Brainscape's Knowledge GenomeTM

Browse over 1 million classes created by top students, professors, publishers, and experts.


See full index

Med Chem Midterm > Lecture 4 Part 2 > Flashcards

Lecture 4 Part 2 Flashcards

You may prefer our related Brainscape-certified flashcards:
Periodic Table flashcards Chemistry 101 flashcards AP® Chemistry flashcards Organic Chemistry 101 flashcards
1
Q

name 2 ways in which bioisosteric replacement can be applied to drug development

A
  1. to develop analogues with a similar biological effect
  2. to develop analogues that act as antagonists to normal metabolites (intermediate or end product of metabolism)
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
2
Q

as mentioned, bioisosteric can be applied to develop analogues with a similar biological effect.

give a specific example of this

A

antihistamines and cholinergic blocking agents and antihistamines are structurally similar, with only 1 functional group being changed to go from a antihistamine to a cholinergic blocking agent.

thus they have some common side effects like drowsiness.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
3
Q

name the nucleic acid purines/pyrimidines

A

purines = adenine and guanine
pyrimidines = thymine, cytosine, and uracil

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
4
Q

as mentioned, bioisosteric replacement can be applied to develop analogues that act as antagonists to normal metabolites.

give a specific example of this

A

when the NH2 group of adenine is replaced by SH (thiol), the molecule becomes 6-mercaptopurine and is an antimetabolite, anti cancer drug

when NH2 group of adenine is replaced with OH, it becomes hypoxanthine – a naturally occurring purine derivative

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
5
Q

what is an antimetabolite?

A

interferes with synthesis of DNA constituents (ex: 6-mercaptopurine inhibits the synthesis of purines (adenine?)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
6
Q

in making a bioisosteric replacement, what 8 factors of the group being replaced should be considered?

A

size
shape
electron distribution
lipid solubility
water solubility
pka
hydrogen bonding capacity
chemical reactivity towards cell components and metabolizing enzymes

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
7
Q

what do you mean that “shape” of the functional group should be considered when making a bioisosteric replacement?

A

the bond angle and hybridization should be considered

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
8
Q

what do you mean when you say that the “electron distribution” of the functional group should be considered when making a bioisosteric replacement?

A

the polarizibility, charge, and dipole should be considered

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
9
Q

what does pka mean?

A

the ability of a functional group to dissociate at physiological pH

lower pka = higher acidity (more likely to give up protons)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
10
Q

give a specific example of why chemical reactivity of a functional group towards cell components and metabolizing enzymes should be considered when making a bioisosteric replacement

A

in the case of toluene, the benzylic carbon is HIGHLY SUSCEPTIBLE TO BIOOXIDATED METABOLISM and is cleared from the system very rapidly – has a very short duration of action.

to enhance and prolong the duration of action, the methyl group on toluene can be replaced with something that is STABLE TO METABOLISM – for instance, Chlorine (if the methyl is just there for its small size)

ex of 1 1st generation hypoglycemic

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
11
Q

why do we not want to use a functional group that is too chemically reactive?

A

this may lead to a premature, irreversible reaction that can lead to cell death, carcinogenesis, or teratogenesis

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
12
Q

true or false

when performing isosteric replacement, there are definitive rules to follow

A

FALSE – there are rough rules, but everything really depends on the situation

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
13
Q

what are optical isomers?

A

stereoisomers (same chemical formula, same connectivity) that are NOT interconverted by rotation about single bonds and this is NOT due to restricted rotation, as in the case of geometric isomers

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
14
Q

differentiate and compare enantiomers and diastereomers

A

both are optical isomers

enantiomers are non-superimposable mirror images. they have the SAME PHYSICAL AND CHEMICAL PROPERTIES, aside from the fact that:

  • they rotate a plane of polarized light in an equal, but opposite direction (physical property)
  • they react with other chiral compounds at different rates

diastereomers are non-superimposable non mirror images. they have 2 or more asymmetric centers. THEY HAVE DIFFERENT PHYSICAL AND CHEMICAL PROPERTIES

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
15
Q

Explain why it is significant that enantiomers react with other chiral compounds at different rates

A

the rates can either be very close to each other (hard to distinguish them apart) OR they can be so different that 1 enantiomer undergoes the reaction while the other enantiomer DOESNT

THIS IS WHY MANY COMPOUNDS ARE BIOLOGICALLY ACTIVE AND THEIR ENANTIOMERS ARE NOT

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
16
Q

how can you separate 2 enantiomers?
explain

A

they CANNOT be separated via a TLC plate because they will both move to the same spot (same melting point)

they can only be separated using a stereochemical technique such as by using a chiral column

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
17
Q

what can you say about the pharmacokinetic properties of enantiomers

A

they have identical pharmacokinetic properties EXCEPT for when they arrive at the binding site. there, they can differentiate.

when introduced to a chiral environment, they will differentiate

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
18
Q

can enantiomers have different transportation/clearance?
where is this most critical?

