE: SA not discovered yet, other mechanisms involved (mitochondrial toxicity, inhibit bile salt export pump (BSEP))

Question 16

phase 2 conjugation reactions

Answer 16

1) glucuronidation
- COOH, OH, NH2, SH
- glucuronic acid
- smooth ER

2) sulfation
- OH, NH2
- sulfate group (SO42-)
- cytosol

3) acetylation
- NH2
- attach acetyl group (Draw)
- cytosol

4) glutathione conjugation
- electrophilic centres
- glutathione acid
- cytosol, smooth ER

5) methylation
- SH, NH, OH
- methyl group
- cytosol

6) amino acid conjugation
- COOH
- glycine, glutamic acid
- mitochondria

Question 17

types of prodrugs

Answer 17

1) carrier-linked prodrugs
- basically attach promoiety through covalent bonds (amide, ester, carboesterase)

2) bioprecurosr
- no promoiety
- oxidation, reduction, rearrangement
- site specific

Question 18

ideal characteristics for prodrugs

Answer 18

1) stability, won’t be prematurely released
2) balance of lipophilicity & solubility
3) conversion & absorption at site of action
4) innocuous product that doesn’t cause AE

Question 19

prodrugs that increase water solubility for parenteral drugs

Answer 19

1) add succinate acid
- to -OH
- provide terminal OH that increases water solubility

2) add phosphate
- to -OH
- if not -OH can make one there
- extra linkage lost as acetaldehyde

Question 20

prodrugs that increase water solubility for oral drugs

Answer 20

requirements for these prodrugs
1) soluble in intestinal fluid
2) enzymes required available at intestinal region
3) conversion & absorption at same site

. must have -OH for phosphate group

Question 21

prodrug to improve passible permeability

Answer 21

• ensure balance between lipophilicity & solubility there
• requirements
  1) log p < 5
  2) MW < 500
  3) solubility > 400

Question 22

prodrugs for carrier mediated active transport

Answer 22

. basically make full use of promoieties that can bind to receptor to be passed through
. for drugs that cannot use passive permeability cuz toxic for concentration required for concentration gradient

Question 23

prodrugs to improve metabolic stability

Answer 23

. skip first pass vibes