A

yes – if they interact with a chiral compartment.
this is most critical at the drug-receptor binding site

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
19
Q

true or false

enantiomers react with chiral compounds at the same rate

A

FALSE

they interact with ACHIRAL compounds at the same rate

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
20
Q

give a specific example of how 1 enantiomer can be biologically active while the other is not/is very weak

A

(-) epinephrine is 12-15 times more active than (+) epinephrine as a vasoconstrictor

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
21
Q

L-amino acids are either ___ or ____ while D-amino acids are ____

A

L-amino acids are either TASTELESS OR BITTER while D-amino acids are SWEET

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
22
Q

true or false

the metabolism for diastereomers may be different

A

true – this is an important consideration

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
23
Q

the biological activity of optical isomers is dependent on what?

A

the asymmetry of the drug molecule relative to the asymmetry of the receptor site

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
24
Q

in order for optical isomers to be biologically active…..

A

the asymmetry of the drug must be complementary to the asymmetry of the receptor for the drug (ex: (-) epinephrine is more active because the 3 binding sites line up)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
25
Q

name the structural features necessary for maximum vasoconstriction activity of epinephrine

A
  • a (+) charged Nitrogen
    -an aromatic ring
    -a hydroxyl group
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
26
Q

what is the sole difference between the 2 enantiomers of epinephrine

A

in the (+) enantiomer, the OH needed for binding is pointing away from the receptor.

in the (-) enantiomer, the OH is positioned correctly, allowing for proper binding at the 3 necessary binding sites

27
Q

besides epinephrine, give another example of how optical isosterism is an important factor in drug-receptor interaction

A

ephedrine and pseudoephedrine are diastereomers.

ephedrine has 2 asymmetric (chiral) carbons. its diastereomer, pseudophedrine, is LESS ACTIVE than ephedrine

28
Q

ephedrine is a ___ agent that causes…..

A

adrenergic agent that causes an increase in blood pressure

29
Q

optical isomers show differences in activity MAINLY because…..

A

they interact with the receptors in a different manner

30
Q

as mentioned, the MAIN reason that optical isomers show differences in activity is because they interact with receptors in a different manner.

what are ADDITIONAL reasons that account for this difference in their biological activity

A

-optically active components of body fluids (like plasma proteins) can form a diastereometric complex with optical isomers, leading to differences in ADME

-there can be preferential metabolism of one isomer over the other by a enzyme that is STEREOSPECIFIC (ie: D-amino oxidase)

-there can be preferential adsorption at a stereospecific site of loss (ex: stereospecific protein binding)

31
Q

diastereomers can result from the presence of….

A

more than 1 chiral center in a molecule, double bonds, or ring systems

32
Q

in enantiomers there is an inversion of ___ chiral centers, while there is an inversion of ___ chiral centers for diastereomers

A

in a pair of enantiomers, both chiral centers are inverted, and for diastereomers only 1 chiral center is inverted

33
Q

can racemic mixtures be used as drugs?

A

the FDA (and other regulatory agencies) have been strict in approving racemic mixtures as drugs.

toxicity data needs to be verified, because sometimes only 1 isomer in the racemic mixture can be metabolized into a toxic substance while the other is totally normal.

sometimes, only 1 enantiomer is active and the other is inactive. this is “okay” as long as the activity of the active enantiomer isn’t affected

34
Q

what makes a molecule chiral?

A

a tetrahedral (sp3) carbon bonded to 4 different groups.

35
Q

what is a chiral center?

A

a carbon with 4 different groups

36
Q

are enantiomers stereoisomers?

A

yes

37
Q

what is geometric isomerism

A

aka cis-trans isomers

stereoisomers that CANNOT be interconverted through rotation about single bonds, due to restricted rotation (either olefins or cyclic compounds)

38
Q

what are olefins?

A

hydrocarbons with one or more double bonds between carbons

39
Q

true or false

cis-trans isomerism arises due to a restricted rotation about a bond

A

true

40
Q

do geometric isomers (cis-trans) show optical isomerism?

A

NO, not unless that happen to be chiral

41
Q

do geometric isomers have the same physical and chemical properties?

A

NO - they have differences in both physical and chemical properties

42
Q

true or false

between geometric isomers, pharmacokinetics and pharmacodynamics are likely to be the same

A

FALSE – likely to be different

like diastereomers, they have different physical and chemical properties

43
Q

in the case of geometric isomerism, ___ and ___ in the biological medium is different due to differences in physical and chemical properties

A

absorption and distribution

44
Q

why does trans diethylstilbesterol have higher estradiol activity than cis diethylstilbesterol?

A

the interatomic distances between the 2 hydroxyl groups is similar to estradiol in the trans version of the molecule

45
Q

define conformational isomers

A

they do NOT have identical spatial arrangement of atoms resulting from rotation about single bond(s)

46
Q

at physiological conditions, what do single bonds do?

A

they rotate

47
Q

as mentioned, conformational isomers can rotate their single bonds.
explain this further as it relates to conformational isomers that enter our body

A

there are various conformations of conformational isomers.

HOWEVER, sometimes the energy barrier to change to a certain isomer may not be possible.

therefore, the conformer with the GREATEST DISTANCE BETWEEN THE LARGEST GROUPS (staggered) usually predominates, because it is the least energy demanding

48
Q

name 4 different conformations of conformational isomers and state which is the most stable and least stable.

which is the most/least energy demandiing?

A

staggered
partially eclipsed
fully eclipsed
skew/gauce

requires the most energy to maintain – fully eclipsed. LEAST STABLE

requires the least energy to maintain = staggered. MOST STABLE

49
Q

as mentioned, the conformational isomer with the greatest distance between the largest groups (skewed) usually predominates.

what is the exception to this?
give a specific example

A

when there are stabilizing interactions present that may OVERCOME THE CONFORMATIONAL PREFERENCES

in 2,3-Butanebiol, the skew conformation is favored due to the intramolecular hydrogen bond that stabilizes the molecule

50
Q

which are more rigid — cyclic or noncyclic structures?
why?

A

cyclic structures are more rigid bc there are fewer conformations possible

51
Q

name cyclic compounds from 3 carbons to 6 carbons.
also, name their conformations

A

3 carbons = cyclopropane. PLANAR. can’t conform

4 carbons = cyclobutane. TWIST

5 carbons = cyclopentane ENVELOPE AND HALF CHAIR

6 carbons = cyclohexane CHAIR, HALF CHAIR, BOAT

52
Q

As mentioned, cyclohexane has 3 possible conformations — half chair, chair, and boat.

rank them according to their stability, and state why the most stable is the most stable

A

least stable = boat

middle = half chair

MOST STABLE = chair. this is because all the substituents are away from each other (staggered)

53
Q

true or false

cyclic structures are rarely found in drug molecules

A

FALSE – they are commonly found in drugs, especially 5 or 6 membered heterocyclic ring

54
Q

besides 5 and 6 membered rings, are there any other rings found in drug molecules?

A

3,4,7 membered rings are also found

55
Q

give an example of a 3 membered ring that is occasionally found in drug molecules.

why are 3 membered rings not used a lot in drugs?

A

EPOXIDE – 3 membered ring with oxygen in the middle.

it is highly chemically reactive which is why it’s not commonly used in drugs

56
Q

name some drugs that have 4 membered rings

A

the beta lactam antibiotics – penicillin and cephalosporins

57
Q

name a drug that has a 7 membered ring

A

diazepam (valium)

it is a benzodiazepine antidepressant/hypnotic

58
Q

recap: what drug represents the importance of considering optical isomerism

A

epinephrine and ephedrine

59
Q

recap: what drug represents the importance of considering geometric isomerism

A

estrasiol and diethylstilibesterol (des)

60
Q

is estradiol endogenous?

A

yes

61
Q

explain the difference between “cis” vs “cisoid”/ “trans” vs “transoid”

A

cis and trans are terms used for true geometric isomers

cisoid (skew) and transoid (staggered) are used to describe conformational isomers (NOT GEOMETRIC ISOMERS) that mimic cis and trans

62
Q

Acetylcholine freely rotates in the body around its single bond.
what is the concern with this?

A

acetylcholine has 2 important cholinergic receptors – nicotinic and muscarinic.
to prevent acetylcholine from binding to the wrong receptor, a rigid analogue is made by inserting a 3 membered ring into the structure of acetylcholine. this prevents the free rotation of the molecule so that its isomers are easier to test

63
Q

true or false

it is possible that isomers bind to different receptors in the body

A

true

64
Q
A

Med Chem Midterm (11 decks)

Brainscape helps you reach your goals faster, through stronger study habits.
© 2024 Bold Learning Solutions. Terms and Conditions